Topic: Journal Club Selection

Abstract

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
Background
There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.
Methods
We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke.
Results
At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery.
Conclusions
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 Mar 2020; 382
Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
N Engl J Med: 26 Mar 2020; 382 | PMID: 31995682
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Abstract

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
Background
Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.
Objectives
This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.
Methods
Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).
Results
Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).
Conclusions
Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

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

J Am Coll Cardiol: 10 Feb 2020; 75:512-521
Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
J Am Coll Cardiol: 10 Feb 2020; 75:512-521 | PMID: 32029134
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Abstract

Long-Term Outcomes and Associations With Major Adverse Limb Events After Peripheral Artery Revascularization.

Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
Background
Long-term cardiovascular and limb outcomes after revascularization for peripheral artery disease and, in particular, prognosis after post-procedure major adverse limb events (MALE) are not well-studied.
Objectives
This study sought to describe outcomes after peripheral revascularization and assess relationships between post-procedure MALE hospitalization and subsequent events.
Methods
Patients undergoing peripheral artery revascularization between January 1, 2009, and September 30, 2015, in the Premier Healthcare Database were examined for the co-primary outcomes of interest, composite myocardial infarction (MI) or stroke and composite major amputation or peripheral revascularization. Multivariable adjusted Cox proportional hazards models with post-procedure MALE hospitalization included as a time-dependent covariate were developed to estimate hazard ratios for outcomes.
Results
Among 393,017 revascularized patients followed for a median of 2.7 years (interquartile range: 1.3 to 4.4 years), the cumulative incidence of MI or stroke was 9.8% and that of major amputation or peripheral revascularization was 41.9%. A total of 50,750 patients (12.9%) had at least 1 post-procedure MALE hospitalization. In time-dependent covariate adjusted models, post-procedure MALE hospitalization was associated with greater risk of subsequent MI or stroke (hazard ratio: 1.34; 95% confidence interval: 1.28 to 1.40) and major amputation or peripheral revascularization (hazard ratio: 8.13; 95% confidence interval: 7.96 to 8.29). After peripheral revascularization with or without post-procedure MALE hospitalization, risk of limb events increased rapidly post-procedure and more slowly after the first year, whereas cardiac risk increased steadily during follow-up.
Conclusions
Revascularized peripheral artery disease patients face earlier limb and later cardiovascular ischemic risk that is heightened among patients with post-procedure MALE hospitalization. Increased provider awareness of these long-term risks may guide efforts to improve post-procedural outcomes.

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

J Am Coll Cardiol: 10 Feb 2020; 75:498-508
Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
J Am Coll Cardiol: 10 Feb 2020; 75:498-508 | PMID: 32029132
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Abstract

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease.

Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
Background
Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.
Objectives
The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.
Methods
Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.
Results
EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.
Conclusions
Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

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

J Am Coll Cardiol: 17 Feb 2020; 75:608-617
Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
J Am Coll Cardiol: 17 Feb 2020; 75:608-617 | PMID: 32057375
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Abstract

Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention.

Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
Background
The majority of stent-related major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are believed to occur within the first year. Very-late (>1-year) stent-related MACE have not been well described.
Objectives
The purpose of this study was to assess the frequency and predictors of very-late stent-related events or MACE by stent type.
Methods
Individual patient data from 19 prospective, randomized metallic stent trials maintained at a leading academic research organization were pooled. Very-late MACE (a composite of cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]), and target lesion failure (cardiac death, target-vessel MI, or ID-TLR) were assessed within year 1 and between 1 and 5 years after PCI with bare-metal stents (BMS), first-generation drug-eluting stents (DES1) and second-generation drug-eluting stents (DES2). A network meta-analysis was performed to evaluate direct and indirect comparisons.
Results
Among 25,032 total patients, 3,718, 7,934, and 13,380 were treated with BMS, DES1, and DES2, respectively. MACE rates within 1 year after PCI were progressively lower after treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1%, respectively, p < 0.0001). Between years 1 and 5, very-late MACE occurred in 9.4% of patients (including 2.9% cardiac death, 3.1% MI, and 5.1% ID-TLR). Very-late MACE occurred in 9.7%, 11.0%, and 8.3% of patients treated with BMS, DES1, and DES2, respectively (p < 0.0001), linearly increasing between 1 and 5 years. Similar findings were observed for target lesion failure in 19,578 patients from 12 trials. Findings were confirmed in the network meta-analysis.
Conclusions
In this large-scale, individual patient data pooled study, very-late stent-related events occurred between 1 and 5 years after PCI at a rate of ∼2%/year with all stent types, with no plateau evident. New approaches are required to improve long-term outcomes after PCI.

