Topic: General Cardiology

Abstract

Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.

Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Aims
We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding.
Methods and results
ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively].
Conclusion
Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 23 Mar 2021; epub ahead of print
Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Eur Heart J: 23 Mar 2021; epub ahead of print | PMID: 33760027
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Abstract

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Aims 
The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function.
Methods and results 
Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration.
Conclusion 
In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 25 Mar 2021; epub ahead of print
de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769473
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Abstract

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Aims
Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE).
Methods and results
We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060).
Conclusion
Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769515
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Abstract

Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients.

Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG
Background
In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non-high-density lipoprotein (non-HDL) cholesterol are secondary targets.
Objectives
This study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction.
Methods
In total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians.
Results
High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval [CI]: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction.
Conclusions
In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Mar 2021; 77:1439-1450
Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG
J Am Coll Cardiol: 22 Mar 2021; 77:1439-1450 | PMID: 33736827
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Abstract

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

Grilz E, Posch F, Nopp S, Königsbrügge O, ... Pabinger I, Ay C
Aims
An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed.
Methods and results
International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 \'C\' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]).
Conclusion
The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Grilz E, Posch F, Nopp S, Königsbrügge O, ... Pabinger I, Ay C
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769475
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Abstract

Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome.

Radfar A, Abohashem S, Osborne MT, Wang Y, ... Wood MJ, Tawakol A
Aims
Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest.
Methods and results
Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028).
Conclusion
Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Radfar A, Abohashem S, Osborne MT, Wang Y, ... Wood MJ, Tawakol A
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33768230
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Abstract

Association of the combined effects of air pollution and changes in physical activity with cardiovascular disease in young adults.

Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Aims
Little is known about the trade-off between the health benefits of physical activity (PA) and the potential harmful effects of increased exposure to air pollution during outdoor PA. We examined the association of the combined effects of air pollution and changes in PA with cardiovascular disease (CVD) in young adults.
Methods and results
This nationwide cohort study included 1 469 972 young adults aged 20-39 years. Air pollution exposure was estimated by the annual average cumulative level of particulate matter (PM). PA was calculated as minutes of metabolic equivalent tasks per week (MET-min/week) based on two consecutive health examinations from 2009 to 2012. Compared with the participants exposed to low-to-moderate levels of PM2.5 or PM10 who continuously engaged in ≥1000 MET-min/week of PA, those who decreased their PA from ≥1000 MET-min/week to 1-499 MET-min/week [PM10 adjusted hazard ratio (aHR) 1.22; 95% confidence interval (CI) 1.00-1.48] and to 0 MET-min/week (physically inactive; PM10 aHR 1.38; 95% CI 1.07-1.78) had an increased risk of CVD (P for trend <0.01). Among participants exposed to high levels of PM2.5 or PM10, the risk of CVD was elevated with an increase in PA above 1000 MET-min/week.
Conclusion
Reducing PA may lead to subsequent elevation of CVD risk in young adults exposed to low-to-moderate levels of PM2.5 or PM10, whereas a large increase in PA in a high-pollution environment may adversely affect cardiovascular health.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Mar 2021; epub ahead of print
Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Eur Heart J: 28 Mar 2021; epub ahead of print | PMID: 33780974
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Abstract

Immediate post-procedural functional assessment of percutaneous coronary intervention: current evidence and future directions.

Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Percutaneous coronary intervention (PCI) guided by coronary physiology provides symptomatic benefit and improves patient outcomes. Nevertheless, over one-fourth of patients still experience recurrent angina or major adverse cardiac events following the index procedure. Coronary angiography, the current workhorse for evaluating PCI efficacy, has limited ability to identify suboptimal PCI results. Accumulating evidence supports the usefulness of immediate post-procedural functional assessment. This review discusses the incidence and possible mechanisms behind a suboptimal physiology immediately after PCI. Furthermore, we summarize the current evidence base supporting the usefulness of immediate post-PCI functional assessment for evaluating PCI effectiveness, guiding PCI optimization, and predicting clinical outcomes. Multiple observational studies and post hoc analyses of datasets from randomized trials demonstrated that higher post-PCI functional results are associated with better clinical outcomes as well as a reduced rate of residual angina and repeat revascularization. As such, post-PCI functional assessment is anticipated to impact patient management, secondary prevention, and resource utilization. Pre-PCI physiological guidance has been shown to improve clinical outcomes and reduce health care costs. Whether similar benefits can be achieved using post-PCI physiological assessment requires evaluation in randomized clinical outcome trials.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 04 Apr 2021; epub ahead of print
Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Eur Heart J: 04 Apr 2021; epub ahead of print | PMID: 33822922
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Abstract

Long Working Hours and Risk of Recurrent Coronary Events.

Trudel X, Brisson C, Talbot D, Gilbert-Ouimet M, Milot A
Background
Evidence from prospective studies has suggested that long working hours are associated with incident coronary heart disease (CHD) events. However, no previous study has examined whether long working hours are associated with an increased risk of recurrent CHD events among patients returning to work after a first myocardial infarction (MI).
Objectives
The purpose of this study was to examine the effect of long working hours on the risk of recurrent CHD events.
Methods
This is a prospective cohort study of 967 men and women age 35 to 59 years who returned to work after a first MI. Patients were recruited from 30 hospitals across the province of Quebec, Canada. The mean follow-up duration was 5.9 years. Long working hours were assessed on average 6 weeks after their return to work. Incident CHD events (fatal or nonfatal MI and unstable angina) occurring during follow-up were determined using patients\' medical files. Hazard ratios were estimated using Cox proportional hazard regression models. Splines and fractional polynomial regressions were used for flexible exposure and time modeling.
Results
Recurrent CHD events occurred among 205 patients. Participants working long hours (≥55 h/week) had a higher risk of recurrent CHD events after controlling for sociodemographics, lifestyle-related risk factors, clinical risk factors, work environment factors, and personality factors (hazard ratio vs. 35 to 40 h/week: 1.67; 95% confidence interval: 1.10 to 2.53). These results showed a linear risk increase after 40 h/week and a stronger effect after the first 4 years of follow-up and when long working hours are combined with job strain.
Conclusions
Among patients returning to work after a first MI, longer working hours per week is associated with an increased risk of recurrent CHD events. Secondary prevention interventions aiming to reduce the number of working hours among these patients may lower the risk of CHD recurrence.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 05 Apr 2021; 77:1616-1625
Trudel X, Brisson C, Talbot D, Gilbert-Ouimet M, Milot A
J Am Coll Cardiol: 05 Apr 2021; 77:1616-1625 | PMID: 33795035
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Abstract

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Rheumatic Aortic Stenosis.

Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
Background
Patients with rheumatic aortic stenosis (AS) were excluded from transcatheter aortic valve replacement (TAVR) trials.
Objectives
The authors sought to examine outcomes with TAVR versus surgical aortic valve replacement (SAVR) in patients with rheumatic AS, and versus TAVR in nonrheumatic AS.
Methods
The authors identified Medicare beneficiaries who underwent TAVR or SAVR from October 2015 to December 2017, and then identified patients with rheumatic AS using prior validated International Classification of Diseases, Version 10 codes. Overlap propensity score weighting analysis was used to adjust for measured confounders. The primary study outcome was all-cause mortality. Multiple secondary outcomes were also examined.
Results
The final study cohort included 1,159 patients with rheumatic AS who underwent aortic valve replacement (SAVR, n = 554; TAVR, n = 605), and 88,554 patients with nonrheumatic AS who underwent TAVR. Patients in the SAVR group were younger and with lower prevalence of most comorbidities and frailty scores. After median follow-up of 19 months (interquartile range: 13 to 26 months), there was no difference in all-cause mortality with TAVR versus SAVR (11.2 vs. 7.0 per 100 person-year; adjusted hazard ratio: 1.53; 95% confidence interval: 0.84 to 2.79; p = 0.2). Compared with TAVR in nonrheumatic AS, TAVR for rheumatic AS was associated with similar mortality (15.2 vs. 17.7 deaths per 100 person-years (adjusted hazard ratio: 0.87; 95% confidence interval: 0.68 to 1.09; p = 0.2) after median follow-up of 17 months (interquartile range: 11 to 24 months). None of the rheumatic TAVR patients, <11 SAVR patients, and 242 nonrheumatic TAVR patients underwent repeat aortic valve replacement (124 redo-TAVR and 118 SAVR) at follow-up.
Conclusions
Compared with SAVR, TAVR could represent a viable and possibly durable option for patients with rheumatic AS.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713
Mentias A, Saad M, Desai MY, Krishnaswamy A, ... Kapadia S, Sarrazin MV
J Am Coll Cardiol: 12 Apr 2021; 77:1703-1713 | PMID: 33832596
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Abstract

Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.

Heerspink HJL, Sjöström CD, Jongs N, Chertow GM, ... Wheeler DC, DAPA-CKD Trial Committees and Investigators
Aims 
Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.
Methods and results 
DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.
Conclusion 
In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 30 Mar 2021; 42:1216-1227
Heerspink HJL, Sjöström CD, Jongs N, Chertow GM, ... Wheeler DC, DAPA-CKD Trial Committees and Investigators
Eur Heart J: 30 Mar 2021; 42:1216-1227 | PMID: 33792669
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Abstract

Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease.

Ten Berg J, Sibbing D, Rocca B, Van Belle E, ... Witkowski A, Mehilli J
Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 04 Apr 2021; epub ahead of print
Ten Berg J, Sibbing D, Rocca B, Van Belle E, ... Witkowski A, Mehilli J
Eur Heart J: 04 Apr 2021; epub ahead of print | PMID: 33822924
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Abstract

The physical activity paradox in cardiovascular disease and all-cause mortality: the contemporary Copenhagen General Population Study with 104 046 adults.

Holtermann A, Schnohr P, Nordestgaard BG, Marott JL
Aims 
Leisure time physical activity associates with reduced risk of cardiovascular disease and all-cause mortality, while these relationships for occupational physical activity are unclear. We tested the hypothesis that leisure time physical activity associates with reduced major adverse cardiovascular events (MACE) and all-cause mortality risk, while occupational physical activity associates with increased risks.
Methods and results 
We studied 104 046 women and men aged 20-100 years in the Copenhagen General Population Study with baseline measurements in 2003-2014 and median 10-year follow-up. Both leisure and occupational physical activity were based on self-report with four response categories. We observed 7913 (7.6%) MACE and 9846 (9.5%) deaths from all causes. Compared to low leisure time physical activity, multivariable adjusted (for lifestyle, health, living conditions, and socioeconomic factors) hazard ratios for MACE were 0.86 (0.78-0.96) for moderate, 0.77 (0.69-0.86) for high, and 0.85 (0.73-0.98) for very high activity; corresponding values for higher occupational physical activity were 1.04 (0.95-1.14), 1.15 (1.04-1.28), and 1.35 (1.14-1.59), respectively. For all-cause mortality, corresponding hazard ratios for higher leisure time physical activity were 0.74 (0.68-0.81), 0.59 (0.54-0.64), and 0.60 (0.52-0.69), and for higher occupational physical activity 1.06 (0.96-1.16), 1.13 (1.01-1.27), and 1.27 (1.05-1.54), respectively. Similar results were found within strata on lifestyle, health, living conditions, and socioeconomic factors, and when excluding individuals dying within the first 5 years of follow-up. Levels of the two domains of physical activity did not interact on risk of MACE (P = 0.40) or all-cause mortality (P = 0.31).
Conclusion 
Higher leisure time physical activity associates with reduced MACE and all-cause mortality risk, while higher occupational physical activity associates with increased risks, independent of each other.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 07 Apr 2021; epub ahead of print
Holtermann A, Schnohr P, Nordestgaard BG, Marott JL
Eur Heart J: 07 Apr 2021; epub ahead of print | PMID: 33831954
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Abstract

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

© European Society of Cardiology 2021 This article has been co-published with permission in European Heart Journal (published by Oxford University Press on behalf of European Society of Cardiology) and European Journal of Heart Failure (published by John Wiley & Sons Ltd on behalf of European Society of Cardiology) These articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Eur Heart J: 06 Apr 2021; epub ahead of print
Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Eur Heart J: 06 Apr 2021; epub ahead of print | PMID: 33825853
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Abstract

Management of Women With Acquired Cardiovascular Disease From Pre-Conception Through Pregnancy and Postpartum: JACC Focus Seminar 3/5.

Park K, Bairey Merz CN, Bello NA, Davis M, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
Acquired cardiovascular conditions are a leading cause of maternal morbidity and mortality. A growing number of pregnant women have acquired and heritable cardiovascular conditions and cardiovascular risk factors. As the average age of childbearing women increases, the prevalence of acute coronary syndromes, cardiomyopathy, and other cardiovascular complications in pregnancy are also expected to increase. This document, the third of a 5-part series, aims to provide practical guidance on the management of such conditions encompassing pre-conception through acute management and considerations for delivery.

Published by Elsevier Inc.

J Am Coll Cardiol: 12 Apr 2021; 77:1799-1812
Park K, Bairey Merz CN, Bello NA, Davis M, ... Lindley KJ, American College of Cardiology Cardiovascular Disease in Women Committee and the Cardio-Obstetrics Work Group
J Am Coll Cardiol: 12 Apr 2021; 77:1799-1812 | PMID: 33832606
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Abstract

Long-Term Cardiovascular Outcomes in Systemic Lupus Erythematosus.

