Topic: Heart Failure

Abstract

Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction.

Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
Background
The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity.
Objectives
The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies.
Methods
Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors.
Results
Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e\' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e\' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e\' ratio, pulmonary artery systolic pressure, and event rates.
Conclusions
Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873
Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873 | PMID: 31806129
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Abstract

Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders.

Diederichsen SZ, Haugan KJ, Brandes A, Lanng MB, ... Højberg S, Svendsen JH
Background
As new heart rhythm monitoring technologies emerge, subclinical atrial fibrillation (AF) signifies a future challenge to health care systems. The pathological characteristics of this condition are largely unknown.
Objectives
This study sought to characterize the natural history of subclinical AF in at-risk patients from the general population.
Methods
The authors studied 590 individuals ≥70 years of age with ≥1 of hypertension, diabetes, previous stroke, or heart failure, without history of AF, undergoing long-term implantable loop recorder monitoring as part of the LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals) study. Baseline assessments included N-terminal pro-B-type natriuretic peptide (NT-proBNP). All day-to-day heart rhythm and symptom data were extracted from the device. Endpoints included AF burden, AF progression, symptom reports, and heart rate during AF.
Results
A total of 685,445 monitoring days were available for analysis. Adjudicated AF episodes lasting ≥6 min were detected in 205 participants (35%). The AF burden was median 0.13% (interquartile range: 0.03% to 1.05%) of the monitoring time and changed by a factor of 1.31 (95% CI: 1.02 to 1.68) per doubling of NT-proBNP. AF episodes were present 2.7% (interquartile range: 1.0% to 15.7%) of monitoring days after debut. Progression to 24-h episodes was seen in 33 of the AF patients (16%), whereas 46 (22%) had no AF episodes in the last 6 months of monitoring or longer. Symptoms were absent in 185 (90%) at debut, and 178 (87%) never reported AF-related symptoms during follow-up. The averaged heart rate during AF was 96 (interquartile range: 83 to 114) beats/min, 24 (interquartile range: 9 to 41) beats/min faster than daytime sinus rates.
Conclusions
Although previously unknown AF was highly prevalent, the burden was low, and progression was limited. In addition, symptoms were scarce, and the heart rate was only modestly elevated. (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals [LOOP]; NCT02036450).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 02 Dec 2019; 74:2771-2781
Diederichsen SZ, Haugan KJ, Brandes A, Lanng MB, ... Højberg S, Svendsen JH
J Am Coll Cardiol: 02 Dec 2019; 74:2771-2781 | PMID: 31779791
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Abstract

Long-Term Safety and Efficacy in Continued Access Left Atrial Appendage Closure Registries.

Holmes DR, Reddy VY, Gordon NT, Delurgio D, ... Stone JE, Kar S
Background
Long-term data on the safety and efficacy of left atrial appendage closure (LAAC) for stroke prevention in patients with nonvalvular atrial fibrillation remain limited.
Objectives
The purpose of this study was to evaluate 4.5- to 5-year data in 2 U.S. Food and Drug Association LAAC mandated registries (CAP [Continued Access to PROTECT-AF] and CAP2 [Continued Access to PREVAIL]) for safety and efficacy.
Methods
Two registries of patients implanted with LAAC devices provide the largest source of follow-up data. Both accompanied their respective randomized clinical trials, PROTECT-AF (Watchman Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device In Patients with Atrial Fibrillation versus Long Term Warfarin Therapy), which used the same endpoints (primary efficacy of composite of stroke, systemic embolism, cardiovascular/unexplained death, and safety).
Results
CAP included 566 patients with an average follow-up of 50.1 months (2,293 patient-years), and CAP2 included 578 patients with an average follow-up of 50.3 months (2,227 patient-years). CAP2 patients were significantly older and had higher CHADS-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) scores (4.51 vs. 3.88; p < 0.001). Procedural success was similar in both (94%). The primary composite endpoint occurred at a rate of 3.05 per 100 patient-years in CAP and 4.80 per 100 patient-years in CAP2; events contributing to this endpoint were most commonly cardiovascular/unexplained death (1.69 per 100 patient-years for CAP and 2.92 per 100 patient-years for CAP2). Hemorrhagic stroke was significantly less than ischemic stroke (0.17 per 100 patient-years in CAP and 0.09 per 100 patient-years in CAP2), and total stroke rates were significantly less than predicted by CHADS-VASc score (78% reduction with CAP, 69% reduction with CAP2).
Conclusions
These registries, which contain the longest and largest follow-up data of patients with the Watchman device, support LAAC as a safe and effective therapy for long-term anticoagulation in patients with nonvalvular atrial fibrillation, and document the lowest rate of hemorrhagic stroke identified in this population.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Dec 2019; 74:2878-2889
Holmes DR, Reddy VY, Gordon NT, Delurgio D, ... Stone JE, Kar S
J Am Coll Cardiol: 09 Dec 2019; 74:2878-2889 | PMID: 31806131
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Abstract

Sex differences in heart failure.

Lam CSP, Arnott C, Beale AL, Chandramouli C, ... Sliwa K, Voors AA

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 03 Dec 2019; epub ahead of print
Lam CSP, Arnott C, Beale AL, Chandramouli C, ... Sliwa K, Voors AA
Eur Heart J: 03 Dec 2019; epub ahead of print | PMID: 31800034
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Abstract

Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

Kotecha D, Gill SK, Flather MD, Holmes J, ... Coats AJS,
Background
Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy.
Objectives
This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR).
Methods
Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm.
Results
Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR.
Conclusions
Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Dec 2019; 74:2893-2904
Kotecha D, Gill SK, Flather MD, Holmes J, ... Coats AJS,
J Am Coll Cardiol: 09 Dec 2019; 74:2893-2904 | PMID: 31806133
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Abstract

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism.

Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
Background
Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.
Objectives
In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.
Methods
During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.
Results
Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.
Conclusions
In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Jan 2020; 75:148-158
Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
J Am Coll Cardiol: 20 Jan 2020; 75:148-158 | PMID: 31948643
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Abstract

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
Background
It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.
Objectives
The purpose of this study was to demonstrate that C-Pittsburgh B compound positron emission tomography (C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.
Methods
This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.
Results
The degree of myocardial C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).
Conclusions
These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:380-390
Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
J Am Coll Cardiol: 03 Feb 2020; 75:380-390 | PMID: 32000949
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Abstract

Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:422-434
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:422-434 | PMID: 32000955
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Abstract

Peripartum Cardiomyopathy: JACC State-of-the-Art Review.

Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U

Peripartum cardiomyopathy is a form of systolic heart failure affecting young women toward the end of pregnancy or in the months following delivery. Incidence is higher in African-American women and in women with older maternal age, hypertensive disorders of pregnancy, and multiple gestation pregnancies. Symptoms of heart failure mimic those of normal pregnancy, often resulting in a delay in diagnosis and preventable complications. Echocardiography showing decreased myocardial function is essential for the diagnosis. Medical management is similar to heart failure with reduced ejection fraction of other etiologies, but adjustments during pregnancy are necessary to ensure fetal safety. Variable outcomes include complete recovery, persistent heart failure, arrhythmias, thromboembolic events, and death. Subsequent pregnancy confers substantial risk of relapse and even death if there is incomplete myocardial recovery. Additional research about the etiology, optimal therapy including the use of bromocriptine, long-term outcomes, and duration of treatment after recovery are needed.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 Jan 2020; 75:207-221
Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U
J Am Coll Cardiol: 20 Jan 2020; 75:207-221 | PMID: 31948651
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Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
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Abstract

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Aims
Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis.
Methods and results
We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing.
Conclusion
We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 21 Dec 2019; epub ahead of print
George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Eur Heart J: 21 Dec 2019; epub ahead of print | PMID: 31865366
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Abstract

Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T).

Alvi RM, Frigault MJ, Fradley MG, Jain MD, ... Locke FL, Neilan TG
Background
Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T.
Objectives
The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T.
Methods
The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death.
Results
The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab.
Conclusions
Among adults, cardiac injury and CV events are common post-CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Dec 2019; 74:3099-3108
Alvi RM, Frigault MJ, Fradley MG, Jain MD, ... Locke FL, Neilan TG
J Am Coll Cardiol: 23 Dec 2019; 74:3099-3108 | PMID: 31856966
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Abstract

Cardiometabolic-Based Chronic Disease, Addressing Knowledge and Clinical Practice Gaps: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:539-555
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:539-555 | PMID: 32029137
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Abstract

A Contemporary Picture of Enterococcal Endocarditis.

Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
Background
Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking.
Objectives
The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort.
Methods
This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses.
Results
Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse.
Conclusions
Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:482-494
Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
J Am Coll Cardiol: 10 Feb 2020; 75:482-494 | PMID: 32029130
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Abstract

Long-Term Follow-Up of Complete Versus Lesion-Only Revascularization in STEMI and Multivessel Disease: The CvLPRIT Trial.

Gershlick AH, Banning AS, Parker E, Wang D, ... Greenwood JP, Curzen N
Background
Randomized trials have shown that complete revascularization in patients with ST-segment elevation myocardial infarction (MI) with multivessel disease results in lower major adverse cardiovascular events (MACE) (all-cause death, MI, ischemia-driven revascularization, heart failure).
Objectives
The goal of this study was to determine whether the benefits of complete revascularization are sustained long-term and their impact on hard endpoints.
Methods
CvLPRIT (Complete versus Lesion-only Primary PCI Trial) was a randomized trial of complete inpatient revascularization versus infarct-related artery revascularization only at the index admission. Randomized patients have been followed longer-term. The components of the original primary endpoint were collected from physical and electronic patient records, and from local databases for all readmissions.
Results
The median follow-up (achieved in >90% patients) from randomization to first event or last follow-up was 5.6 years (0.0 to 7.3 years). The primary MACE endpoint rate at this time point was 24.0% in the complete revascularization group but 37.7% of the infarct-related artery-only group (hazard ratio: 0.57; 95% confidence interval: 0.37 to 0.87; p = 0.0079). The composite endpoint of all-cause death/MI was 10.0% in the complete revascularization group versus 18.5% in the infarct-related artery-only group (hazard ratio: 0.47; 95% confidence interval: 0.25 to 0.89; p = 0.0175). In a landmark analysis (from 12 months to final follow-up), there was no significant difference between MACE, death/MI, and individual components of the primary endpoint.
Conclusions
Long-term follow-up of the CvLPRIT trial shows that the significantly lower rate of MACE in the complete revascularization group, previously seen at 12 months, is sustained to a median of 5.6 years. A significant difference in composite all-cause death/MI favoring the complete revascularization was also observed. (Complete versus Lesion-only Primary PCI Trial; ISRCTN70913605).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 23 Dec 2019; 74:3083-3094
Gershlick AH, Banning AS, Parker E, Wang D, ... Greenwood JP, Curzen N
J Am Coll Cardiol: 23 Dec 2019; 74:3083-3094 | PMID: 31856964
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Impact:
Abstract

Left Bundle Branch Pacing: JACC Review Topic of the Week.

Zhang S, Zhou X, Gold MR

Right ventricular pacing causes electric and mechanical dyssynchrony, which is associated with an increased risk for heart failure and atrial fibrillation. Cardiac resynchronization therapy with biventricular pacing reduces ventricular dyssynchrony and results in clinical benefits in subsets of patients with heart failure with QRS prolongation. Recently, His bundle pacing has increased in use as a physiological pacing modality but is limited by difficult implantation, lower success rates in patients with QRS prolongation, and high, often unstable, pacing capture threshold. Thus, the concept of pacing the conduction system distal to the His bundle to bypass the region of conduction block was proposed. Early clinical studies demonstrated the procedural feasibility of left bundle branch pacing using a transventricular septal approach that generates narrow paced QRS duration, fast synchronized left ventricular activation, and correction of left bundle branch block. The current status and future direction of left bundle branch pacing are summarized in this paper.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Dec 2019; 74:3039-3049
Zhang S, Zhou X, Gold MR
J Am Coll Cardiol: 16 Dec 2019; 74:3039-3049 | PMID: 31865972
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Impact:
Abstract

Does type 2 diabetes confer higher relative rates of cardiovascular events in women compared with men?