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

J Am Coll Cardiol: 17 Feb 2020; 75:590-604
Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
J Am Coll Cardiol: 17 Feb 2020; 75:590-604 | PMID: 32057373
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Abstract

Short-Term Hemodynamic and Electrophysiological Effects of Cardiac Resynchronization by Left Ventricular Septal Pacing.

Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
Background
Cardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated.
Objectives
The authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients.
Methods
Temporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax).
Results
As compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 ± 22 μVs) and SDAT (to 26 ± 7 ms) than BiV (to 93 ± 26 μVs and 31 ± 7 ms; both p < 0.05) and LVs+RV pacing (to 108 ± 37 μVs; p < 0.05; and 29 ± 8 ms; p = 0.05). The increase in LVdP/dtmax was similar during LVs and BiV pacing (17 ± 10% vs. 17 ± 9%, respectively) and larger than during LVs+RV pacing (11 ± 9%; p < 0.05). There were no significant differences between basal, mid-, or apical LVs levels in LVdP/dtmax and SDAT. In a subgroup of 16 patients, changes in QRS area, SDAT, and LVdP/dtmax were comparable between LVs and HB pacing.
Conclusions
LVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT.

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

J Am Coll Cardiol: 03 Feb 2020; 75:347-359
Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
J Am Coll Cardiol: 03 Feb 2020; 75:347-359 | PMID: 32000945
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Abstract

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

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

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
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Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

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: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
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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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Abstract

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Aims
Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF.
Methods and results
We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95).
Conclusion
Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

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: 10 Feb 2020; epub ahead of print
Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047884
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Abstract

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction.

Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
Background
Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
Objectives
The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.
Methods
In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).
Results
Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.
Conclusions
Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295
Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295 | PMID: 32192654
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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

Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.

Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
Background
Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.
Objectives
The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.
Methods
To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.
Results
At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.
Conclusions
The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174
Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174 | PMID: 32164890
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Abstract

Prognostic Value of Left Ventricular Global Longitudinal Strain in Patients With Secondary Mitral Regurgitation.

Namazi F, van der Bijl P, Hirasawa K, Kamperidis V, ... Delgado V, Bax JJ
Background
Left ventricular (LV) systolic function may be overestimated in patients with secondary mitral regurgitation (MR) when using LV ejection fraction (EF). LV global longitudinal strain (GLS) is a less load-dependent measure of LV function. However, the prognostic value of LV GLS in secondary MR has not been evaluated.
Objectives
This study sought to demonstrate the prognostic value of LV GLS over LVEF in patients with secondary MR.
Methods
A total of 650 patients (mean 66 ± 11 years of age, 68% men) with significant secondary MR were included. The study population was subdivided based on the LV GLS value at which the hazard ratio (HR) for all-cause mortality was >1 using a spline curve analysis (LV GLS <7.0%, impaired LV systolic function vs. LV GLS ≥7.0%, preserved LV systolic function). The primary endpoint was all-cause mortality.
Results
During a median follow-up of 56 (interquartile range: 28 to 106 months) months, 334 (51%) patients died. Patients with a more impaired LV GLS showed significantly higher mortality rates at 1-, 2-, and 5-year follow-up (13%, 23%, and 44%, respectively) when compared with patients with more preserved LV systolic function (5%, 14%, and 31%, respectively). On multivariable analysis, LV GLS <7.0% was associated with increased mortality (HR: 1.337; 95% confidence interval: 1.038 to 1.722; p = 0.024), whereas LVEF ≤30% was not (HR: 1.055; 95% confidence interval: 0.794 to 1.403; p = 0.711).
Conclusions
In patients with secondary MR, impaired LV GLS was independently associated with an increased risk for all-cause mortality, whereas LVEF was not. LV GLS may therefore be useful in the risk stratification of patients with secondary MR.