Yafasova A, Fosbøl EL, Schou M, Baslund B, ... Køber L, Butt JH
Background
Data on long-term cardiovascular outcomes in systemic lupus erythematosus (SLE) are sparse.
Objectives
This study sought to examine the long-term risk and prognosis associated with cardiovascular outcomes, including heart failure (HF), in patients with SLE.
Methods
Using Danish administrative registries, risks of outcomes were compared between SLE patients (diagnosed 1996 to 2018, no history of cardiovascular disease) and age-, sex-, and comorbidity-matched control subjects from the background population (matched 1:4). Furthermore, mortality following HF diagnosis was compared between SLE patients developing HF and age- and sex-matched non-SLE control subjects with HF (matched 1:4).
Results
A total of 3,411 SLE patients (median age: 44.6 years [25th to 75th percentile: 31.9 to 57.0 years]; 14.1% men) were matched with 13,644 control subjects. The median follow-up was 8.5 years (25th to 75th percentile: 4.0 to 14.4 years). Absolute 10-year risks of outcomes were: HF, 3.71% (95% confidence interval [CI]: 3.02% to 4.51%) for SLE patients, 1.94% (95% CI: 1.68% to 2.24%) for control subjects; atrial fibrillation, 4.35% (95% CI: 3.61% to 5.18%) for SLE patients, 2.82% (95% CI: 2.50% to 3.16%) for control subjects; ischemic stroke, 3.75% (95% CI: 3.06% to 4.54%) for SLE patients, 1.92% (95% CI: 1.66% to 2.20%) for control subjects; myocardial infarction, 2.17% (95% CI: 1.66% to 2.80%) for SLE patients, 1.49% (95% CI: 1.26% to 1.75%) for control subjects; venous thromboembolism, 6.03% (95% CI: 5.17% to 6.98%) for SLE patients, 1.68% (95% CI: 1.44% to 1.95%) for control subjects; and the composite of implantable cardioverter-defibrillator implantation/ventricular arrhythmias/cardiac arrest, 0.89% (95% CI: 0.58% to 1.31%) for SLE patients, 0.30% (95% CI: 0.20% to 0.43%) for control subjects. SLE with subsequent HF was associated with higher mortality compared with HF without SLE (adjusted hazard ratio: 1.50; 95% CI: 1.08 to 2.08).
Conclusions
SLE patients had a higher associated risk of HF and other cardiovascular outcomes compared with matched control subjects. Among patients developing HF, a history of SLE was associated with higher mortality.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 12 Apr 2021; 77:1717-1727
Yafasova A, Fosbøl EL, Schou M, Baslund B, ... Køber L, Butt JH
J Am Coll Cardiol: 12 Apr 2021; 77:1717-1727 | PMID: 33832598
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Abstract

Cardiovascular Risk in Patients With Psoriasis: JACC Review Topic of the Week.

Garshick MS, Ward NL, Krueger JG, Berger JS
Psoriasis is a chronic inflammatory skin disease that affects 2% to 3% of the U.S. population. The immune response in psoriasis includes enhanced activation of T cells and myeloid cells, platelet activation, and up-regulation of interferons, tumor necrosis factor-α, and interleukins (ILs) IL-23, IL-17, and IL-6, which are linked to vascular inflammation and atherosclerosis development. Patients with psoriasis are up to 50% more likely to develop cardiovascular disease (CV) disease, and this CV risk increases with skin severity. Major society guidelines now advocate incorporating a psoriasis diagnosis into CV risk prediction and prevention strategies. Although registry data suggest treatment targeting psoriasis skin disease reduces vascular inflammation and coronary plaque burden, and may reduce CV risk, randomized placebo-controlled trials are inconclusive to date. Further studies are required to define traditional CV risk factor goals, the optimal role of lipid-lowering and antiplatelet therapy, and targeted psoriasis therapies on CV risk.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 05 Apr 2021; 77:1670-1680
Garshick MS, Ward NL, Krueger JG, Berger JS
J Am Coll Cardiol: 05 Apr 2021; 77:1670-1680 | PMID: 33795041
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Abstract

Effects of Fluoroquinolones on Outcomes of Patients With Aortic Dissection or Aneurysm.

Chen SW, Chan YH, Chien-Chia Wu V, Cheng YT, ... Chu PH, Chou AH
Background
Recent population-based studies have revealed that the use of fluoroquinolones (FQs) is associated with an increased risk of aortic dissection (AD) and aneurysm (AA). However, no evidence is available on whether FQs increase adverse events in patients who had been diagnosed with AD or AA.
Objectives
This study investigated whether the use of FQs increases the risk of aortic-related adverse events and death in this high-risk population.
Methods
A retrospective cohort study was conducted by using the Taiwan National Health Insurance Research Database. A total of 31,570 adult patients who survived after admission for AD or AA between 2001 and 2013 were identified. We divided each calendar year into 6 data units (2 months) for each patient and each year during follow-up. Covariates and exposure of interest (FQs) were reassessed every 2 months. We used another common antibiotic, amoxicillin, as a negative control exposure.
Results
Exposure to FQs was associated with a higher risk of all-cause death (adjusted hazard ratio: 1.61; 95% confidence interval: 1.50 to 1.73), aortic death (adjusted hazard ratio: 1.80; 95% confidence interval: 1.50 to 2.15), and later aortic surgery. However, amoxicillin exposure was not significantly associated with risk of any of the outcomes. A subgroup analysis revealed that the effect of FQs was not significantly different between the AD and AA groups.
Conclusions
Relative to amoxicillin use, FQ exposure in patients with AD or AA was associated with a higher risk of adverse outcomes. FQs should not be used by high-risk patients unless no other treatment options are available.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 19 Apr 2021; 77:1875-1887
Chen SW, Chan YH, Chien-Chia Wu V, Cheng YT, ... Chu PH, Chou AH
J Am Coll Cardiol: 19 Apr 2021; 77:1875-1887 | PMID: 33858624
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Abstract

Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.

VARC-3 WRITING COMMITTEE, Généreux P, Piazza N, Alu MC, ... Cohen DJ, Leon MB
Aims
The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.
Methods and results
Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.
Conclusions
Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 18 Apr 2021; epub ahead of print
VARC-3 WRITING COMMITTEE, Généreux P, Piazza N, Alu MC, ... Cohen DJ, Leon MB
Eur Heart J: 18 Apr 2021; epub ahead of print | PMID: 33871579
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Abstract

Extracellular Vesicles from Epicardial Fat Facilitate Atrial Fibrillation.