Malmborg M, Schmiegelow MDS, Nørgaard CH, Munch A, ... Hlatky MA, Gislason G
Aims
To investigate whether diabetes confers higher relative rates of cardiovascular events in women compared with men using contemporary data, and whether these sex-differences depend on age.
Methods and results
All Danish residents aged 40-89 years without a history major adverse cardiovascular events, including heart failure, as of 1 January 2012 until 31 December 2016 were categorized by diabetes-status and characterized by individual-level linkage of Danish nationwide administrative registers. We used Poisson regression to calculate overall and age-dependent incidence rates, incidence rate ratios, and women-to-men ratios for myocardial infarction, heart failure, ischaemic stroke, or cardiovascular death (MACE-HF). Among 218 549 (46% women) individuals with diabetes, the absolute rate of MACE-HF was higher in men than in women (24.9 vs. 19.9 per 1000 person-years). Corresponding absolute rates in men and women without diabetes were 10.1 vs. 7.0 per 1000 person-years. Comparing individuals with and without diabetes, women had higher relative rates of MACE-HF than men [2.8 (confidence interval, CI 2.9-2.9) in women vs. 2.5 (CI 2.4-2.5) in men] with a women-to-men ratio of 1.15 (CI 1.11-1.19, P < 0.001). The relative rates of MACE-HF were highest in the youngest and decreased with advancing age for both men and women, but the relative rates were higher in women across all ages, with the highest women-to-men ratio between age 50 and 60 years.
Conclusion
Although men have higher absolute rates of cardiovascular complications, the relative rates of cardiovascular complications associated with diabetes are higher in women than in men across all ages in the modern era.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 19 Dec 2019; epub ahead of print
Malmborg M, Schmiegelow MDS, Nørgaard CH, Munch A, ... Hlatky MA, Gislason G
Eur Heart J: 19 Dec 2019; epub ahead of print | PMID: 31860067
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Impact:
Abstract

A Novel Role of Cyclic Nucleotide Phosphodiesterase 10A in Pathological Cardiac Remodeling and Dysfunction.

Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, ... Small EM, Yan C

Heart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the role of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction.We used isolated adult mouse cardiac myocytes (CMs) and fibroblasts (CFs), as well as preclinical mouse models of hypertrophy and/or heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice (PDE10A-KO) were used.We found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. , PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated CM pathological hypertrophy induced by Angiotensin II (Ang II), phenylephrine (PE), and isoproterenol (ISO), but did not affect CM physiological hypertrophy induced by insulin-like growth factor 1 (IGF-1). TP-10 also reduced transforming growth factor-β (TGF-β)-stimulated CF activation, proliferation, migration and ECM synthesis. TP-10 treatment elevated both cAMP and cGMP levels in CM and CF, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. , global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and/or dysfunction induced by chronic pressure overload via thoracic aorta constriction (TAC) or chronic neurohormonal stimulation via Ang II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy.Taken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.



Circulation: 04 Dec 2019; epub ahead of print
Chen S, Zhang Y, Lighthouse JK, Mickelsen DM, ... Small EM, Yan C
Circulation: 04 Dec 2019; epub ahead of print | PMID: 31801360
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Impact:
Abstract

Outcomes of Women Compared With Men After Non-ST-Segment Elevation Acute Coronary Syndromes.

Sarma AA, Braunwald E, Cannon CP, Guo J, ... Sabatine MS, O\'Donoghue ML
Background
It remains disputed whether women are at excess risk of adverse outcomes versus men after non-ST-segment elevation acute coronary syndromes (NSTEACS) or whether differences are explained by discordant risk factors.
Objectives
A sex-specific analysis of cardiovascular outcomes after NSTEACS across trials conducted by the Thrombolysis In Myocardial Infarction (TIMI) Study Group was performed to determine the impact of sex on cardiovascular outcomes in this dataset.
Methods
Ten TIMI trials were identified that enrolled >2,500 patients with NSTEACS within 30 days of hospitalization. Cox proportional hazards models were used to examine the association of sex with major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, or stroke) after adjusting for relevant risk factors in individual trials; point estimates were then combined by using random effects models. Individual components of the composite outcome and all-cause mortality were also analyzed.
Results
Among 68,730 patients with NSTEACS, 19,827 (29%) were women. Women were older and more frequently had hypertension, diabetes, prior heart failure, and renal impairment than men. Before considering relevant confounders, women were at similar risk of MACE compared with men (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.99 to 1.09; p = 0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.03). After adjustment for baseline differences, risks of MACE (HR: 0.93; 95% CI: 0.88 to 0.98; p < 0.01) and all-cause death (HR: 0.84; 95% CI: 0.78 to 0.90; p < 0.0001) were lower among women compared with men.
Conclusions
After accounting for cardiovascular risk factors, women enrolled in clinical trials were at lower risk of MACE than men after NSTEACS. Women, however, remain undertreated with many evidence-based therapies.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Dec 2019; 74:3013-3022
Sarma AA, Braunwald E, Cannon CP, Guo J, ... Sabatine MS, O'Donoghue ML
J Am Coll Cardiol: 16 Dec 2019; 74:3013-3022 | PMID: 31865968
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Impact:
Abstract

Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes.

Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, ... Holm H, Stefansson K
Background
Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D).
Objectives
This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal.
Methods
This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D.
Results
Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D.
Conclusions
Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 16 Dec 2019; 74:2982-2994
Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, ... Holm H, Stefansson K
J Am Coll Cardiol: 16 Dec 2019; 74:2982-2994 | PMID: 31865966
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Impact:
Abstract

Temporal trends in the incidence, treatment patterns, and outcomes of coronary artery disease and peripheral artery disease in the UK, 2006-2015.

Sundaram V, Bloom C, Zakeri R, Halcox J, ... Rajagopalan S, Quint JK
Aims
Most reports estimating national incidence rates of coronary (CAD) and peripheral arterial disease (PAD) have focused on stable outpatients or acute or elective hospital admissions, but not on the overall burden of disease. In this study, we report the changing trends in the population-level incidence of CAD and PAD, respectively from 2006 to 2015, statin utilization for secondary prevention and survival outcomes using multiple nationally representative data sources from the UK (primary care encounters, hospital admissions, and procedure-level data).
Methods and results
A nationally representative study of linked primary and secondary care electronic health records of 4.6 million individuals from the UK. We calculated crude and standardized annual incidence rates separately for CAD and PAD. Statin use for secondary prevention, trends in annual major vascular event rates, and mortality between 2006 and 2015, were estimated for CAD and PAD, respectively. We identified 160 376 and 70 753 patients with incident CAD and PAD, respectively. The age- and sex-standardized incidence of CAD was similar in 2006 (443 per 100 000 person-years) and 2015 [436 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.98, 95% confidence interval (CI) 0.96-1.00]. In contrast, there was a 15% decline in the standardized incidence of PAD (236 per 100 000 person-years in 2006 to 202 per 100 000 person-years in 2015; adjusted IRR 0.85, 95% CI 0.82-0.88). The proportion of incident CAD and PAD patients prescribed long-term statins, was only 66% and 55%, respectively and was less common amongst women, patients aged >70 years, with heart failure, chronic lung disease, or depression. Cardiovascular mortality declined by 43% for incident CAD (adjusted IRR 0.57, 95% CI 0.50-0.64) between 2006 and 2015 but did not decline for incident PAD (adjusted IRR 0.84, 95% CI 0.70-1.00).
Conclusion and relevance
In the UK, the standardized incidence of CAD appears stable but mortality rates are falling, whereas the standardized incidence of PAD is falling but mortality rates are not.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J: 27 Dec 2019; epub ahead of print
Sundaram V, Bloom C, Zakeri R, Halcox J, ... Rajagopalan S, Quint JK
Eur Heart J: 27 Dec 2019; epub ahead of print | PMID: 31883328
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Impact:
Abstract

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
Background
Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.
Objectives
The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
Methods
From the [email protected], clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Results
Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Conclusions
Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 17 Feb 2020; 75:620-628
Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
J Am Coll Cardiol: 17 Feb 2020; 75:620-628 | PMID: 32057377
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Impact:
Abstract

Ambient Air Pollution and Mortality After Cardiac Transplantation.

Al-Kindi SG, Sarode A, Zullo M, Brook J, ... Brook R, Rajagopalan S
Background
Heart transplant recipients are at high risk for mortality, with traditional risk scores performing modestly in predicting post-transplant survival, underscoring the importance of as yet unidentified factors in determining prognosis. In this analysis, the association between PM exposure levels and survival after heart transplantation were investigated.
Objectives
This study sought to study the association between PM exposure and mortality following heart transplantation.
Methods
On the basis of the zip code of residence, mortality data in patients who underwent heart transplantation (2004 to 2015) in the United Network for Organ Sharing (UNOS) database were linked with validated estimates of fine particulate matter concentrations (particles with diameter <2.5 μm [PM]; 1 × 1-km grids) for each calendar year during which a UNOS cardiac transplant recipient was at risk for death. Cox proportional hazard models were used to estimate the relationship between exposure and overall mortality adjusting for recipient, donor, and neighborhood variables.
Results
A total of 21,800 patients with 86,713 patient-years of follow-up was included. Mean age at transplantation was 52.6 ± 12.6 years, 75% were male, 69% were white, and 39% had ischemic etiology of heart failure. Mean annual exposure to PM was 10.6 ± 2.3 μg/m. At a median follow-up of 4.8 (95% confidence interval: 2.0 to 7.8) years, 5,208 patients (23.9%) had died. The estimated mortality hazard ratio, per 10 μg/m increment increase in annual PM exposure was 1.43 (95% confidence interval: 1.21 to 1.49). After adjusting for 30 recipient, donor, and neighborhood variables, the estimated mortality hazard ratio per 10 μg/m increment in annual exposure to PM was 1.26 (95% confidence interval: 1.11 to 1.43) relative increase in hazard of mortality. This association was consistent across subgroups.
Conclusions
This study provides evidence linking air pollution with mortality after heart transplantation. These results suggest an important influence of a key environmental factor in outcomes following heart transplantation, and supports the need for further studies in this population.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 16 Dec 2019; 74:3026-3035
Al-Kindi SG, Sarode A, Zullo M, Brook J, ... Brook R, Rajagopalan S
J Am Coll Cardiol: 16 Dec 2019; 74:3026-3035 | PMID: 31865970
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Impact:
Abstract

Clinical impact of conduction disturbances in transcatheter aortic valve replacement recipients: a systematic review and meta-analysis.

Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Aims
The clinical impact of new-onset persistent left bundle branch block (NOP-LBBB) and permanent pacemaker implantation (PPI) on transcatheter aortic valve replacement (TAVR) recipients remains controversial. We aimed to evaluate the impact of (i) periprocedural NOP-LBBB and PPI post-TAVR on 1-year all-cause death, cardiac death, and heart failure hospitalization and (ii) NOP-LBBB on the need for PPI at 1-year follow-up.
Methods and results
We performed a systematic search from PubMed and EMBASE databases for studies reporting raw data on 1-year clinical impact of NOP-LBBB or periprocedural PPI post-TAVR. Data from 30 studies, including 7792 patients (12 studies) and 42 927 patients (21 studies) for the evaluation of the impact of NOP-LBBB and PPI after TAVR were sourced, respectively. NOP-LBBB was associated with an increased risk of all-cause death [risk ratio (RR) 1.32, 95% confidence interval (CI) 1.17-1.49; P < 0.001], cardiac death (RR 1.46, 95% CI 1.20-1.78; P < 0.001), heart failure hospitalization (RR 1.35, 95% CI 1.05-1.72; P = 0.02), and PPI (RR 1.89, 95% CI 1.58-2.27; P < 0.001) at 1-year follow-up. Periprocedural PPI after TAVR was associated with a higher risk of all-cause death (RR 1.17, 95% CI 1.11-1.25; P < 0.001) and heart failure hospitalization (RR 1.18, 95% CI 1.03-1.36; P = 0.02). Permanent pacemaker implantation was not associated with an increased risk of cardiac death (RR 0.84, 95% CI 0.67-1.05; P = 0.13).
Conclusion
NOP-LBBB and PPI after TAVR are associated with an increased risk of all-cause death and heart failure hospitalization at 1-year follow-up. Periprocedural NOP-LBBB also increased the risk of cardiac death and PPI within the year following the procedure. Further studies are urgently warranted to enhance preventive measures and optimize the management of conduction disturbances post-TAVR.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Jan 2020; epub ahead of print
Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899484
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Impact:
Abstract

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Aims
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis.
Methods and results
We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e\' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001).
Conclusion
The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 16 Jan 2020; epub ahead of print
Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31950987
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Impact:
Abstract

Trends in U.S. Ambulatory Cardiovascular Care 2013 to 2017: JACC Review Topic of the Week.

Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA

The National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry is the largest outpatient cardiovascular practice registry in the world. It tracks real-world management and quality of 4 common cardiovascular conditions: heart failure, coronary artery disease, atrial fibrillation, and hypertension. In 2013, the PINNACLE Registry contained information on 2,898,505 patients, cared for by 4,859 providers in 431 practices. By 2017, the registry contained information on 6,040,996 patients, cared for by 8,853 providers in 724 practices. During this time period, care processes for PINNACLE patients generally improved. Among patients with heart failure, combined beta-blocker and renin-angiotensin antagonist medication rates increased from 60.7% to 72.8%. Among patients with coronary artery disease, statin medication rates increased from 66% to 80.1%. Among patients with atrial fibrillation, oral anticoagulation rates increased from 52.7% to 65.2%. In contrast, blood pressure control rates among patients with hypertension were largely stable. PINNACLE data also fueled a variety of quality measurement programs and 51 peer-reviewed publications.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 06 Jan 2020; 75:93-112
Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA
J Am Coll Cardiol: 06 Jan 2020; 75:93-112 | PMID: 31918838
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Impact:
Abstract

Increased Myocardial Stiffness in Patients with High Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B HFpEF.

Hieda M, Sarma S, Hearon CM, Dias KA, ... Howden E, Levine BD

Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle-age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated LV myocardial stiffness when compared to healthy controls as a key marker for future HFpEF.Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers [NT-proBNP (>40 pg/ml) or TnT (>0.6 pg/ml)] were recruited, along with 61 age- and sexmatched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3D-echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion.There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (e.g., PCWP: LVH: 13.4 ± 2.7, vs. control: 11.7 ± 1.7mmHg, P<0.0001). The LV was less distensible in LVH than controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (PCWP - RAP), LV myocardial stiffness was nearly 30% greater in LVH compared to controls (LVH stiffness constant: 0.053 ± 0.027, vs. controls: 0.042 ± 0.020, P=0.028).LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than age- and sex- matched controls, and thus appears to represent a transitional state from a \"normal healthy-heart\" to HFpEF. Although, LV myocardial stiffness of LVH patients is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high risk individuals.URL: https://clinicaltrials.gov Unique Identifiers: NCT03476785 and NCT02039154.



Circulation: 22 Dec 2019; epub ahead of print
Hieda M, Sarma S, Hearon CM, Dias KA, ... Howden E, Levine BD
Circulation: 22 Dec 2019; epub ahead of print | PMID: 31865771
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Impact:
Abstract

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Aim
Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking.
Methods and results
We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001).
Conclusions
The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Feb 2020; epub ahead of print
López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016393
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Impact:
Abstract

S-Nitrosylation of Muscle LIM Protein Facilitates Myocardial Hypertrophy Through Toll-Like Receptor 3-Mediated Receptor-Interacting Protein Kinase 3 and NLRP3 Inflammasome Activation.

Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.



Circulation: 05 Jan 2020; epub ahead of print
Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902237
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Abstract

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J

Orai1 is a critical ion channel subunit, best recognized as a mediator of storeoperated Ca entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop JPIII, a small-molecule Orai1 channel inhibitor suitable fordelivery.Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. 5 weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and pro-hypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca]i transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from CdnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.



Circulation: 06 Jan 2020; epub ahead of print
Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J
Circulation: 06 Jan 2020; epub ahead of print | PMID: 31906693
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Abstract

Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure Overloaded Hearts.

Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K

Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, themRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although themRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction ofmRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.



Circulation: 13 Jan 2020; epub ahead of print
Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931613
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Abstract

OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance for Patients with Non-Ischemic Heart Failure (IMAGE-HF 1B).

Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,

Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF), however there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Hypothesis: Routine use of CMR will yield more specific diagnoses in non-ischemic HF. Secondary hypothesis: Routine use of CMR will improve patient outcomes.Patients with non-ischemic HF were randomized to Routine versus Selective CMR. Patients in the Routine strategy underwent echo and CMR whereas those assigned to Selective use underwent echo with or without CMR according to the clinical presentation. HF etiology was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months.500 patients (344 male), mean age 59±13, were randomized. The Routine and Selective CMR strategies had similar rates of specific HF etiologies at 3 months clinical follow-up, 44% vs. 50% respectively, p=0.22. At image interpretation, rates of specific HF etiology were also not different between Routine and Selective CMR, 34% vs. 30% respectively, p=0.34. However, 24% of patients in the Selective group underwent a non-protocol CMR. Patients with specific HF etiologies had more clinical events than those with non-specific etiologies based on imaging classification, 19% vs. 12% respectively, p=0.02, but not on clinical assessment, 15% vs. 14%, p=0.49.In patients with non-ischemic HF, Routine CMR does not yield more specific HF etiologies on clinical assessment. Patients with specific HF etiologies from imaging had worse outcomes whereas HF etiologies defined clinically did not.URL: https://clinicaltrials.gov. Unique Identifier: NCT01281384.



Circulation: 07 Jan 2020; epub ahead of print
Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910649
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Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
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Abstract

Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association.

Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.



Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print
Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,
Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print | PMID: 31902242
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Abstract

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T

Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis.Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanisticandstudies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression.findings were confirmed , using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing.High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (fromspecies) to be effective anti-fibrotic molecules bothandleading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds.We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.



Circulation: 16 Jan 2020; epub ahead of print
Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T
Circulation: 16 Jan 2020; epub ahead of print | PMID: 31948273
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Abstract

First in Human Experience with Peritoneal Direct Sodium Removal Using a Zero Sodium Solution: A New Candidate Therapy for Volume Overload.

Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM

Loop diuretics have well described toxicities and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Non-renal removal of sodium directly across the peritoneal membrane (direct sodium removal, DSR) using a sodium free osmotic solution should result in extraction of large quantities of sodium with limited off target solute removal.This report describes the pre-clinical development and first-in-human proof of concept for DSR. Sodium free 10% dextrose was utilized as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, scalability, and to determine the effect of experimental HF. In the human study, participants with end stage renal disease (ESRD) on peritoneal dialysis (PD) underwent randomization and crossover to either a two-hour dwell with one liter of DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary endpoint was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary endpoint was difference in sodium removal between DSR and standard PD solution.Porcine experiments revealed that one liter of DSR solution removed 4.1±0.4 grams of sodium in 2 hours with negligible off target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (p=0.005). In the setting of experimental HF with elevated right atrial pressure, sodium removal was ~4 times greater than in healthy animals (p<0.001). In the human proof of concept study, DSR solution was well-tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable and off target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 grams) compared to standard PD solution (1.0±0.3 grams, p<0.0001).DSR was well-tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in HF is warranted.URL: https://clinicaltrials.gov Unique identifier: NCT03801226.



Circulation: 07 Jan 2020; epub ahead of print
Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910658
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Abstract

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multi-Cohort Study.

Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA

A \"malignant\" subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk.Participants (n=15, 710) without prevalent cardiovascular disease were pooled from three population-based cohort studies, the Atherosclerosis Risk in Communities Study (ARIC), the Dallas Heart Study (DHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were classified into three groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT < 6 ng/L and NT-proBNP < 100 pg/mL), and those with ECGLVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF.Over the 10 year follow up period, HF occurred in 512 (3.3%) participants, with rates 5.2% among black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women vs white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI 2.1 to 3.5) in those with malignant LVH and 0.9 (95% CI 0.6 to 1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction (PAF) of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding PAF, were intermediate and similar among black women and white men and lowest among white women.A higher prevalence of malignant LVH may in part explain the higher risk of heart failure among blacks vs whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower heart failure risk and mitigate racial disparities.



Circulation: 13 Jan 2020; epub ahead of print
Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931608
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Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
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Abstract

Regulatory RNAs in Heart Failure.

Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.



Circulation: 27 Jan 2020; 141:313-328
Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,
Circulation: 27 Jan 2020; 141:313-328 | PMID: 31986093
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Abstract

Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium.

Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL

Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified post-translationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium.Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from non-failing and HF hearts, and viscoelasticity was characterized following interventions targeting microtubules. Next, intact left-ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and post-treatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains.Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared to non-failing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a two-fold reduction in energy dissipation upon microtubule depolymerization. Post-hoc sub-group analysis revealed that myocardium from patients with HF with reduced ejection fraction (HFrEF) were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction (HFpEF), which were relatively more viscous. Colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium.Failing cardiomyocytes exhibit elevated viscosity, and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix and/or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.



Circulation: 15 Jan 2020; epub ahead of print
Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941365
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Abstract

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.We assayed myosin ATP binding to define the proportions of myosin in SRX or DRX conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants with unknown clinical significance (VUS) that were identified in HCM patients, predicted functional consequences and associations with heart failure and arrhythmias.Myosins undergo physiologic shifts between SRX conformations that maximized energy-conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacologic modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased SRX conformations while pathogenic variants destabilized these and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify VUS, we showed that variants that unbalanced myosin conformations were associated with higher rates of heart failure and arrhythmias in HCM patients.Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy conserving states promotes contractile abnormalities, morphological and metabolic remodeling and adverse clinical outcomes in HCM patients. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in HCM patients.



Circulation: 26 Jan 2020; epub ahead of print
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983222
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Abstract

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Background
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
Methods
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year\'s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year\'s edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association\'s 2020 Impact Goals.
Results
Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
Conclusions
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.



Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print
Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print | PMID: 31992061
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Abstract

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB

Responding to concerns about the potential for increased risk of adverse cardiovascular (CV) outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were primarily granted regulatory approval from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on CV outcomes. The 2008 guidance aimed to ensure CV safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new CV outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated CV benefits of the newer agents, resulting in the first-ever CV protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed CV outcome trials. The group made several recommendations for future regulatory guidance and for CV outcome trials regarding glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.



Circulation: 28 Jan 2020; epub ahead of print
Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992065
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Abstract

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,

Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implanted cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation in order to prevent ICD shocks for VT) and deferred ablation after three ICD shocks for VT.The Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction (BERLIN VT) study was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population.During a mean follow-up of 396{plus minus}284 days, the primary endpoint occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09; 95% CI, 0.62-1.92; P=0.77). Using prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, six versus two patients died (7.9% vs. 2.4%; P=0.18), eight versus two patients were admitted for worsening heart failure (10.4% vs. 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% vs. 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% vs. 48.2%; P=0.050) and appropriate ICD therapy (34.2% vs. 47.0%; P=0.030) were numerically reduced in the preventive ablation group.Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up when compared to the deferred ablation strategy.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02501005.



Circulation: 30 Jan 2020; epub ahead of print
Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,
Circulation: 30 Jan 2020; epub ahead of print | PMID: 32000514
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Abstract

2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.

Bonow RO, O\'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ

Mitral regurgitation (MR) is a complex valve lesion that can pose significant management challenges. This Expert Consensus Decision Pathway emphasizes that recognition of MR should prompt an assessment of its etiology, mechanism, and severity, as well as consideration of the indications for treatment. The document is a focused update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation, with some sections updated and others added in light of the publication of new trial data related to secondary MR, among other developments. A structured approach to evaluation based on clinical findings, accurate echocardiographic imaging, and, when necessary, adjunctive testing, can help clarify decision making. Treatment goals include timely intervention by an experienced multidisciplinary heart team to prevent left ventricular dysfunction, heart failure, reduced quality of life, and premature death.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Feb 2020; epub ahead of print
Bonow RO, O'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ
J Am Coll Cardiol: 09 Feb 2020; epub ahead of print | PMID: 32068084
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Abstract

Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Aims 
Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD.
Methods and results 
In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo.
Conclusion 
Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 19 Feb 2020; epub ahead of print
Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32077924
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Abstract

Readmission and Mortality After Hospitalization for Myocardial Infarction and Heart Failure.

Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
Background
Readmission rates after acute myocardial infarction (AMI) and heart failure (HF) hospitalizations have decreased in the United States since the implementation of the Hospital Readmissions Reduction Program.
Objectives
This study was designed to examine the temporal trends of readmission and mortality after AMI and HF in Ontario, Canada, where reducing hospital readmissions has not had a policy incentive.
Methods
The cohort was comprised of AMI or HF patients 65 years of age or older who had been hospitalized from 2006 to 2017. Primary outcomes were 30-day readmission and post-discharge mortality. Secondary outcomes included in-hospital mortality, 30-day mortality from admission, and in-hospital mortality or 30-day mortality post-discharge. Adjusted monthly trends for each outcome were examined over the study period.
Results
Our cohorts included 152,808 AMI and 223,283 HF patients. Age- and sex-standardized AMI hospitalization rates in Ontario declined 32% from 2006 to 2017 while HF hospitalization rates declined slightly (9.1%). For AMI, risk-adjusted 30-day readmission rates declined from 17.4% in 2006 to 14.7% in 2017. All AMI risk-adjusted mortality rates also declined from 2006 to 2017 with 30-day post-discharge mortality from 5.1% to 4.4%. For HF, overall risk-adjusted 30-day readmission was largely unchanged from 2006 to 2014 at 21.9%, followed by a decline to 20.8% in 2017. Risk-adjusted 30-day post-discharge mortality declined from 7.1% in 2006 to 6.6% in 2017.
Conclusions
The patterns of outcomes in Ontario are consistent with the United States for AMI, but diverge for HF. For AMI and HF, admissions, readmissions, and mortality rates declined over this period. The reasons for the country-specific patterns for HF need further exploration.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 24 Feb 2020; 75:736-746
Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
J Am Coll Cardiol: 24 Feb 2020; 75:736-746 | PMID: 32081282
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Abstract

Medical Therapies for Heart Failure With Preserved Ejection Fraction.