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

J Am Coll Cardiol: 24 Feb 2020; 75:750-758
Namazi F, van der Bijl P, Hirasawa K, Kamperidis V, ... Delgado V, Bax JJ
J Am Coll Cardiol: 24 Feb 2020; 75:750-758 | PMID: 32081284
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Abstract

Transcatheter Correction of Superior Sinus Venosus Atrial Septal Defects as an Alternative to Surgical Treatment.

Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
Background
The superior sinus venosus atrial septal defect (SVASD) is characterized by deficiency of the common wall between the superior vena cava (SVC) and the right upper pulmonary vein (RUPV), which is no longer committed to the left atrium.
Objectives
This study sought to evaluate the potential for redirecting the SVC and RUPV flow to the right and left atria, respectively, by implantation of a covered stent in the SVC.
Methods
Review of 48 consecutive adult SVASD patients undergoing assessment for correction. Pre-procedural evaluation included cross-sectional imaging and ex vivo simulation using printed or virtual 3-dimensional models.
Results
Transcatheter correction was performed in 25 patients, with a further 6 awaiting stent implantation. Only 8 patients were deemed technically unsuitable. The procedure involved balloon test inflation in the anticipated stent landing zone with simultaneous transesophageal echocardiography and pulmonary venography to confirm defect closure and unobstructed pulmonary venous drainage, followed by deployment of a 10-zig covered Cheatham platinum stent. Stents of lengths between 5 and 8 cm were implanted. A second, uncovered stent was used for anchoring in 9 patients. The RUPV was protected with a high-pressure balloon during stent implantation to prevent pulmonary venous obstruction in 4 patients. The median follow-up period was 1.4 (interquartile range: 0.8 to 1.7) years, with no mortality. Stent embolization occurred in 1 patient; another required drainage of hemopericardium. Cardiac computed tomography after 3 months confirmed unobstructed pulmonary venous return. At latest follow-up, a residual shunt was present in 1 patient.
Conclusions
Transcatheter correction of SVASD may be considered as an alternative to surgery in a substantial proportion of patients.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278
Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278 | PMID: 32192652
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Abstract

Tricuspid Intervention Following Pulmonary Valve Replacement in Adults With Congenital Heart Disease.

Deshaies C, Trottier H, Khairy P, Al-Aklabi M, ... Poirier NC,
Background
Tricuspid regurgitation (TR) is common among adults with corrected tetralogy of Fallot (TOF) or pulmonary stenosis (PS) referred for pulmonary valve replacement (PVR). Yet, combined valve surgery remains controversial.
Objectives
This study sought to evaluate the impact of concomitant tricuspid valve intervention (TVI) on post-operative TR, length of hospital stay, and on a composite endpoint consisting of 7 early adverse events (death, reintervention, cardiac electronic device implantation, infection, thromboembolic event, hemodialysis, and readmission).
Methods
The national Canadian cohort enrolled 542 patients with TOF or PS and mild to severe TR who underwent isolated PVR (66.8%) or PVR+TVI (33.2%). Outcomes were abstracted from charts and compared between groups using multivariable logistic and negative binomial regression.
Results
Median age at reintervention was 35.3 years. Regardless of surgery type, TR decreased by at least 1 echocardiographic grade in 35.4%, 66.9%, and 92.8% of patients with pre-operative mild, moderate, and severe insufficiency. In multivariable analyses, PVR+TVI was associated with an additional 2.3-fold reduction in TR grade (odds ratio [OR]: 0.44; 95% confidence interval [CI]: 0.25 to 0.77) without an increase in early adverse events (OR: 0.85; 95% CI: 0.46 to 1.57) or hospitalization time (incidence rate ratio: 1.17; 95% CI: 0.93 to 1.46). Pre-operative TR severity and presence of transvalvular leads independently predicted post-operative TR. In contrast, early adverse events were strongly associated with atrial tachyarrhythmia, extracardiac arteriopathy, and a high body mass index.
Conclusions
In patients with TOF or PS and significant TR, concomitant TVI is safe and results in better early tricuspid valve competence than isolated PVR.

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

J Am Coll Cardiol: 09 Mar 2020; 75:1033-1043
Deshaies C, Trottier H, Khairy P, Al-Aklabi M, ... Poirier NC,
J Am Coll Cardiol: 09 Mar 2020; 75:1033-1043 | PMID: 32138963
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Abstract

Complement C5 Protein as a Marker of Subclinical Atherosclerosis.