Shaihov-Teper O, Ram E, Ballan N, Brzezinski RY, ... Gepstein L, Leor J
Background: The role of epicardial fat (eFat)-derived extracellular vesicles (EVs) in the pathogenesis of atrial fibrillation (AF) has never been studied. We tested the hypothesis that eFat-EVs transmit proinflammatory, profibrotic, and proarrhythmic molecules that induce atrial myopathy and fibrillation.
Methods:
We collected eFat specimens from patients with (n=32) and without AF (n=30) during elective heart surgery. eFat samples were grown as organ cultures, and the culture medium was collected every two days. We then isolated and purified eFat-EVs from the culture medium, and analyzed the EV number, size, morphology, specific markers, encapsulated cytokines, proteome, and miRNAs. Next, we evaluated the biological effects of unpurified and purified EVs on atrial mesenchymal stromal cells (MSCs) and endothelial cells (ECs) in vitro. To establish a causal association between eFat-EVs and vulnerability to AF, we modeled AF in vitro using induced pluripotent stem cell-derived cardiomyocytes (iCMs).
Results:
Microscopic examination revealed excessive inflammation, fibrosis, and apoptosis in fresh and cultured eFat tissues. Cultured explants from patients with AF secreted more EVs and harbored greater amounts of proinflammatory and profibrotic cytokines, as well as profibrotic miRNA, than those without AF. The proteomic analysis confirmed the distinctive profile of purified eFat-EVs from patients with AF. In vitro, purified and unpurified eFat-EVs from patients with AF had a greater effect on proliferation and migration of human MSCs and ECs, compared to eFat-EVs from patients without AF. Finally, while eFat-EVs from patients with and without AF shortened the action potential duration of iCMs, only eFat-EVs from patients with AF induced sustained reentry (rotor) in iCMs. Conclusions: We show, for the first time, a distinctive proinflammatory, profibrotic, and proarrhythmic signature of eFat-EVs from patients with AF. Our findings uncover another pathway by which eFat promotes the development of atrial myopathy and fibrillation.




Circulation: 31 Mar 2021; epub ahead of print
Shaihov-Teper O, Ram E, Ballan N, Brzezinski RY, ... Gepstein L, Leor J
Circulation: 31 Mar 2021; epub ahead of print | PMID: 33793321
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Abstract

Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

Hijazi Z, Alexander JH, Li Z, Wojdyla DM, ... Storey RF, Lopes RD
Background
In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function.
Methods
In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial.
Results
Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min-1·1.73 m-2, respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min-1·1.73 m-2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min-1·1.73 m-2: 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively.
Conclusions
The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.



Circulation: 22 Mar 2021; 143:1215-1223
Hijazi Z, Alexander JH, Li Z, Wojdyla DM, ... Storey RF, Lopes RD
Circulation: 22 Mar 2021; 143:1215-1223 | PMID: 33461308
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Abstract

Deep Neural Networks Can Predict New-Onset Atrial Fibrillation From the 12-Lead ECG and Help Identify Those at Risk of Atrial Fibrillation-Related Stroke.

Raghunath S, Pfeifer JM, Ulloa-Cerna AE, Nemani A, ... Fornwalt BK, Haggerty CM
Background
Atrial fibrillation (AF) is associated with substantial morbidity, especially when it goes undetected. If new-onset AF could be predicted, targeted screening could be used to find it early. We hypothesized that a deep neural network could predict new-onset AF from the resting 12-lead ECG and that this prediction may help identify those at risk of AF-related stroke.
Methods
We used 1.6 M resting 12-lead digital ECG traces from 430 000 patients collected from 1984 to 2019. Deep neural networks were trained to predict new-onset AF (within 1 year) in patients without a history of AF. Performance was evaluated using areas under the receiver operating characteristic curve and precision-recall curve. We performed an incidence-free survival analysis for a period of 30 years following the ECG stratified by model predictions. To simulate real-world deployment, we trained a separate model using all ECGs before 2010 and evaluated model performance on a test set of ECGs from 2010 through 2014 that were linked to our stroke registry. We identified the patients at risk for AF-related stroke among those predicted to be high risk for AF by the model at different prediction thresholds.
Results
The area under the receiver operating characteristic curve and area under the precision-recall curve were 0.85 and 0.22, respectively, for predicting new-onset AF within 1 year of an ECG. The hazard ratio for the predicted high- versus low-risk groups over a 30-year span was 7.2 (95% CI, 6.9-7.6). In a simulated deployment scenario, the model predicted new-onset AF at 1 year with a sensitivity of 69% and specificity of 81%. The number needed to screen to find 1 new case of AF was 9. This model predicted patients at high risk for new-onset AF in 62% of all patients who experienced an AF-related stroke within 3 years of the index ECG.
Conclusions
Deep learning can predict new-onset AF from the 12-lead ECG in patients with no previous history of AF. This prediction may help identify patients at risk for AF-related strokes.



Circulation: 29 Mar 2021; 143:1287-1298
Raghunath S, Pfeifer JM, Ulloa-Cerna AE, Nemani A, ... Fornwalt BK, Haggerty CM
Circulation: 29 Mar 2021; 143:1287-1298 | PMID: 33588584
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Abstract

Cell-Free DNA to Detect Heart Allograft Acute Rejection.

Agbor-Enoh S, Shah P, Tunc I, Hsu S, ... Valantine HA, GRAfT Investigators
Background
After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.
Methods
This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.
Results
The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31-0.83%], versus 0.03% [IQR, 0.01-0.14%]; P<0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% [IQR, 0.49-2.79%] versus ACR grade ≥2R, 0.34% [IQR, 0.28-0.72%]), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.
Conclusions
We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.



Circulation: 22 Mar 2021; 143:1184-1197
Agbor-Enoh S, Shah P, Tunc I, Hsu S, ... Valantine HA, GRAfT Investigators
Circulation: 22 Mar 2021; 143:1184-1197 | PMID: 33435695
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Abstract

Effects of a 2-Year Primary Care Lifestyle Intervention on Cardiometabolic Risk Factors: A Cluster-Randomized Trial.