Kjeldsen SE, von Lueder TG, Smiseth OA, Wachtell K, ... Devereux RB, Zannad F

Current cardiovascular pharmacotherapy targets maladaptive overactivation of the renin-angiotensin-aldosterone system (RAAS), which occurs throughout the continuum of cardiovascular disease spanning from hypertension to heart failure with reduced ejection fraction. Over the past 16 years, 4 prospective, randomized, placebo-controlled clinical trials using candesartan, perindopril, irbesartan, and spironolactone in patients with heart failure with preserved ejection fraction (HFpEF) failed to demonstrate increased efficacy of RAAS blockade added to guideline-directed medical therapy. We reappraise these trials and their weaknesses, which precluded statistically significant findings. Recently, dual-acting RAAS blockade with sacubitril-valsartan relative to stand-alone valsartan failed to improve outcome in the PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared with Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The majority of patients with HFpEF experience hypertension, frequently with subclinical left ventricular dysfunction, contributed to by comorbidities such as coronary disease, diabetes mellitus, overweight, and atrial fibrillation. Contrasting the findings in HFpEF, trials evaluating RAAS blockade on either side of HFpEF on the cardiovascular continuum in patients with high-risk hypertension and heart failure with reduced ejection fraction, respectively, showed positive outcomes. We do not have a biologically plausible explanation for such divergent efficacy of RAAS blockade. Based on considerations of well-established clinical efficacy in hypertension and heart failure with reduced ejection fraction and the shortcomings of aforementioned clinical trials in HFpEF, we argue that RAAS blockers including MRAs (mineralocorticoid receptor antagonists; aldosterone antagonists) should be used in the treatment of patients with HFpEF.



Hypertension: 01 Dec 2019:HYPERTENSIONAHA11914057; epub ahead of print
Kjeldsen SE, von Lueder TG, Smiseth OA, Wachtell K, ... Devereux RB, Zannad F
Hypertension: 01 Dec 2019:HYPERTENSIONAHA11914057; epub ahead of print | PMID: 31786973
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Abstract

High Blood Pressure and Cardiovascular Disease.

Fuchs FD, Whelton PK

Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD). Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure. Biologically, normal levels of BP are considerably lower than what has typically been characterized as normal in research and clinical practice. We propose that CVD is primarily caused by a right-sided shift in the population distribution of BP. Our view that BP is the predominant risk factor for CVD is based on conceptual postulates that have been tested in observational investigations and clinical trials. Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke. In multivariate modeling, the presumed attributable risk of high BP for stroke and coronary heart disease has increased steadily with progressive use of lower values for normal BP. Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies. Prevention of age-related increases in BP would, in large part, reduce the vascular consequences usually attributed to aging, and together with intensive treatment of established hypertension would eliminate a large proportion of the population burden of BP-related CVD.



Hypertension: 22 Dec 2019:HYPERTENSIONAHA11914240; epub ahead of print
Fuchs FD, Whelton PK
Hypertension: 22 Dec 2019:HYPERTENSIONAHA11914240; epub ahead of print | PMID: 31865786
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Abstract

Women\'s Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Background
Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials.
Methods
We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation).
Results
We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (=0.007) and heart failure (=0.01) trials compared with previous periods.
Conclusions
Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.



Circulation: 17 Feb 2020; 141:540-548
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Circulation: 17 Feb 2020; 141:540-548 | PMID: 32065763
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Abstract

Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer: A Population-Based Cohort Study.

Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Background
The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern.
Methods
We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality).
Results
The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]).
Conclusions
In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.



Circulation: 17 Feb 2020; 141:549-559
Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Circulation: 17 Feb 2020; 141:549-559 | PMID: 32065766
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Abstract

Body Mass Index in Young Women and Risk of Cardiomyopathy: A Long-Term Follow-Up Study in Sweden.

Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Background
Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy.
Methods
This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18-45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers.
Results
In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81-7.89) was found for severely obese subjects (BMI ≥35 kg/m), as compared with BMI 20 to <22.5.
Conclusions
Elevated BMI among young women was associated with an increased risk of being diagnosed with a subsequent cardiomyopathy, especially dilated cardiomyopathy, starting already at mildly elevated body weight, whereas severe obesity entailed an almost 5-fold increase in risk. With the increasing numbers of persons who are overweight or obese, higher rates of cardiomyopathy can be expected in the future, along with an altered disease burden related to adiposity.



Circulation: 17 Feb 2020; 141:520-529
Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Circulation: 17 Feb 2020; 141:520-529 | PMID: 32065765
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Abstract

Identification of the Uric Acid Thresholds Predicting an Increased Total and Cardiovascular Mortality Over 20 Years.

Virdis A, Masi S, Casiglia E, Tikhonoff V, ... Grassi G, Borghi C

Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 [95% CI, 1.21-1.93]) or CVM (hazard ratio, 2.08 [95% CI, 1.146-2.97]; <0.001). Cutoff values of SUA able to discriminate total mortality (4.7 mg/dL [95% CI, 4.3-5.1 mg/dL]) and CVM status (5.6 mg/dL [95% CI, 4.99-6.21 mg/dL]) were identified. The information on SUA levels provided a significant net reclassification improvement of 0.26 and of 0.27 over the Heart Score risk chart for total mortality and CVM, respectively (<0.001). Sex-specific cutoff values for total mortality and CVM were also identified and validated. In conclusion, SUA levels increasing the risk of total mortality and CVM are significantly lower than those used for the definition of hyperuricemia in clinical practice. Our data provide evidence of a cardiovascular SUA threshold that might contribute in clinical practice to improve identification of patients at higher risk of CVM.



Hypertension: 08 Dec 2019:HYPERTENSIONAHA11913643; epub ahead of print
Virdis A, Masi S, Casiglia E, Tikhonoff V, ... Grassi G, Borghi C
Hypertension: 08 Dec 2019:HYPERTENSIONAHA11913643; epub ahead of print | PMID: 31813345
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Abstract

Post-discharge acute care and outcomes following readmission reduction initiatives: national retrospective cohort study of Medicare beneficiaries in the United States.

Khera R, Wang Y, Bernheim SM, Lin Z, Krumholz HM
Objectives
To determine whether patients discharged after hospital admissions for conditions covered by national readmission programs who received care in emergency departments or observation units but were not readmitted within 30 days had an increased risk of death and to evaluate temporal trends in post-discharge acute care utilization in inpatient units, emergency departments, and observation units for these patients.
Design
Retrospective cohort study.
Setting
Medicare claims data for 2008-16 in the United States.
Participants
Patients aged 65 or older admitted to hospital with heart failure, acute myocardial infarction, or pneumonia-conditions included in the US Hospital Readmissions Reduction Program.
Main outcome measures
Post-discharge 30 day mortality according to patients\' 30 day acute care utilization; acute care utilization in inpatient and observation units and the emergency department during the 30 day and 31-90 day post-discharge period.
Results
3 772 924 hospital admissions for heart failure, 1 570 113 for acute myocardial infarction, and 3 131 162 for pneumonia occurred. The overall post-discharge 30 day mortality was 8.7% for heart failure, 7.3% for acute myocardial infarction, and 8.4% for pneumonia. Risk adjusted mortality increased annually by 0.05% (95% confidence interval 0.02% to 0.08%) for heart failure, decreased by 0.06% (-0.09% to -0.04%) for acute myocardial infarction, and did not significantly change for pneumonia. Specifically, mortality increased for patients with heart failure who did not utilize any post-discharge acute care, increasing at a rate of 0.08% (0.05% to 0.12%) per year, exceeding the overall absolute annual increase in post-discharge mortality in heart failure, without an increase in mortality in observation units or the emergency department. Concurrent with a reduction in 30 day readmission rates, stays for observation and visits to the emergency department increased across all three conditions during and beyond the 30 day post-discharge period. Overall 30 day post-acute care utilization did not change significantly.
Conclusions
The only condition with increasing mortality through the study period was heart failure; the increase preceded the policy and was not present among patients who received emergency department or observation unit care without admission to hospital. During this period, the overall acute care utilization in the 30 days after discharge significantly decreased for heart failure and pneumonia, but not for acute myocardial infarction.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 14 Jan 2020; 368:l6831
Khera R, Wang Y, Bernheim SM, Lin Z, Krumholz HM
BMJ: 14 Jan 2020; 368:l6831 | PMID: 31941686
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Abstract

Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

Mulrooney DA, Hyun G, Ness KK, Ehrhardt MJ, ... Hudson MM, Armstrong GT
Objective
To investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.
Design
Retrospective cohort study.
Setting
27 institutions participating in the Childhood Cancer Survivor Study.
Participants
23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.
Main outcome measures
Cumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute\'s Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.
Results
The 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).
Conclusions
Historical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.
Trial registration
ClinicalTrials.gov NCT01120353.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 14 Jan 2020; 368:l6794
Mulrooney DA, Hyun G, Ness KK, Ehrhardt MJ, ... Hudson MM, Armstrong GT
BMJ: 14 Jan 2020; 368:l6794 | PMID: 31941657
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Abstract

Cost-Effectiveness of Transitional Care Services After Hospitalization With Heart Failure.

Blum MR, Øien H, Carmichael HL, Heidenreich P, Owens DK, Goldhaber-Fiebert JD
Background
Patients with heart failure (HF) discharged from the hospital are at high risk for death and rehospitalization. Transitional care service interventions attempt to mitigate these risks.
Objective
To assess the cost-effectiveness of 3 types of postdischarge HF transitional care services and standard care.
Design
Decision analytic microsimulation model.
Data sources
Randomized controlled trials, clinical registries, cohort studies, Centers for Disease Control and Prevention life tables, Centers for Medicare & Medicaid Services data, and National Inpatient Sample (Healthcare Cost and Utilization Project) data.
Target population
Patients with HF who were aged 75 years at hospital discharge.
Time horizon
Lifetime.
Perspective
Health care sector.
Intervention
Disease management clinics, nurse home visits (NHVs), and nurse case management.
Outcome measures
Quality-adjusted life-years (QALYs), costs, net monetary benefits, and incremental cost-effectiveness ratios (ICERs).
Results of base-case analysis
All 3 transitional care interventions examined were more costly and effective than standard care, with NHVs dominating the other 2 interventions. Compared with standard care, NHVs increased QALYs (2.49 vs. 2.25) and costs ($81 327 vs. $76 705), resulting in an ICER of $19 570 per QALY gained.
Results of sensitivity analysis
Results were largely insensitive to variations in in-hospital mortality, age at baseline, or costs of rehospitalization. Probabilistic sensitivity analysis confirmed that transitional care services were preferred over standard care in nearly all 10 000 samples, at willingness-to-pay thresholds of $50 000 or more per QALY gained.
Limitation
Transitional care service designs and implementations are heterogeneous, leading to uncertainty about intervention effectiveness and costs when applied in particular settings.
Conclusion
In older patients with HF, transitional care services are economically attractive, with NHVs being the most cost-effective strategy in many situations. Transitional care services should become the standard of care for postdischarge management of patients with HF.
Primary funding source
Swiss National Science Foundation, Research Council of Norway, and an Intermountain-Stanford collaboration.



Ann Intern Med: 27 Jan 2020; epub ahead of print
Blum MR, Øien H, Carmichael HL, Heidenreich P, Owens DK, Goldhaber-Fiebert JD
Ann Intern Med: 27 Jan 2020; epub ahead of print | PMID: 31986526
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Abstract

Blood Pressure Control and the Association With Diabetes Mellitus Incidence: Results From SPRINT Randomized Trial.