Martínez-López D, Roldan-Montero R, García-Marqués F, Nuñez E, ... Vázquez J, Martin-Ventura JL
Background
The mechanisms underlying early atherosclerotic plaque formation are not completely understood. Moreover, plasma biomarkers of subclinical atherosclerosis are lacking.
Objectives
The purpose of this study was to analyze the temporal and topologically resolved protein changes taking place in human aortas with early atherosclerosis to find new potential diagnostic and/or therapeutic targets.
Methods
The protein composition of healthy aortas (media layer) or with early atheroma (fatty streak and fibrolipidic, media and intima layers) was analyzed by deep quantitative multiplexed proteomics. Further analysis was performed by Western blot, immunohistochemistry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. Plasma levels of complement C5 were analyzed in relation to the presence of generalized (>2 plaques) or incipient (0 to 2 plaques) subclinical atherosclerosis in 2 independent clinical cohorts (PESA [Progression of Early Subclinical Atherosclerosis] [n = 360] and NEFRONA [National Observatory of Atherosclerosis in Nephrology] [n = 394]).
Results
Proteins involved in lipid transport, complement system, immunoglobulin superfamily, and hemostasis are increased in early plaques. Components from the complement activation pathway were predominantly increased in the intima of fibrolipidic plaques. Among them, increased C5 protein levels were further confirmed by Western blot, enzyme-linked immunosorbent assay and immunohistochemistry, and associated with in situ complement activation. Plasma C5 was significantly increased in individuals with generalized subclinical atherosclerosis in both PESA and NEFRONA cohorts, independently of risk factors. Moreover, in the PESA study, C5 plasma levels positively correlated with global plaque volume and coronary calcification.
Conclusions
Activation of the complement system is a major alteration in early atherosclerotic plaques and is reflected by increased C5 plasma levels, which have promising value as a novel circulating biomarker of subclinical atherosclerosis.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Apr 2020; 75:1926-1941
Martínez-López D, Roldan-Montero R, García-Marqués F, Nuñez E, ... Vázquez J, Martin-Ventura JL
J Am Coll Cardiol: 27 Apr 2020; 75:1926-1941 | PMID: 32327104
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Abstract

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.

Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G

The cAMP-hydrolyzing phosphodiesterase 4B (PDE4B) is a key negative regulator of cardiac β-adrenergic receptor (β-AR) stimulation. PDE4B deficiency leads to abnormal Ca handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure (HF).We measured PDE4B expression in human cardiac tissues, developed two transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B (PDE4B-TG), and an adeno-associated virus serotype 9 encoding PDE4B (AAV9-PDE4B). Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Cyclic AMP and PKA activity were monitored by Förster resonance energy transfer, I by whole cell patch-clamp, and cardiomyocyte shortening and Ca transients with an Ionoptix system. HF was induced by 2 weeks infusion of isoproterenol (Iso) or transverse aortic constriction (TAC). Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis and histology.PDE4B protein was decreased in human failing hearts. The first PDE4B-TG mouse line (TG15) had a ~15-fold increase in cardiac cAMP-PDE activity and a ~30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basalmyocardial function was unchanged, but β-AR stimulation of cardiac inotropy, cAMP, PKA, I, Ca transients and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion and fibrosis induced by chronic Iso treatment. In the second PDE4B-TG mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ~50-fold increase in cardiac cAMP-PDE activity caused a ~50% decrease in fractional shortening, hypertrophy, dilatation and premature death. In contrast, mice injected with AAV9-PDE4B (10 viral particles/mouse) had a ~50% increase in cardiac cAMP-PDE activity which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis and fibrosis, while attenuating hypertrophy induced by chronic Iso infusion. Similarly, AAV9-PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion and prevented apoptosis and fibrotic remodeling in TAC.Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat HF.



Circulation: 07 Apr 2020; epub ahead of print
Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G
Circulation: 07 Apr 2020; epub ahead of print | PMID: 32264695
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Abstract

The associations of major foods and fibre with risks of ischaemic and haemorrhagic stroke: a prospective study of 418 329 participants in the EPIC cohort across nine European countries.