Höchsmann C, Dorling JL, Martin CK, Newton RL, ... Katzmarzyk PT, PROPEL Research Group
Background
Intensive lifestyle interventions (ILIs) are the first-line approach to effectively treat obesity and manage associated cardiometabolic risk factors. Because few people have access to ILIs in academic health centers, primary care must implement similar approaches for a meaningful effect on obesity and cardiometabolic disease prevalence. To date, however, effective lifestyle-based obesity treatment in primary care is limited. We examined the effectiveness of a pragmatic ILI for weight loss delivered in primary care among a racially diverse, low-income population with obesity for improving cardiometabolic risk factors over 24 months.
Methods
The PROPEL trial (Promoting Successful Weight Loss in Primary Care in Louisiana) randomly allocated 18 clinics equally to usual care or an ILI and subsequently enrolled 803 (351 usual care, 452 ILI) adults (67% Black, 84% female) with obesity from participating clinics. The usual care group continued to receive their normal primary care. The ILI group received a 24-month high-intensity lifestyle-based obesity treatment program, embedded in the clinic setting and delivered by health coaches in weekly sessions initially and monthly sessions in months 7 through 24.
Results
As recently demonstrated, participants receiving the PROPEL ILI lost significantly more weight over 24 months than those receiving usual care (mean difference, -4.51% [95% CI, -5.93 to -3.10]; P<0.01). Fasting glucose decreased more in the ILI group compared with the usual care group at 12 months (mean difference, -7.1 mg/dL [95% CI, -12.0 to -2.1]; P<0.01) but not 24 months (mean difference, -0.8 mg/dL [95% CI, -6.2 to 4.6]; P=0.76). Increases in high-density lipoprotein cholesterol were greater in the ILI than in the usual care group at both time points (mean difference at 24 months, 4.6 mg/dL [95% CI, 2.9-6.3]; P<0.01). Total:high-density lipoprotein cholesterol ratio and metabolic syndrome severity (z score) decreased more in the ILI group than in the usual care group at both time points, with significant mean differences of the change of -0.31 (95% CI, -0.47 to -0.14; P<0.01) and -0.21 (95% CI, -0.36 to -0.06; P=0.01) at 24 months, respectively. Changes in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and blood pressure did not differ significantly between groups at any time point.
Conclusions
A pragmatic ILI consistent with national guidelines and delivered by trained health coaches in primary care produced clinically relevant improvements in cardiometabolic health in an underserved population over 24 months. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02561221.



Circulation: 22 Mar 2021; 143:1202-1214
Höchsmann C, Dorling JL, Martin CK, Newton RL, ... Katzmarzyk PT, PROPEL Research Group
Circulation: 22 Mar 2021; 143:1202-1214 | PMID: 33557578
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Abstract

High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial.

Anand A, Lee KK, Chapman AR, Ferry AV, ... Mills NL, HiSTORIC Investigators
Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early-rule out pathway is safe and effective for patients with suspected acute coronary syndrome.
Methods:
We performed a stepped-wedge cluster randomized controlled trial in the Emergency Departments of seven acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were <5 ng/L at presentation. During a prior validation phase, myocardial infarction was ruled out where troponin concentrations were <99th centile at 6-12 hours after symptom onset. The co-primary outcome was length of stay (efficacy), and myocardial infarction or cardiac death after discharge at 30 days (safety). Patients were followed for 1 year to evaluate safety and other secondary outcomes.
Results:
We enrolled 31,492 patients (59±17 years, 45% women) with troponin concentrations <99th centile at presentation. Length of stay was reduced from 10.1±4.1 to 6.8±3.9 hours (adjusted geometric mean ratio 0.78, 95% confidence interval [CI] 0.73 to 0.83, P<0.001) following implementation, and the proportion of patients discharged increased from 50% to 71% (adjusted odds ratio [aOR] 1.59, 95% CI 1.45 to 1.75). Non-inferiority was not demonstrated for the 30-day safety outcome (upper limit of one-sided 95% CI for adjusted risk difference 0.70%, non-inferiority margin 0.50%, P=0.068), but the observed differences favoured the early rule-out pathway (0.4% [57/14,700] versus 0.3% [56/16,792]). At 1 year, the safety outcome occurred in 2.7% (396/14,700) and 1.8% (307/16,792) of patients before and after implementation (aOR 1.02, 95% CI 0.74 to 1.40, P=0.894), and there were no differences in hospital reattendance or all-cause mortality. Conclusions: Implementation of an early rule-out pathway for myocardial infarction reduced length of stay and hospital admission. Whilst non-inferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and healthcare providers. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03005158.




Circulation: 22 Mar 2021; epub ahead of print
Anand A, Lee KK, Chapman AR, Ferry AV, ... Mills NL, HiSTORIC Investigators
Circulation: 22 Mar 2021; epub ahead of print | PMID: 33752439
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Abstract

Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Addition of SGLT2 Inhibitors Versus Sulfonylureas to Baseline GLP-1RA Therapy.

Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E
Background
Several glucagon-like peptide receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents, and it remains unknown whether the addition of SGLT2i to GLP-1RA therapy has further cardiovascular benefits.
Methods
Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 US claims datasets (2013-2018) and were 1:1 propensity score-matched, adjusting for >95 baseline covariates. The primary outcomes were a composite cardiovascular end point (comprising myocardial infarction, stroke, and all-cause mortality) and heart failure hospitalization. Adjusted hazard ratios (HRs) and 95% CIs were estimated in each dataset and pooled through fixed-effects meta-analysis.
Results
Among 12 584 propensity score-matched pairs (mean [SD] age, 58.3 [10.9] years; 48.2% male) across the 3 datasets, there were 107 composite cardiovascular end point events (incidence rate per 1000 person-years, 9.9 [95% CI, 8.1-11.9]) among SGLT2i initiators compared with 129 events (incidence rate, 13.0 [95% CI, 10.9-15.3]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.76 (95% CI, 0.59-0.98); this decrease in composite cardiovascular end point was driven by numeric decreases in the risk of myocardial infarction (HR, 0.71 [95% CI, 0.51-1.003]) and all-cause mortality (HR, 0.68 [95% CI, 0.40-1.14]) but not stroke (HR, 1.05 [95% CI, 0.62-1.79]). For the outcome of heart failure hospitalization, there were 141 events (incidence rate, 13.0 [95% CI, 11.0-15.2]) among SGLT2i initiators versus 206 events (incidence rate, 20.8 [95% CI, 18.1-23.8]) among sulfonylurea initiators, corresponding to an adjusted pooled HR of 0.65 (95% CI, 0.50-0.82).
Conclusions
Risk of residual confounding cannot be fully excluded. Individual therapeutic agents within each class may have different magnitudes of effect. In this large real-world cohort of patients with diabetes already on GLP-1RA, addition of SGLT2i conferred greater cardiovascular benefit compared with addition of sulfonylurea. The magnitude of the cardiovascular risk reduction was comparable with the benefit seen in cardiovascular outcome trials of SGLT2i versus placebo, where baseline GLP-1RA use was minimal.



Circulation: 22 Mar 2021; 143:770-779
Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E
Circulation: 22 Mar 2021; 143:770-779 | PMID: 33302723
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Abstract

Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.