Roumie CL, Hung AM, Russell GB, Basile J, ... Cushman WC,

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure <120 mm Hg) versus standard strategy (<140 mm Hg). Participants were ≥50 years of age, with systolic 130 to 180 mm Hg and increased cardiovascular risk. Participants were excluded if they had diabetes mellitus, polycystic kidney disease, proteinuria >1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ≥126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ≥126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100-125 mg/dL [5.55-6.94 mmol/L]) among those with normoglycemia (<100 mg/dL [5.55 mmol/L]). There were 9361 participants randomized and 981 excluded, yielding 4187 and 4193 participants assigned to intensive and standard strategies. There were 299 incident diabetes mellitus events (2.3% per year) for intensive and 251 events (1.9% per year) for standard, rates of 22.6 (20.2-25.3) versus 19.0 (16.8-21.5) events per 1000 person-years of treatment, respectively (adjusted hazard ratio, 1.19 [95% CI, 0.95-1.49]). Impaired fasting glucose rates were 26.4 (24.9-28.0) and 22.5 (21.1-24.1) per 100 person-years for intensive and standard strategies (adjusted hazard ratio, 1.17 [1.06-1.30]). Intensive treatment strategy was not associated with increased diabetes mellitus but was associated with more impaired fasting glucose. The risks and benefits of intensive blood pressure targets should be factored into individualized patient treatment goals. Clinical trial registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01206062.



Hypertension: 22 Dec 2019:HYPERTENSIONAHA11812572; epub ahead of print
Roumie CL, Hung AM, Russell GB, Basile J, ... Cushman WC,
Hypertension: 22 Dec 2019:HYPERTENSIONAHA11812572; epub ahead of print | PMID: 31865790
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Abstract

The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence Based Approach Using Perfusion Mapping.

Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC

Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance (CMR) perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF).A two center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for co-morbidities and CMR parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization and death.1049 patients were included with median follow-up 605 (interquartile range 464-814) days. There were 42 (4.0%) deaths and 188 MACE in 174 (16.6%) patients. Stress MBF and MPR were independently associated with both death and MACE. For each 1ml/g/min decrease in stress MBF the adjusted hazard ratio (HR) for death and MACE were 1.93 (95% CI 1.08-3.48, P=0.028) and 2.14 (95% CI 1.58-2.90, P<0.0001) respectively, even after adjusting for age and co-morbidity. For each 1 unit decrease in MPR the adjusted HR for death and MACE were 2.45 (95% CI 1.42-4.24, P=0.001) and 1.74 (95% CI 1.36-2.22, P<0.0001) respectively. In patients without regional perfusion defects on clinical read and no known macrovascular coronary artery disease (n=783), MPR remained independently associated with death and MACE, with stress MBF remaining associated with MACE only.In patients with known or suspected coronary artery disease, reduced MBF and MPR measured automatically inline using artificial intelligence quantification of CMR perfusion mapping provides a strong, independent predictor of adverse cardiovascular outcomes.



Circulation: 13 Feb 2020; epub ahead of print
Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC
Circulation: 13 Feb 2020; epub ahead of print | PMID: 32078380
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Abstract

How Do SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors and GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists Reduce Cardiovascular Outcomes?: Completed and Ongoing Mechanistic Trials.

Lee MMY, Petrie MC, McMurray JJV, Sattar N
Objective
There is substantial interest in how glucagon-like peptide-1 receptor agonists (GLP-1RA) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated.
Conclusions
We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.



Arterioscler Thromb Vasc Biol: 29 Jan 2020:ATVBAHA119311904; epub ahead of print
Lee MMY, Petrie MC, McMurray JJV, Sattar N
Arterioscler Thromb Vasc Biol: 29 Jan 2020:ATVBAHA119311904; epub ahead of print | PMID: 31996025
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Abstract

Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy.

Kazi DS, Bellows BK, Baron SJ, Shen C, ... Maurer MS, Shah SJ

In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), tafamidis reduces all-cause mortality and cardiovascular hospitalizations, and slows decline in quality-oflife compared with placebo. In May 2019, tafamidis received expedited approval from the US FDA as a breakthrough drug for a rare disease. However, at $225,000 per year, it is the most expensive cardiovascular drug ever launched in the US, and its long-term cost-effectiveness and budget impact are uncertain. We therefore sought to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.We developed a Markov model of patients with wild-type or variant ATTR-CM and heart failure (mean age 74.5 years) using inputs from the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment (\"usual care\") with tafamidis therapy. The model reproduced 30-month survival, quality-of-life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life years (QALYs) by 3% annually, and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental costeffectiveness ratio (ICER) and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.Compared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) QALYs at an incremental cost of $1,135,000 (872,000-1,377,000), resulting in an ICER of $880,000 (697,000-1,564,000) per QALY gained. Assuming a threshold of $100,000 per QALY gained and current drug price, tafamidis was cost-effective in 0% of 10,000 probabilistic simulations. A 92.6% price reduction from $225,000 to $16,563 would be necessary to make tafamidis cost-effective at $100,000/QALY. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with ATTR-CM in the US with tafamidis (n = 120,000) was estimated to increase annual healthcare spending by $32.3 billion.Treatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. Based on recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.



Circulation: 11 Feb 2020; epub ahead of print
Kazi DS, Bellows BK, Baron SJ, Shen C, ... Maurer MS, Shah SJ
Circulation: 11 Feb 2020; epub ahead of print | PMID: 32078382
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Abstract

Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses.

Wallach JD, Wang K, Zhang AD, Cheng D, ... Krumholz HM, Ross JS
Objectives
To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing.
Design
Systematic review and meta-analysis of randomized controlled trials.
Data sources
GlaxoSmithKline\'s (GSK\'s) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK\'s Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data.
Eligibility criteria for selecting studies
Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults.
Data extraction and synthesis
For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals.
Results
33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK\'s summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.
Conclusions
The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety.
Systematic review registration
OSF Home https://osf.io/4yvp2/.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 04 Feb 2020; 368:l7078
Wallach JD, Wang K, Zhang AD, Cheng D, ... Krumholz HM, Ross JS
BMJ: 04 Feb 2020; 368:l7078 | PMID: 32024657
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Abstract

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; ≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, =0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print
Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print | PMID: 32008434
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Abstract

Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure.

Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM

Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.



Circulation: 24 Feb 2020; 141:678-693
Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM
Circulation: 24 Feb 2020; 141:678-693 | PMID: 32091921
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Abstract

Screening Rates for Primary Aldosteronism in Resistant Hypertension: A Cohort Study.

Jaffe G, Gray Z, Krishnan G, Stedman M, ... Leppert JT, Bhalla V

Resistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 persons with hypertension and excluded persons with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 persons ages 18 to <90 from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in persons with resistant hypertension was 2.1%. Screened persons were younger (55.9±13.3 versus 65.5±11.6 years; <0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; =0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; <0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; =0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; =0.04) than unscreened persons. Screened persons had significantly higher rates of prescription for calcium channel blockers, mixed α/β-adrenergic receptor antagonists, sympatholytics, and vasodilators, and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (=0.20). In conclusion, only 2.1% of eligible persons received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914359; epub ahead of print
Jaffe G, Gray Z, Krishnan G, Stedman M, ... Leppert JT, Bhalla V
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914359; epub ahead of print | PMID: 32008436
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Abstract

Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy.

Ren Z, Yu P, Li D, Li Z, ... Zhou B, Wang L

Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart\'s workload after the onset of heart failure. Thus, more etiology-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular level.By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and non-cardiomyocytes, based on their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay amongst cell types, and tested potential pharmacologic treatment strategies to retard its progression .We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific non-cardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose co-transporter 2 inhibitor in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Importantly, similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy, but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.



Circulation: 25 Feb 2020; epub ahead of print
Ren Z, Yu P, Li D, Li Z, ... Zhou B, Wang L
Circulation: 25 Feb 2020; epub ahead of print | PMID: 32098504
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Abstract

Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure.

Wood K, Gladwin M, Straub A

Sickle cell disease (SCD) is caused by a single point mutation in the gene that codes for beta globin synthesis, causing haemoglobin polymerisation, red blood cell stiffening and haemolysis under low oxygen and pH conditions. Downstream effects include widespread vasculopathy due to recurring vaso-occlusive events and haemolytic anaemia, affecting all organ systems. Cardiopulmonary complications are the leading cause of death in patients with SCD, primarily resulting from diastolic heart failure (HF) and/or pulmonary hypertension (PH). HF in SCD often features biventricular cardiac hypertrophy and left ventricular (LV) diastolic dysfunction. Among HF cases in the general population, approximately half occur with preserved ejection fraction (HFpEF). The insidious evolution of HFpEF differs from the relatively acute evolution of HF with reduced ejection fraction. The PH of SCD has diverse origins, which can be pulmonary arterial (precapillary), pulmonary venous (postcapillary) or pulmonary thromboembolic. It is also appreciated that patients with SCD can develop both precapillary and postcapillary PH, with elevations in LV diastolic pressures, as well as elevations in transpulmonary pressure gradient and pulmonary vascular resistance. Regardless of the cause of PH in SCD, its presence significantly reduces functional capacity and increases mortality. PH that occurs in the presence of HFpEF is usually of postcapillary origin. This review aims to assemble what has been learnt from clinical and animal studies about the manifestation of PH-HFpEF in SCD, specifically the contributions of LV diastolic dysfunction and myocardial fibrosis, in an attempt to gain an understanding of its evolution.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 09 Dec 2019; epub ahead of print
Wood K, Gladwin M, Straub A
Heart: 09 Dec 2019; epub ahead of print | PMID: 31822569
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Abstract

External Performance of the HAVOC Score for the Prediction of New Incident Atrial Fibrillation.

Ntaios G, Perlepe K, Lambrou D, Sirimarco G, ... Vemmos K, Michel P

Background and Purpose- The HAVOC score (hypertension, age, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, coronary artery disease) was proposed for the prediction of atrial fibrillation (AF) after cryptogenic stroke. It showed good model discrimination (area under the curve, 0.77). Only 2.5% of patients with a low-risk HAVOC score (ie, 0-4) were diagnosed with new incident AF. We aimed to assess its performance in an external cohort of patients with embolic stroke of undetermined source. Methods- In the AF-embolic stroke of undetermined source dataset, we assessed the discriminatory power, calibration, specificity, negative predictive value, and accuracy of the HAVOC score to predict new incident AF. Patients with a HAVOC score of 0 to 4 were considered as low-risk, as proposed in its original publication. Results- In 658 embolic stroke of undetermined source patients (median age, 67 years; 44% women), the median HAVOC score was 2 (interquartile range, 3). There were 540 (82%) patients with a HAVOC score of 0 to 4 and 118 (18%) with a score of ≥5. New incident AF was diagnosed in 95 (14.4%) patients (28.8% among patients with HAVOC score ≥5 and 11.3% among patients with HAVOC score 0-4 [age- and sex-adjusted odds ratio, 2.29 (95% CI,1.37-3.82)]). The specificity of low-risk HAVOC score to identify patients without new incident AF was 88.7%. The negative predictive value of low-risk HAVOC score was 85.1%. The accuracy was 78.0%, and the area under the curve was 68.7% (95% CI, 62.1%-73.3%). Conclusions- The previously reported low rate of AF among embolic stroke of undetermined source patients with low-risk HAVOC score was not confirmed in our cohort. Further assessment of the HAVOC score is warranted before it is routinely implemented in clinical practice.



Stroke: 11 Dec 2019:STROKEAHA119027990; epub ahead of print
Ntaios G, Perlepe K, Lambrou D, Sirimarco G, ... Vemmos K, Michel P
Stroke: 11 Dec 2019:STROKEAHA119027990; epub ahead of print | PMID: 31826729
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Abstract

Valve regurgitation in patients surviving endocarditis and the subsequent risk of heart failure.

Østergaard L, Dahl A, Bruun NE, Oestergaard LB, ... Ihlemann N, Fosbøl EL
Background
Significant valve regurgitation is common in patients surviving native valve infective endocarditis (IE), however the associated risk of heart failure (HF) subsequent to hospital discharge after IE is sparsely described.
Methods
We linked data from the East Danish Endocarditis Registry with administrative registries from 2002 to 2016 and included patients treated medically for IE who were discharged alive. Left-sided valve regurgitation was assessed by echocardiography at IE discharge and examined for longitudinal risk of HF. Multivariable adjusted Cox analysis was used to assess the associated risk of HF in patients with regurgitation (moderate or severe) compared with patients without regurgitation.
Results
We included 192 patients, 87 patients with regurgitation at discharge (30 with aortic regurgitation and 57 with mitral regurgitation) and 105 patients without. The cumulative risk of HF at 5 years of follow-up was 28.7% in patients with regurgitation at IE discharge and 12.4% in patients without regurgitation; the corresponding multivariable adjusted HR was 3.53 (95% CI 1.72 to 7.25). We identified an increased associated risk of HF for patients with aortic regurgitation (HR=2.91, 95% CI 1.14 to 7.43) and mitral regurgitation (HR=3.95, 95% CI 1.80 to 8.67) compared with patients without regurgitation. During follow-up, 21.9% and 5.7% underwent left-sided valve surgery among patients with and without regurgitation.
Conclusion
In patients surviving IE, treated medically, we observed that severe or moderate left-sided native valve regurgitation was associated with a significantly higher risk of HF compared with patients without regurgitation at IE discharge. Close monitoring of these patients is needed to initiate surgery timely.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 09 Dec 2019; epub ahead of print
Østergaard L, Dahl A, Bruun NE, Oestergaard LB, ... Ihlemann N, Fosbøl EL
Heart: 09 Dec 2019; epub ahead of print | PMID: 31822570
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Abstract

Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure: The GALACTIC Randomized Clinical Trial.