Tong TYN, Appleby PN, Key TJ, Dahm CC, ... Butterworth AS, Perez-Cornago A
Aim
To investigate the associations between major foods and dietary fibre with subtypes of stroke in a large prospective cohort.
Methods and results
We analysed data on 418 329 men and women from nine European countries, with an average of 12.7 years of follow-up. Diet was assessed using validated country-specific questionnaires which asked about habitual intake over the past year, calibrated using 24-h recalls. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HRs) for ischaemic and haemorrhagic stroke associated with consumption of red and processed meat, poultry, fish, dairy foods, eggs, cereals, fruit and vegetables, legumes, nuts and seeds, and dietary fibre. For ischaemic stroke (4281 cases), lower risks were observed with higher consumption of fruit and vegetables combined (HR; 95% CI per 200 g/day higher intake, 0.87; 0.82-0.93, P-trend < 0.001), dietary fibre (per 10 g/day, 0.77; 0.69-0.86, P-trend < 0.001), milk (per 200 g/day, 0.95; 0.91-0.99, P-trend = 0.02), yogurt (per 100 g/day, 0.91; 0.85-0.97, P-trend = 0.004), and cheese (per 30 g/day, 0.88; 0.81-0.97, P-trend = 0.008), while higher risk was observed with higher red meat consumption which attenuated when adjusted for the other statistically significant foods (per 50 g/day, 1.07; 0.96-1.20, P-trend = 0.20). For haemorrhagic stroke (1430 cases), higher risk was associated with higher egg consumption (per 20 g/day, 1.25; 1.09-1.43, P-trend = 0.002).
Conclusion
Risk of ischaemic stroke was inversely associated with consumption of fruit and vegetables, dietary fibre, and dairy foods, while risk of haemorrhagic stroke was positively associated with egg consumption. The apparent differences in the associations highlight the importance of examining ischaemic and haemorrhagic stroke subtypes separately.

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

Eur Heart J: 23 Feb 2020; epub ahead of print
Tong TYN, Appleby PN, Key TJ, Dahm CC, ... Butterworth AS, Perez-Cornago A
Eur Heart J: 23 Feb 2020; epub ahead of print | PMID: 32090257
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Abstract

Integrin β1D Deficiency-Mediated RyR2 Dysfunction Contributes to Catecholamine-Sensitive Ventricular Tachycardia in ARVC.

Wang Y, Li C, Shi L, Chen X, ... Song LS, Zhao S

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary heart disease characterized by fatty infiltration, life-threatening arrhythmias and increased risk of sudden cardiac death (SCD). The guideline for management of ARVC patients is to improve quality of life by reducing arrhythmic symptoms and to prevent SCD. However, the mechanism underlying ARVC-associated cardiac arrhythmias remains poorly understood.Using protein mass spectrometry analyses, we identified integrin β1 is down-regulated in ARVC hearts without changes to Ca-handling proteins. As adult cardiomyocytes express only the β1D isoform, we generated a cardiac specific β1D knockout (β1D) mouse model, and performed functional imaging and biochemical analyses to determine the consequences from integrin β1D loss of function in the heart in vivo and in vitro.Integrin β1D deficiency and RyR2 Ser-2030 hyper-phosphorylation were detected by western blotting in left ventricular tissues from patients with ARVC but not in patients with ischemic or hypertrophic cardiomyopathy. Using lipid bilayer patch clamp single channel recordings, we found purified integrin β1D protein could stabilize RyR2 function by decreasing RyR2 open probability (Po), mean open time (To), and increasing mean close time (Tc). β1D mice exhibited normal cardiac function and morphology, but presented with catecholaminesensitive polymorphic ventricular tachycardia, consistent with increased RyR2 Ser-2030 phosphorylation and aberrant Ca handling in β1D cardiomyocytes. Mechanistically, we revealed that loss of desmoplakin induces integrin β1D deficiency in ARVC mediated through an ERK1/2 - fibronectin - ubiquitin/lysosome pathway.Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC.



Circulation: 02 Mar 2020; epub ahead of print
Wang Y, Li C, Shi L, Chen X, ... Song LS, Zhao S
Circulation: 02 Mar 2020; epub ahead of print | PMID: 32122157
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Abstract

Inherited Thoracic Aortic Disease: New Insights and Translational Targets.

Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.



Circulation: 11 May 2020; 141:1570-1587
Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL
Circulation: 11 May 2020; 141:1570-1587 | PMID: 32392100
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This program is still in alpha version.