Yamaguchi N, Xiao J, Narke D, Shaheen D, ... Chung MK, Park DS
Background
Elevated intracardiac pressure attributable to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 (ETS translocation variant 1) signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling.
Methods
We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between 2 murine models of cardiac pressure overload, transverse aortic constriction banding and angiotensin II infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout (Etv1 f/f Mlc2aCre/+).
Results
Using the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the NRG1 (Neuregulin 1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1, ERBB4, SCN5A, and GJA5 levels in human LA samples. In a similar fashion to patients with heart failure, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA sequencing datasets from transverse aortic constriction and angiotensin II-treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4, Etv1, Scn5a, and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1, and numerous collagen genes. Etv1 f/f Mlc2aCre/+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1 f/f Mlc2aCre/+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA sequencing dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes.
Conclusions
ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.



Circulation: 22 Mar 2021; 143:805-820
Yamaguchi N, Xiao J, Narke D, Shaheen D, ... Chung MK, Park DS
Circulation: 22 Mar 2021; 143:805-820 | PMID: 33225722
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Abstract

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, ... Tsao CW, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Background
The American Heart Association, in conjunction with the National Institutes of Health, annually reports 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 2021 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, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.
Results
Each of the 27 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, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.



Circulation: 22 Mar 2021; 143:e254-e743
Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, ... Tsao CW, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee
Circulation: 22 Mar 2021; 143:e254-e743 | PMID: 33501848
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Abstract

Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40 and Beyond.

Goff DC, Khan SS, Lloyd-Jones D, Arnett DK, ... Wei GS, Wright JS
More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the \"Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40\" symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.



Circulation: 22 Mar 2021; 143:837-851
Goff DC, Khan SS, Lloyd-Jones D, Arnett DK, ... Wei GS, Wright JS
Circulation: 22 Mar 2021; 143:837-851 | PMID: 33617315
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Abstract

Adverse Pregnancy Outcomes and Cardiovascular Disease Risk: Unique Opportunities for Cardiovascular Disease Prevention in Women: A Scientific Statement From the American Heart Association.

Parikh NI, Gonzalez JM, Anderson CAM, Judd SE, ... American Heart Association Council on Epidemiology and Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and the Stroke Council
This statement summarizes evidence that adverse pregnancy outcomes (APOs) such as hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss increase a woman\'s risk of developing cardiovascular disease (CVD) risk factors and of developing subsequent CVD (including fatal and nonfatal coronary heart disease, stroke, peripheral vascular disease, and heart failure). This statement highlights the importance of recognizing APOs when CVD risk is evaluated in women, although their value in reclassifying risk may not be established. A history of APOs is a prompt for more vigorous primordial prevention of CVD risk factors and primary prevention of CVD. Adopting a heart-healthy diet and increasing physical activity among women with APOs, starting in the postpartum setting and continuing across the life span, are important lifestyle interventions to decrease CVD risk. Lactation and breastfeeding may lower a woman\'s later cardiometabolic risk. Black and Asian women experience a higher proportion APOs, with more severe clinical presentation and worse outcomes, than White women. More studies on APOs and CVD in non-White women are needed to better understand and address these health disparities. Future studies of aspirin, statins, and metformin may better inform our recommendations for pharmacotherapy in primary CVD prevention among women who have had an APO. Several opportunities exist for health care systems to improve transitions of care for women with APOs and to implement strategies to reduce their long-term CVD risk. One proposed strategy includes incorporation of the concept of a fourth trimester into clinical recommendations and health care policy.



Circulation: 28 Mar 2021:CIR0000000000000961; epub ahead of print
Parikh NI, Gonzalez JM, Anderson CAM, Judd SE, ... American Heart Association Council on Epidemiology and Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and the Stroke Council
Circulation: 28 Mar 2021:CIR0000000000000961; epub ahead of print | PMID: 33779213
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Abstract

Development and Validation of Machine Learning-Based Race-Specific Models to Predict 10-Year Risk of Heart Failure: A Multi-Cohort Analysis.

Segar MW, Jaeger BC, Patel KV, Nambi V, ... de Lemos JA, Pandey A
Background: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and elucidate important contributors of HF development across races.
Methods:
We performed a retrospective analysis of four large, community cohort studies (ARIC, DHS, JHS, and MESA) with adjudicated HF events. Participants were aged >40 years and free of HF at baseline. Race-specific ML models for HF risk prediction were developed in the JHS cohort (for Black race-specific model) and White adults from ARIC (for White rate-specific model). The models included 39 candidate variables across demographic, anthropometric, medical history, laboratory, and electrocardiographic domains. The ML models were externally validated and compared with prior established traditional and non-race specific ML models in race-specific subgroups of the pooled MESA/DHS cohort and Black participants of ARIC. Harrell\'s C-index and Greenwood-Nam-D\'Agostino chi-square tests were used to assess discrimination and calibration, respectively.
Results:
The ML models had excellent discrimination in the derivation cohorts for Black (N=4,141 in JHS, C-index=0.88) and White (N=7,858 in ARIC, C-index=0.89) participants. In the external validation cohorts, the race-specific ML model demonstrated adequate calibration and superior discrimination (C-indices=0.80-0.83 [for Black individuals] and 0.82 [for White individuals]) compared with established HF risk models or with non-race specific ML models derived using race as a covariate. Among the risk factors, natriuretic peptide levels were the most important predictor of HF risk across both races, followed by troponin levels in Black and EKG-based Cornell voltage in White individuals. Other key predictors of HF risk among Black individuals were glycemic parameters and socioeconomic factors. In contrast, prevalent cardiovascular (CV) disease and traditional CV risk factors were stronger predictors of HF risk in White adults. Conclusions: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance when compared with traditional HF risk and non-race specific ML models. This approach identifies distinct race-specific contributors of HF.




Circulation: 12 Apr 2021; epub ahead of print
Segar MW, Jaeger BC, Patel KV, Nambi V, ... de Lemos JA, Pandey A
Circulation: 12 Apr 2021; epub ahead of print | PMID: 33845593
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Abstract

Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study.