Kozhuharov N, Goudev A, Flores D, Maeder MT, ... Mueller C,
Importance
Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF).
Objective
To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF.
Design, setting, and participants
Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019.
Interventions
Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan.
Main outcomes and measures
The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days.
Results
Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%).
Conclusions and relevance
Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.
Trial registration
ClinicalTrials.gov Identifier: NCT00512759.



JAMA: 16 Dec 2019; 322:2292-2302
Kozhuharov N, Goudev A, Flores D, Maeder MT, ... Mueller C,
JAMA: 16 Dec 2019; 322:2292-2302 | PMID: 31846016
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Impact:
Abstract

Sex differences of resource utilisation and outcomes in patients with atrial arrhythmias and heart failure.

Ueberham L, König S, Hohenstein S, Mueller-Roething R, ... Bollmann A,
Objective
Atrial fibrillation or atrial flutter (AF) and heart failure (HF) often go hand in hand and, in combination, lead to an increased risk of death compared with patients with just one of both entities. Sex-specific differences in patients with AF and HF are under-reported. Therefore, the aim of this study was to investigate sex-specific catheter ablation (CA) use and acute in-hospital outcomes in patients with AF and concomitant HF in a retrospective cohort study.
Methods
Using International Statistical Classification of Diseases and Related Health Problems and Operations and Procedures codes, administrative data of 75 hospitals from 2010 to 2018 were analysed to identify cases with AF and HF. Sex differences were compared for baseline characteristics, right and left atrial CA use, procedure-related adverse outcomes and in-hospital mortality.
Results
Of 54 645 analysed cases with AF and HF, 46.2% were women. Women were significantly older (75.4±9.5 vs 68.7±11.1 years, p<0.001), had different comorbidities (more frequently: cerebrovascular disease (2.4% vs 1.8%, p<0.001), dementia (5.3% vs 2.2%, p<0.001), rheumatic disease (2.1% vs 0.8%, p<0.001), diabetes with chronic complications (9.7% vs 9.1%, p=0.033), hemiplegia or paraplegia (1.7% vs 1.2%, p<0.001) and chronic kidney disease (43.7% vs 33.5%, p<0.001); less frequently: myocardial infarction (5.4% vs 10.5%, p<0.001), peripheral vascular disease (6.9% vs 11.3%, p<0.001), mild liver disease (2.0% vs 2.3%, p=0.003) or any malignancy (1.0% vs 1.3%, p<0.001), underwent less often CA (12.0% vs 20.7%, p<0.001), had longer hospitalisations (6.6±5.8 vs 5.2±5.2 days, p<0.001) and higher in-hospital mortality (1.6% vs 0.9%, p<0.001). However, in the multivariable generalised linear mixed model for in-hospital mortality, sex did not remain an independent predictor (OR 0.96, 95% CI 0.82 to 1.12, p=0.579) when adjusted for age and comorbidities. Vascular access complications requiring interventions (4.8% vs 4.2%, p=0.001) and cardiac tamponade (0.3% vs 0.1%, p<0.001) occurred more frequently in women, whereas stroke (0.6% vs 0.5%, p=0.179) and death (0.3% vs 0.1%, p=0.101) showed no sex difference in patients undergoing CA.
Conclusions
There are sex differences in patients with AF and HF with respect to demographics, resource utilisation and in-hospital outcomes. This needs to be considered when treating women with AF and HF, especially for a sufficient patient informed decision making in clinical practice.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 18 Dec 2019; epub ahead of print
Ueberham L, König S, Hohenstein S, Mueller-Roething R, ... Bollmann A,
Heart: 18 Dec 2019; epub ahead of print | PMID: 31857353
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Impact:
Abstract

Identification of novel pheno-groups in heart failure with preserved ejection fraction using machine learning.

Hedman ÅK, Hage C, Sharma A, Brosnan MJ, ... Ziemek D, Lund L
Objective
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups (\'phenogroups\') based on clinical and echocardiogram data using machine learning, and to compare clinical characteristics, proteomics and outcomes across the phenogroups.
Methods
We applied model-based clustering to 32 echocardiogram and 11 clinical and laboratory variables collected in stable condition from 320 HFpEF outpatients in the Karolinska-Rennes cohort study (56% female, median 78 years (IQR: 71-83)). Baseline proteomics and the composite end point of all-cause mortality or heart failure (HF) hospitalisation were used in secondary analyses.
Results
We identified six phenogroups, for which significant differences in the prevalence of concomitant atrial fibrillation (AF), anaemia and kidney disease were observed (p<0.05). Fifteen out of 86 plasma proteins differed between phenogroups (false discovery rate, FDR<0.05), including biomarkers of HF, AF and kidney function. The composite end point was significantly different between phenogroups (log-rank p<0.001), at short-term (100 days), mid-term (18 months) and longer-term follow-up (1000 days). Phenogroup 2 was older, with poorer diastolic and right ventricular function and higher burden of risk factors as AF (85%), hypertension (83%) and chronic obstructive pulmonary disease (30%). In this group a third experienced the primary outcome to 100 days, and two-thirds to 18 months (HR (95% CI) versus phenogroups 1, 3, 4, 5, 6: 1.5 (0.8-2.9); 5.7 (2.6-12.8); 2.9 (1.5-5.6); 2.7 (1.6-4.6); 2.1 (1.2-3.9)).
Conclusions
Using machine learning we identified distinct HFpEF phenogroups with differential characteristics and outcomes, as well as differential levels of inflammatory and cardiovascular proteins.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 06 Jan 2020; epub ahead of print
Hedman ÅK, Hage C, Sharma A, Brosnan MJ, ... Ziemek D, Lund L
Heart: 06 Jan 2020; epub ahead of print | PMID: 31911501
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Abstract

Characteristics and Outcomes of Retinal Artery Occlusion: Nationally Representative Data.

Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS

Background and Purpose- There are few large studies examining comorbidities, outcomes, and acute interventions for patients with retinal artery occlusion (RAO). RAO shares pathophysiology with acute ischemic stroke (AIS); direct comparison may inform emergent treatment, evaluation, and secondary prevention. Methods- The National Readmissions Database contains data on ≈50% of US hospitalizations from 2013 to 2015. We used , , codes to identify and compare index RAO and AIS admissions, comorbidities, and interventions and Clinical Comorbidity Software codes to identify readmissions causes, using survey-weighted methods when possible. Cumulative risk of all-cause readmission after RAO ≤1 year was estimated by Kaplan-Meier analysis. Results- Among 4871 RAO and 1 239 963 AIS admissions, patients with RAO were less likely (<0.0001) than patients with AIS to have diabetes mellitus (RAO, 24.3% versus AIS, 36.8%), congestive heart failure (9.1% versus 14.8%), atrial fibrillation (15.5% versus 25.2%), or hypertension (62.2% versus 67.6%) but more likely to have valvular disease (13.3% versus 10.5%) and tobacco usage (38.6% versus 32.9%). In RAO admissions, thrombolysis was administered in 2.9% (5.8% in central RAO subgroup, versus 8.0% of AIS), therapeutic anterior chamber paracentesis in 1.0%, thrombectomy in none; 1.4% received carotid endarterectomy during index admission, 1.6% within 30 days. Nearly 1 in 10 patients with RAO were readmitted within 30 days and were more than twice as likely as patients with AIS to be readmitted for dysrhythmia or endocarditis. Readmission for stroke after RAO was the highest within the first 150 days after index admission, and risk was higher in central RAO than in branch RAO. Conclusions- Patients with RAO had high prevalence of many stroke risk factors, particularly valvular disease and smoking, which can be addressed to minimize subsequent risk. Despite less baseline atrial fibrillation, RAO patients were more likely to be readmitted for atrial fibrillation/dysrhythmias. A variety of interventions was administered. AIS risk is the highest shortly after RAO, emphasizing the importance of urgent, thorough neurovascular evaluation.



Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print
Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS
Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print | PMID: 31951154
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Abstract

Quality evaluation and future priorities for delivering acute myocardial infarction care in Sri Lanka.

Beane A, Ranasinghe WG, Vithanage TDP, Priyadarshani GDD, ... Dondorp AM, Haniffa R
Aim
This study evaluates the quality of care for patients admitted with acute myocardial infarction (AMI) in a tertiary hospital in Colombo using the European Society of Cardiology Quality of Care Working Group\'s guidelines (2017).
Methods
A recently implemented electronic AMI registry m-Health tool was used for prospective data collection. Each patient was assessed for eligibility for each of the six domains of quality. Global Registry of Acute Coronary Events Risk Model for predicted probability of mortality, and scores for risk of bleeding complications (CRUSADE) and severity of heart failure (Killip classification) were calculated as per published guidelines. A composite measure of quality was derived from compliance with the six domains. Patients were followed up via telephone at 30 days following discharge to evaluate outcome and satisfaction. Organisational information was assessed by administrative review and interview.
Results
Between March 2017 and April 2018, 934 patients with AMI presented to the cardiology department. The majority of patients (90.4%) presented with features of ST-elevation myocardial infarction (STEMI). Mean (SD) overall compliance with the composite quality indicator (CQI) was 44% (0.07). Compliance of ≥50% to the CQI was achieved in 9.8% of STEMI patients. The highest compliance was observed for antithrombotics during hospitalisation (79.1%) and continuous measure of patient satisfaction (76.1%). The lowest compliance was for organisational structure and care processes (22.4%).
Conclusion
This study reports a registry-based continuous evaluation of the quality of AMI care from a low and middle-income country. Priorities for improvement include improved referral, and networking of primary and secondary health facilities with the percutaneous coronary intervention centre.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Dec 2019; epub ahead of print
Beane A, Ranasinghe WG, Vithanage TDP, Priyadarshani GDD, ... Dondorp AM, Haniffa R
Heart: 15 Dec 2019; epub ahead of print | PMID: 31843877
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Impact:
Abstract

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy beyond ejection fraction.

Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G

Sudden cardiac death and arrhythmia-related events in patients with non-ischaemic dilated cardiomyopathy (NICM) have been significantly reduced over the last couple of decades as a result of evidence-based pharmacological and non-pharmacological therapeutic strategies. Nevertheless, the arrhythmic stratification in patients with NICM remains extremely challenging, and the simple indication based on left ventricular ejection fraction appears to be insufficient. Therefore, clinicians need to go beyond the current criteria for implantable cardioverter-defibrillator implantation in the direction of a multiparametric evaluation of arrhythmic risk. Several parameters for arrhythmic risk stratification, ranging from electrocardiographic, echocardiographic, imaging-derived and genetic markers, are crucial for proper arrhythmic risk stratification and a multiparametric evaluation of risk in patients with NICM. In particular, integration of cardiac magnetic resonance parameters (mostly late gadolinium enhancement) and specific genetic information (ie, presence ofmutations) appears fundamental for proper implementation of the current arrhythmic risk stratification. Finally, a novel approach focused on both arrhythmic risk and prediction of left ventricular reverse remodelling during follow-up might be useful for effective multiparametric and dynamic arrhythmic risk stratification in NICM. In the future, a complete and integrated evaluation might be mandatory to implement arrhythmic risk prediction in patients with NICM and to discriminate the competing risk between heart failure-related events and life-threatening arrhythmias.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 20 Jan 2020; epub ahead of print
Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G
Heart: 20 Jan 2020; epub ahead of print | PMID: 31964657
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Impact:
Abstract

Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress.

Dikalova AE, Pandey AK, Xiao L, Arslanbaeva L, ... Harrison DG, Dikalov SI

Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure and affects 30% of the adult population. Mitochondrial dysfunction contributes to hypertension, but specific mechanisms are unclear. The mitochondrial deacetylase Sirt3 is critical in the regulation of metabolic and antioxidant functions which are associated with hypertension, and cardiovascular disease risk factors diminish Sirt3 level.We hypothesized that reduced Sirt3 expression contributes to vascular dysfunction in hypertension but increased Sirt3 protects vascular function and decreases hypertension.To test the therapeutic potential of targeting Sirt3 expression we developed new transgenic mice with global Sirt3 overexpression (Sirt3OX) which protects from endothelial dysfunction, vascular oxidative stress and hypertrophy, attenuates angiotensin II- and DOCA-salt induced hypertension. Global Sirt3 depletion inmice results in oxidative stress due to SOD2 hyperacetylation, increases HIF1α, reduces endothelial cadherin, stimulates vascular hypertrophy, increases vascular permeability and vascular inflammation (p65, caspase 1, VCAM, ICAM and MCP1), increases inflammatory cell infiltration in the kidney, reduces telomerase expression, and accelerates vascular senescence and age-dependent hypertension; conversely, increased Sirt3 expression in Sirt3OX mice prevents these deleterious effects. The clinical relevance of Sirt3 depletion was confirmed in arterioles from human mediastinal fat in patients with essential hypertension showing a 40% decrease in vascular Sirt3, coupled with Sirt3 dependent 3-fold increases in SOD2 acetylation, NfKB activity, VCAM, ICAM and MCP1 levels in hypertensive subjects compared with normotensive subjects.We suggest that Sirt3 depletion in hypertension promotes endothelial dysfunction, vascular hypertrophy, vascular inflammation and end-organ damage. Our data support a therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension.



Circ Res: 18 Dec 2019; epub ahead of print
Dikalova AE, Pandey AK, Xiao L, Arslanbaeva L, ... Harrison DG, Dikalov SI
Circ Res: 18 Dec 2019; epub ahead of print | PMID: 31852393
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Abstract

Association of Isolated Diastolic Hypertension as Defined by the 2017 ACC/AHA Blood Pressure Guideline With Incident Cardiovascular Outcomes.

McEvoy JW, Daya N, Rahman F, Hoogeveen RC, ... Coresh J, Selvin E
Importance
In the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, the definition of hypertension was lowered from a blood pressure (BP) of greater than or equal to 140/90 to greater than or equal to 130/80 mm Hg. The new diastolic BP threshold of 80 mm Hg was recommended based on expert opinion and changes the definition of isolated diastolic hypertension (IDH).
Objective
To compare the prevalence of IDH in the United States, by 2017 ACC/AHA and 2003 Joint National Committee (JNC7) definitions, and to characterize cross-sectional and longitudinal associations of IDH with outcomes.
Design, setting, and participants
Cross-sectional analyses of the National Health and Nutrition Examination Survey (NHANES 2013-2016) and longitudinal analyses of the Atherosclerosis Risk in Communities (ARIC) Study (baseline 1990-1992, with follow-up through December 31, 2017). Longitudinal results were validated in 2 external cohorts: (1) the NHANES III (1988-1994) and NHANES 1999-2014 and (2) the Give Us a Clue to Cancer and Heart Disease (CLUE) II cohort (baseline 1989).
Exposures
IDH, by 2017 ACC/AHA (systolic BP <130 mm Hg, diastolic BP ≥80 mm Hg) and by JNC7 (systolic BP <140 mm Hg, diastolic BP ≥90 mm Hg) definitions.
Main outcomes and measures
Weighted estimates for prevalence of IDH in US adults and prevalence of US adults recommended BP pharmacotherapy by the 2017 ACC/AHA guideline based solely on the presence of IDH. Risk of incident atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD) in the ARIC Study.
Results
The study population included 9590 adults from the NHANES (mean [SD] baseline age, 49.6 [17.6] years; 5016 women [52.3%]) and 8703 adults from the ARIC Study (mean [SD] baseline age, 56.0 [5.6] years; 4977 women [57.2%]). The estimated prevalence of IDH in the NHANES was 6.5% by the 2017 ACC/AHA definition and 1.3% by the JNC7 definition (absolute difference, 5.2% [95% CI, 4.7%-5.7%]). Among those newly classified as having IDH, an estimated 0.6% (95% CI, 0.5%-0.6%) also met the guideline threshold for antihypertensive therapy. Compared with normotensive ARIC participants, IDH by the 2017 ACC/AHA definition was not significantly associated with incident ASCVD (n = 1386 events; median follow-up, 25.2 years; hazard ratio [HR], 1.06 [95% CI, 0.89-1.26]), HF (n = 1396 events; HR, 0.91 [95% CI, 0.76-1.09]), or CKD (n = 2433 events; HR, 0.98 [95% CI, 0.65-1.11]). Results were also null for cardiovascular mortality in the 2 external cohorts (eg, HRs of IDH by the 2017 ACC/AHA definition were 1.17 [95% CI, 0.87-1.56] in the NHANES [n = 1012 events] and 1.02 [95% CI, 0.92-1.14] in CLUE II [n = 1497 events]).
Conclusions and relevance
In this analysis of US adults, the estimated prevalence of IDH was more common when defined by the 2017 ACC/AHA BP guideline compared with the JNC7 guideline. However, IDH was not significantly associated with increased risk for cardiovascular outcomes.



JAMA: 27 Jan 2020; 323:329-338
McEvoy JW, Daya N, Rahman F, Hoogeveen RC, ... Coresh J, Selvin E
JAMA: 27 Jan 2020; 323:329-338 | PMID: 31990314
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Abstract

Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation.

Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Objective
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells () led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice withdeletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers ofmutants. The SMAD3 phosphorylation was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells ofmice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels inmutant mice.
Conclusions
The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.



Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print
Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print | PMID: 32078339
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Impact:
Abstract

Financial and resource costs of transvenous lead extraction in a high-volume lead extraction centre.

Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Objectives
Transvenous lead extraction (TLE) poses a significant economic and resource burden on healthcare systems; however, limited data exist on its true cost. We therefore estimate real-world healthcare reimbursement costs of TLE to the UK healthcare system at a single extraction centre.
Methods
Consecutive admissions entailing TLE at a high-volume UK centre between April 2013 and March 2018 were prospectively recorded in a computer registry. In the hospital\'s National Health Service (NHS) clinical coding/reimbursement database, 447 cases were identified. Mean reimbursement cost (n=445) and length of stay (n=447) were calculated. Ordinary least squares regressions estimated the relationship between cost (bed days) and clinical factors.
Results
Mean reimbursement cost per admission was £17 399.09±£13 966.49. Total reimbursement for all TLE admissions was £7 777 393.51. Mean length of stay was 16.3±15.16 days with a total of 7199 bed days. Implantable cardioverter-defibrillator and cardiac resynchronisation therapy defibrillator devices incurred higher reimbursement costs (70.5% and 68.7% higher, respectively, both p<0.001). Heart failure and prior valve surgery also incurred significantly higher reimbursement costs. Prior valve surgery and heart failure were associated with 8.3 (p=0.017) and 5.5 (p=0.021) additional days in hospital, respectively.
Conclusions
Financial costs to the NHS from TLE are substantial. Consideration should therefore be given to cost/resource-sparing potential of leadless/extravascular cardiac devices that negate the need for TLE particularly in patients with prior valve surgery and/or heart failure. Additionally, use of antibiotic envelopes and other interventions that reduce infection risk in patients receiving transvenous leads should be considered.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Jan 2020; epub ahead of print
Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Heart: 12 Jan 2020; epub ahead of print | PMID: 31932286
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Impact:
Abstract

First-Ever Ischemic Stroke and Incident Major Adverse Cardiovascular Events in 93 627 Older Women and Men.

Sposato LA, Lam M, Allen B, Shariff SZ, Saposnik G

Background and Purpose- Stroke risk is sex-specific, but little is known about sex differences of poststroke major adverse cardiovascular events (MACEs). Stroke-related brain damage causes autonomic dysfunction and inflammation, sometimes resulting in cardiac complications. Sex-specific cardiovascular susceptibility to stroke without the confounding effect of preexisting heart disease constitutes an unexplored field because previous studies focusing on sex differences in poststroke MACE have not excluded patients with known cardiovascular comorbidities. We therefore investigated sex-specific risks of incident MACE in a heart disease-free population-based cohort of patients with first-ever ischemic stroke and propensity-matched individuals without stroke. Methods- We included Ontario residents ≥66 years, without known cardiovascular comorbidities, with first-ever ischemic stroke between 2002 and 2012 and propensity-matched individuals without stroke. We investigated the 1-year risk of incident MACE (acute coronary syndrome, myocardial infarction, incident coronary artery disease, coronary revascularization procedures, incident heart failure, or cardiovascular death) separately for females and males. For estimating cause-specific adjusted hazard ratios, we adjusted Cox models for variables with weighted standardized differences >0.10 or those known to influence MACE risk. Results- We included 93 627 subjects without known cardiovascular comorbidities; 21 931 with first-ever ischemic stroke and 71 696 propensity-matched subjects without stroke. Groups were well-balanced on propensity-matching variables. There were 53 476 women (12 421 with and 41 055 without ischemic stroke) and 40 151 men (9510 with and 30 641 without ischemic stroke). First-ever ischemic stroke was associated with increased risk of incident MACE in both sexes. The risk was time-dependent, highest within 30 days (women: adjusted hazard ratio, 25.1 [95% CI, 19.3-32.6]; men: aHR, 23.4 [95% CI, 17.2-31.9]) and decreasing but remaining significant between 31 and 90 days (women: aHR, 4.8 [95% CI, 3.8-6.0]; men: aHR, 4.2 [95% CI, 3.3-5.4]), and 91 to 365 days (aHR, 2.1 [95% CI, 1.8-2.3]; men: aHR, 2.0 [95% CI, 1.7-2.3]). Conclusions- In this large population-based study, ischemic stroke was independently associated with increased risk of incident MACE in both sexes.



Stroke: 08 Jan 2020:STROKEAHA119028066; epub ahead of print
Sposato LA, Lam M, Allen B, Shariff SZ, Saposnik G
Stroke: 08 Jan 2020:STROKEAHA119028066; epub ahead of print | PMID: 31914883
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Impact:
Abstract

Enhanced CaMKII-Dependent Late I Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing.

Lebek S, Pichler K, Reuthner K, Trum M, ... Arzt M, Wagner S

Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis.We hypothesized that CaMKII-dependent dysregulation of Na current (I) may contribute to atrial pro-arrhythmic activity in SDB patients.We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index, AHI {greater than or equal to}15/h) was assessed with a portable SDB monitor the night before surgery. Compared to 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I. There was a significantly enhanced late I but reduced peak I due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions (PACs) in atrial trabeculae of SDB patients, which could be blocked by either AIP or KN93. In multivariable linear regression models incorporating age, gender, body mass index, existing AF, existing heart failure, diabetes and creatinine levels, AHI was independently associated with increased CaMKII activity, enhanced late I and correlated with PAC severity.In atrial myocardium of SDB patients, increased CaMKII-dependent phosphorylation of Na1.5 results in dysregulation of I with pro-arrhythmic activity that was independent from pre-existing co-morbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.



Circ Res: 05 Jan 2020; epub ahead of print
Lebek S, Pichler K, Reuthner K, Trum M, ... Arzt M, Wagner S
Circ Res: 05 Jan 2020; epub ahead of print | PMID: 31902278
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Impact:
Abstract

Cardiac monocytes and macrophages after myocardial infarction.

Peet C, Ivetic A, Bromage DI, Shah AM

Improvements in early interventions after acute myocardial infarction (AMI), notably the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart. However, maladaptive immune cell behaviour contributes to ventricular remodelling in mouse models, prompting experimental efforts to modulate the immune response to prevent the development of HF. Seminal work in macrophage biology defined macrophages as monocyte-derived cells that are comprised of two populations, pro-inflammatory M1 macrophages and reparative M2 macrophages, and initial investigations into cardiac macrophage populations following AMI suggested they aligned well to this model. However, more recent data, in the heart and other tissues, demonstrate remarkable heterogeneity and plasticity in macrophage development, phenotype and function. These recent insights into macrophage biology may explain the failure of non-specific immunosuppressive strategies and offer novel opportunities for therapeutic targeting to prevent HF following AMI. Here we summarise the traditional monocyte-macrophage paradigm, experimental evidence for the significance of these cells in HF after AMI, and the potential relevance of emerging evidence that refutes canonical models of monocyte and macrophage biology.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 15 Dec 2019; epub ahead of print
Peet C, Ivetic A, Bromage DI, Shah AM
Cardiovasc Res: 15 Dec 2019; epub ahead of print | PMID: 31841135
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Impact:
Abstract

NADPH oxidase-4 promotes eccentric cardiac hypertrophy in response to volume overload.