Näslund E, Stenberg E, Hofmann R, Ottosson J, ... Szummer K, Jernberg T
Background
The number of patients with myocardial infarction and severe obesity is increasing and there is a lack of evidence how these patients should be treated. The aim of this study was to investigate the association between metabolic surgery (Roux-en-Y gastric bypass and sleeve gastrectomy) and major adverse cardiovascular events in patients with previous myocardial infarction (MI) and severe obesity.
Methods
Of 566 patients with previous MI registered in the SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) undergoing metabolic surgery and registered in the nationwide Scandinavian Obesity Surgery Registry, 509 patients (Roux-en-Y gastric bypass n=465; sleeve gastrectomy n=44) could be matched 1:1 to a control with MI from SWEDEHEART, but no subsequent metabolic surgery regarding sex, age (±3 years), year of MI (±3 years), and body mass index (±3). The 2 groups were well matched, except for a lower proportion of reduced ejection fraction after MI (7% versus 12%), previous heart failure (10% versus 19%), atrial fibrillation (6% versus 10%), and chronic obstructive pulmonary disease (4% versus 7%) in patients undergoing metabolic surgery.
Results
The median (interquartile range) follow-up time was 4.6 (2.7-7.1) years. The 8-year cumulative probability of major adverse cardiovascular events was lower in patients undergoing metabolic surgery (18.7% [95% CI, 15.9-21.5%] versus 36.2% [33.2-39.3%], adjusted hazard ratio, 0.44 [95% CI, 0.32-0.61]). Patients undergoing metabolic surgery had also a lower risk of death (adjusted HR, 0.45 [95% CI, 0.29-0.70]; MI, 0.24 [0.14-0.41]) and new onset heart failure, but there were no significant differences regarding stroke (0.91 [0.38-2.20]) and new onset atrial fibrillation (0.56 [0.31-1.01]).
Conclusions
In severely obese patients with previous MI, metabolic surgery is associated with a low risk for serious complications, lower risk of major adverse cardiovascular events, death, new MI, and new onset heart failure. These findings need to be confirmed in a randomized, controlled trial.



Circulation: 12 Apr 2021; 143:1458-1467
Näslund E, Stenberg E, Hofmann R, Ottosson J, ... Szummer K, Jernberg T
Circulation: 12 Apr 2021; 143:1458-1467 | PMID: 33103469
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Abstract

Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease:: A Population-Based Retrospective Cohort Study.

Doumouras AG, Wong JA, Paterson JM, Lee Y, ... Yusuf S, Anvari M
Background
Bariatric surgery has been shown to significantly reduce cardiovascular risk factors. However, whether surgery can reduce major adverse cardiovascular events (MACE), especially in patients with established cardiovascular disease, remains poorly understood. The present study aims to determine the association between bariatric surgery and MACE among patients with cardiovascular disease and severe obesity.
Methods
This was a propensity score-matched cohort study using province-wide multiple-linked administrative databases in Ontario, Canada. Patients with previous ischemic heart disease or heart failure who received bariatric surgery were matched on age, sex, heart failure history, and a propensity score to similar controls from a primary care medical record database in a 1:1 ratio. The primary outcome was the incidence of extended MACE (first occurrence of all-cause mortality, myocardial infarction, coronary revascularization, cerebrovascular events, and heart failure hospitalization). Secondary outcome included 3-component MACE (myocardial infarction, ischemic stroke, and all-cause mortality). Outcomes were evaluated through a combination of matching via propensity score and subsequent multivariable adjustment.
Results
A total of 2638 patients (n=1319 in each group) were included, with a median follow-up time of 4.6 years. The primary outcome occurred in 11.5% (151/1319) of the surgery group and 19.6% (259/1319) of the controls (adjusted hazard ratio [HR], 0.58 [95% CI, 0.48-0.71]; P<0.001). The association was notable for those with heart failure (HR, 0.44 [95% CI, 0.31-0.62]; P<0.001; absolute risk difference, 19.3% [95% CI, 12.0%-26.7%]) and in those with ischemic heart disease (HR, 0.60 [95% CI, 0.48-0.74]; P<0.001; absolute risk difference, 7.5% [95% CI, 4.7%-10.5%]). Surgery was also associated with a lower incidence of the secondary outcome (HR, 0.66 [95% CI, 0.52-0.84]; P=0.001) and cardiovascular mortality (HR, 0.35 [95% CI, 0.15-0.80]; P=0.001).
Conclusions
Bariatric surgery was associated with a lower incidence of MACE in patients with cardiovascular disease and obesity. These findings require confirmation by a large-scale randomized trial.



Circulation: 12 Apr 2021; 143:1468-1480
Doumouras AG, Wong JA, Paterson JM, Lee Y, ... Yusuf S, Anvari M
Circulation: 12 Apr 2021; 143:1468-1480 | PMID: 33813836
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Abstract

Perioperative Neurological Evaluation and Management to Lower the Risk of Acute Stroke in Patients Undergoing Noncardiac, Nonneurological Surgery: A Scientific Statement From the American Heart Association/American Stroke Association.

Benesch C, Glance LG, Derdeyn CP, Fleisher LA, ... American Heart Association Stroke Council; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Epidemiology and Prevention
Perioperative stroke is a potentially devastating complication in patients undergoing noncardiac, nonneurological surgery. This scientific statement summarizes established risk factors for perioperative stroke, preoperative and intraoperative strategies to mitigate the risk of stroke, suggestions for postoperative assessments, and treatment approaches for minimizing permanent neurological dysfunction in patients who experience a perioperative stroke. The first section focuses on preoperative optimization, including the role of preoperative carotid revascularization in patients with high-grade carotid stenosis and delaying surgery in patients with recent strokes. The second section reviews intraoperative strategies to reduce the risk of stroke, focusing on blood pressure control, perioperative goal-directed therapy, blood transfusion, and anesthetic technique. Finally, this statement presents strategies for the evaluation and treatment of patients with suspected postoperative strokes and, in particular, highlights the value of rapid recognition of strokes and the early use of intravenous thrombolysis and mechanical embolectomy in appropriate patients.



Circulation: 07 Apr 2021:CIR0000000000000968; epub ahead of print
Benesch C, Glance LG, Derdeyn CP, Fleisher LA, ... American Heart Association Stroke Council; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Epidemiology and Prevention
Circulation: 07 Apr 2021:CIR0000000000000968; epub ahead of print | PMID: 33827230
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Abstract

Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation.

Benz AP, Hijazi Z, Lindbäck J, Connolly SJ, ... Siegbahn A, Wallentin L
Background: The novel ABC (Age, Biomarkers, Clinical History) scores outperform traditional risk scores for stroke, major bleeding and death in patients with atrial fibrillation (AF) receiving oral anticoagulation. To refine their utility, the ABC-AF scores needed to be validated in patients not receiving oral anticoagulation.
Methods:
We measured plasma levels of the ABC biomarkers (N-terminal pro-B-type natriuretic peptide, cardiac troponin-T and growth-differentiation factor-15) to apply the previously developed ABC-AF scores in patients with AF receiving aspirin (n=3,195) or aspirin and clopidogrel (n=1,110) in two large clinical trials. Calibration was assessed by comparing estimated with observed one-year risks. Cox-regression models were used for recalibration. Discrimination was evaluated separately for the aspirin only and the overall cohort (n=4,305).
Results:
The ABC-AF-stroke score yielded a c-index of 0.70 (95% confidence interval [CI] 0.67-0.73) in both cohorts. The ABC-AF-bleeding score had a c-index of 0.76 (95% CI 0.71-0.81) in the aspirin only cohort and 0.73 (95% CI 0.69-0.77) overall. Both scores were superior to risk scores recommended by current guidelines. The ABC-AF-death score yielded a c-index of 0.78 (95% CI 0.76-0.80) overall. Calibrated in patients receiving oral anticoagulation, the ABC-AF-stroke score underestimated, and the ABC-AF-bleeding score overestimated the risk of events in both cohorts. These scores were recalibrated for prediction of absolute event rates in the absence of oral anticoagulation. Conclusions: The biomarker-based ABC-AF scores showed better discrimination than traditional risk scores and were recalibrated for precise risk estimation in patients not receiving oral anticoagulation. They can now provide improved decision support regarding treatment of an individual patient with AF.