Schnelle M, Sawyer I, Anilkumar N, Mohamed BA, ... Hasenfuss G, Shah AM
Aims
Chronic pressure or volume overload induce concentric versus eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species (ROS)-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.
Methods and results
We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4-/-) versus wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4-/- mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs 0.27, p < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs 43%, p < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs 379 μm2, p < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice whereas levels decreased in Nox4-/- mice (+29% vs -21%, p < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4-/- mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A (PP2A).
Conclusion
Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.
Translational perspective
Cardiac volume overload resulting, for example, from aortic or mitral regurgitation contributes to the development of heart failure. Its underlying pathophysiology differs from that of cardiac pressure overload. Our study identifies the reactive oxygen species generating enzyme NADPH oxidase-4 (Nox4) as an important regulator of volume overload-induced cardiac remodelling by promoting eccentric LV hypertrophy, an adaptive response to the increased volume. As Nox inhibition is currently being developed as a potential therapeutic approach for several human diseases (e.g. lung fibrosis), our findings highlight the importance of assessing the potential impact on cardiac function in patients with co-existent valvular regurgitation.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 09 Dec 2019; epub ahead of print
Schnelle M, Sawyer I, Anilkumar N, Mohamed BA, ... Hasenfuss G, Shah AM
Cardiovasc Res: 09 Dec 2019; epub ahead of print | PMID: 31821410
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Abstract

Myocardial slices come to age: An intermediate complexity in vitro cardiac model for translational research.

Pitoulis FG, Watson SA, Perbellini F, Terracciano CM

Although past decades have witnessed significant reductions in mortality of heart failure together with advances in our understanding of its cellular, molecular, and whole-heart features, a lot of basic cardiac research still fails to translate into clinical practice. In this review we examine myocardial slices, a novel model in the translational arena. Myocardial slices are living ultra-thin sections of heart tissue. Slices maintain the myocardium\'s native function (contractility, electrophysiology) and structure (multicellularity, extracellular matrix), and can be prepared from animal and human tissue. The discussion begins with the history and current advances in the model, the different interlaboratory methods of preparation and their potential impact on results. We then contextualise slices\' advantages and limitations by comparing it with other cardiac models. Recently, sophisticated methods have enabled slices to be cultured chronically in vitro while preserving the functional and structural phenotype. This is more timely now than ever where chronic physiologically relevant in vitro platforms for assessment of therapeutic strategies are urgently needed. We interrogate the technological developments that have permitted this, their limitations, and future directions. Finally, we look into the general obstacles faced by the translational field, and how implementation of research systems utilising slices could help in resolving these.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Dec 2019; epub ahead of print
Pitoulis FG, Watson SA, Perbellini F, Terracciano CM
Cardiovasc Res: 22 Dec 2019; epub ahead of print | PMID: 31868875
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Abstract

Characteristics and outcomes of patients with normal left atrial pressure undergoing transcatheter mitral valve repair.

Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Objective
A subset of patients at the time of transcatheter mitral valve repair (TMVR) will have normal left atrial pressure (LAP) (<13 mm Hg) despite having severe mitral regurgitation (MR). The goal of this study was to determine clinical characteristics and outcomes in patients with normal LAP undergoing TMVR.
Methods
A single-centre retrospective cohort of consecutive patients who underwent transcatheter edge-to-edge mitral valve clip and continuous LAP monitoring between 5/1/2014 and 5/1/2018 was analysed. One-year mortality was compared by Kaplan-Meier survival curves. Multivariable analysis was performed to identify predictors of normal LAP and 1 year mortality.
Results
Of the 204 patients undergoing TMVR, 65% were men and the mean age was 81. Of these patients, 31 (15%) had normal LAP (mean LAP 10.5 mm Hg, mean V wave 16.5 mm Hg) and 173 had elevated LAP (mean LAP 19 mm Hg, mean V wave 32.5 mm Hg). The prevalence of severe MR was not different between groups, although the normal LAP group had significantly lower effective regurgitant orifice area and regurgitant volume. Other notable baseline characteristics including prior cardiac surgery, atrial fibrillation, hypertension, diabetes, congestive heart failure, body mass index, mechanism of MR and ejection fraction were similar between groups. However, there was an increased prevalence of chronic lung disease (CLD) (45.2% vs 17.3%, p<0.001) in the normal LAP group. On multivariate analysis, the only significant predictor of normal LAP was the presence of CLD (OR 4.79 (1.83-12.36), p=0.001) and 1-year mortality was significantly higher in the normal LAP group (32.3% vs 12.7%, p=0.006). After adjustment for comorbidities, normal LAP was no longer a predictor of 1-year mortality (RR 1.62 (0.64-4.06), p=0.32); however, CLD (RR 3.44 (1.37-8.67), p=0.01) remained a statistically significant predictor.
Conclusion
Normal LAP at the time of TMVR is associated with a higher incidence of CLD which independently predicts increased 1-year mortality. In patients with CLD and apparently severe MR, measurement of LAP may help identify those with lower likelihood of benefit from TMVR.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 23 Jan 2020; epub ahead of print
Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Heart: 23 Jan 2020; epub ahead of print | PMID: 31980440
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Abstract

Brain Damage with Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline.

Mueller K, Thiel F, Beutner F, Teren A, ... Villringer A, Schroeter ML

Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF, however, the underlying mechanisms leading to the observed brain changes remain unclear. To study the relationship between impaired heart function, hampered blood circulation and structural brain change in a case-control study.Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain\'s gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain\'s gray matter. Moreover, we also obtained a relationship between GMD and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) - a biomarker that is used for screening, diagnosis and prognosis of HF. Here we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.We obtained significant correlations between brain structure and markers of heart failure including EF and NT-proBNP. A diminished GMD was found with decreased EF and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition, however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.



Circ Res: 22 Jan 2020; epub ahead of print
Mueller K, Thiel F, Beutner F, Teren A, ... Villringer A, Schroeter ML
Circ Res: 22 Jan 2020; epub ahead of print | PMID: 31969053
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Abstract

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodeling.

Guichard JB, Xiong F, Qi XY, L\'Heureux N, ... Costa AD, Nattel S
Aims
No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial versus associated ventricular arrhythmia to remodeling. This study assessed the roles of atrial arrhythmia versus high ventricular rate in AF-associated remodeling.
Methods and results
Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-bpm atrial-tachypacing maintaining AF (AF w/o-AVB); atrial-tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80-bpm); 160-bpm ventricular-tachypacing (V160) reproducing the response-rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-bpm (CTL). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF-groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF-groups (w/o-AVB and AF+AVB) and modestly in V160. AF-duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene upregulation only in AF w/o-AVB. Connexin43 gene-expression was reduced only in AF w/o-AVB. An additional group of 240-bpm ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: versus other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF-duration, strongly decreased left-ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation.
Conclusions
The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control.
Translational perspective
AF often produces a rapid and irregular arrhythmia in both the atria and ventricles. This study evaluates the contributions of AF-induced atrial versus ventricular arrhythmia to atrial remodeling. Each component produced discrete features: AF-induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing and moderate atrial fibrosis; whereas ventricular arrhythmia slightly increased vulnerability, slowed conduction and induced moderate fibrosis without affecting repolarization/refractoriness,. Combined atrial and ventricular arrhythmia abbreviated refractoriness, strongly increased vulnerability and fibrosis and greatly increased AF stability/duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt heart failure; further research is needed to clarify the clinical relevance of these findings.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 23 Jan 2020; epub ahead of print
Guichard JB, Xiong F, Qi XY, L'Heureux N, ... Costa AD, Nattel S
Cardiovasc Res: 23 Jan 2020; epub ahead of print | PMID: 31977017
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Abstract

GHSR Deficiency Exacerbates Cardiac Fibrosis: Role in Macrophage Inflammasome Activation and Myofibroblast Differentiation.

Wang M, Qian L, Li J, Ming H, ... Liu Y, Wang N
Aims
Sustained activation of β-adrenergic signaling induces cardiac fibrosis, which marks progression to heart failure. GHSR (growth hormone secretagogue receptor) is the receptor for ghrelin, which is an orexigenic gastric hormone with newly defined cardiovascular effects. The present study determined the effects of GHSR deficiency in a mouse model of isoproterenol (ISO)-induced cardiac fibrosis and examined the underlying mechanism.
Methods and results
Histochemical studies showed that GHSR deficiency exacerbated cardiac fibrosis. Quantitative RT-PCR, western blotting and immunofluorescence staining demonstrated that cardiac fibroblasts isolated from GHSR-/- mice exhibited increased expression of marker genes for myofibroblast trans-differentiation (α-SMA, SM22, and calponin) upon Transforming growth factor-β (TGF-β) treatment compared to wild-type mice. RNA-Sequencing of heart transcriptomes revealed that differentially expressed genes in GHSR-/- hearts were enriched in such biological processes as extracellular matrix (ECM) organization, inflammatory response, lipid metabolism, cell cycle, migration and adhesion. Particularly, GHSR deficiency increased Wnt/β-catenin pathway activation in ISO-induced myocardial fibrosis. In addition, loss of GHSR in macrophages instigated inflammasome activation with increased cleavage and release of IL-18.
Conclusions
These results for the first time demonstrated that GHSR deficiency aggravated ISO-induced cardiac fibrosis, suggesting that GHSR was a potential target for the intervention of cardiac fibrosis.
Translational perspective
We revealed a cardiac protective role of GHSR, a receptor for gastric hormone ghrelin. Our study provided a novel therapeutic strategy against cardiac fibrosis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions please email: [email protected]

Cardiovasc Res: 01 Dec 2019; epub ahead of print
Wang M, Qian L, Li J, Ming H, ... Liu Y, Wang N
Cardiovasc Res: 01 Dec 2019; epub ahead of print | PMID: 31790138
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Abstract

Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.

Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Aims
Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic postganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF.
Methods and results
Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time PCR and Western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry ECG recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/fibrillation (VT/VF), but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats.
Conclusions
Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.
Translational perspectives
Our present study demonstrates that inhibition of N-type Ca2+ channels in CSP neurons attenuates CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias. The clinical significance of this study is to open a new avenue in therapeutics working against lethal ventricular arrhythmias in patients with CHF. N-type Ca2+ channels in CSP neurons could be a new therapeutic target for cardiac sympathetic overactivation and ventricular arrhythmias in CHF. Exploring specific, small-molecule N-type Ca2+ channel blockers with local targeting drug delivery system could translate to clinical trials and applications that improve outcomes for patients with CHF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 28 Jan 2020; epub ahead of print
Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Cardiovasc Res: 28 Jan 2020; epub ahead of print | PMID: 31995173
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Abstract

Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signalling.

Tual-Chalot S, Garcia-Collado M, Redgrave RE, Singh E, ... Jakobsson L, Arthur HM

Endoglin (ENG) is a co-receptor for BMP9/10, and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder Hereditary Haemorrhagic Telangiectasia (HHT) characterised by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood. The goal of the work was to determine how ENG maintains vessel calibre in adult life to prevent AVM formation and thereby protect heart function.Genetic depletion of endothelial ENG in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of haemorrhage, anaemia or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis, a non-capsulated cartilage with a naturally high endogenous expression of vascular endothelial growth factor (VEGF). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure (HOHF). Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells (ECs) leads to increased sensitivity to VEGF and a hyper-proliferative response. Development of AVMs and associated progression to HOHF in the absence of endothelial ENG was attenuated by targeting VEGF signalling with an anti-VEGFR2 antibody.ENG promotes the normal balance of VEGF signalling in quiescent ECs to maintain vessel calibre, an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.



Circ Res: 05 Dec 2019; epub ahead of print
Tual-Chalot S, Garcia-Collado M, Redgrave RE, Singh E, ... Jakobsson L, Arthur HM
Circ Res: 05 Dec 2019; epub ahead of print | PMID: 31805812
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Abstract

Coagulation factor VIII: Relationship to Cardiovascular Disease Risk and Whole Genome Sequence and Epigenome-Wide Analysis in African Americans.

Raffield LM, Lu AT, Szeto MD, Little A, ... Zakai NA, Reiner AP
Background
Prospective studies have suggested higher factor VIII (FVIII) levels is an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans.
Objectives
We measured FVIII levels in ~3,400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations.
Methods
We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array.
Results
Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant.
Conclusions
Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.

© 2020 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 26 Jan 2020; epub ahead of print
Raffield LM, Lu AT, Szeto MD, Little A, ... Zakai NA, Reiner AP
J Thromb Haemost: 26 Jan 2020; epub ahead of print | PMID: 31985870
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