Circulation: 13 Apr 2021; epub ahead of print
Benz AP, Hijazi Z, Lindbäck J, Connolly SJ, ... Siegbahn A, Wallentin L
Circulation: 13 Apr 2021; epub ahead of print | PMID: 33849281
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Abstract

Relationship of LVEF and Myocardial Scar to Long-Term Mortality Risk and Mode of Death in Patients With Nonischemic Cardiomyopathy.

Klem I, Klein M, Khan M, Yang EY, ... Heitner JF, Shah DJ
Background
Nonischemic cardiomyopathy is a leading cause of reduced left ventricular ejection fraction (LVEF) and is associated with high mortality risk from progressive heart failure and arrhythmias. Myocardial scar on cardiovascular magnetic resonance imaging is increasingly recognized as a risk marker for adverse outcomes; however, left ventricular dysfunction remains the basis for determining a patient\'s eligibility for primary prophylaxis with implantable cardioverter-defibrillator. We investigated the relationship of LVEF and scar with long-term mortality and mode of death in a large cohort of patients with nonischemic cardiomyopathy.
Methods
This study is a prospective, longitudinal outcomes registry of 1020 consecutive patients with nonischemic cardiomyopathy who underwent clinical cardiovascular magnetic resonance imaging for the assessment of LVEF and scar at 3 centers.
Results
During a median follow-up of 5.2 (interquartile range, 3.8, 6.6) years, 277 (27%) patients died. On survival analysis, LVEF ≤35% and scar were strongly associated with all-cause (log-rank test P=0.002 and P<0.001, respectively) and cardiac death (P=0.001 and P<0.001, respectively). Whereas scar was strongly related to sudden cardiac death (SCD; P=0.001), there was no significant association between LVEF ≤35% and SCD risk (P=0.57). On multivariable analysis including established clinical factors, LVEF and scar are independent risk markers of all-cause and cardiac death. The addition of LVEF provided incremental prognostic value but insignificant discrimination improvement by C-statistic for all-cause and cardiac death, but no incremental prognostic value for SCD. Conversely, scar extent demonstrated significant incremental prognostic value and discrimination improvement for all 3 end points. On net reclassification analysis, the addition of LVEF resulted in no significant improvement for all-cause death (11.0%; 95% CI, -6.2% to 25.9%), cardiac death (9.8%; 95% CI, -5.7% to 29.3%), or SCD (7.5%; 95% CI, -41.2% to 42.9%). Conversely, the addition of scar extent resulted in significant reclassification improvement of 25.5% (95% CI, 11.7% to 41.0%) for all-cause death, 27.0% (95% CI, 11.6% to 45.2%) for cardiac death, and 40.6% (95% CI, 10.5% to 71.8%) for SCD.
Conclusions
Myocardial scar and LVEF are both risk markers for all-cause and cardiac death in patients with nonischemic cardiomyopathy. However, whereas myocardial scar has strong and incremental prognostic value for SCD risk stratification, LVEF has no incremental prognostic value over clinical measures. Scar assessment should be incorporated into patient selection criteria for primary prevention implantable cardioverter-defibrillator placement.



Circulation: 05 Apr 2021; 143:1343-1358
Klem I, Klein M, Khan M, Yang EY, ... Heitner JF, Shah DJ
Circulation: 05 Apr 2021; 143:1343-1358 | PMID: 33478245
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Abstract

Taking a Stand Against Air Pollution-The Impact on Cardiovascular Disease: A Joint Opinion From the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology.

Brauer M, Casadei B, Harrington RA, Kovacs R, Sliwa K, WHF Air Pollution Expert Group
Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to comorbidities that are known to worsen outcomes among those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.



Circulation: 05 Apr 2021; 143:e800-e804
Brauer M, Casadei B, Harrington RA, Kovacs R, Sliwa K, WHF Air Pollution Expert Group
Circulation: 05 Apr 2021; 143:e800-e804 | PMID: 33506685
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Abstract

Primary Outcome Evaluation of a Next Generation Left Atrial Appendage Closure Device: Results from the PINNACLE FLX Trial.

Kar S, Doshi SK, Sadhu A, Horton R, ... Reddy VY, PINNACLE FLX Investigators
Background: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation (OAC) for thromboembolic risk reduction in patients with non-valvular atrial fibrillation (NVAF). Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with NVAF in whom OAC is indicated, but who have an appropriate rationale to seek a non-pharmaceutical alternative.
Methods:
This was a prospective, non-randomized, multi-center FDA study. The primary safety endpoint was the occurrence of one of the following events within 7 days post-procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness endpoint was the incidence of effective LAA closure (peri-device flow ≤5mm), as assessed by the echocardiography core laboratory at 12-month follow-up.
Results:
A total of 400 patients were enrolled. The mean age was 73.8{plus minus}8.6 years and the mean CHA2DS2-VASc score was 4.2{plus minus}1.5. The incidence of the primary safety endpoint was 0.5% with a one-sided 95% upper confidence interval (CI) of 1.6%, meeting the performance goal (PG) of 4.2% (P<0.0001). The incidence of the primary effectiveness endpoint was 100%, with a onesided 95% lower CI of 99.1%, again meeting the PG of 97.0% (P<0.0001). Device-related thrombus was reported in 7 patients, no patients experienced pericardial effusion requiring open cardiac surgery, and there were no device embolizations. Conclusions: LAA closure with this next generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Clinical Trial Registration: URL https://clinicaltrials.gov Unique Identifier NCT02702271.




Circulation: 05 Apr 2021; epub ahead of print
Kar S, Doshi SK, Sadhu A, Horton R, ... Reddy VY, PINNACLE FLX Investigators
Circulation: 05 Apr 2021; epub ahead of print | PMID: 33820423
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Abstract

Prevention of Viridans Group Streptococcal Infective Endocarditis: A Scientific Statement From the American Heart Association.

Wilson WR, Gewitz M, Lockhart PB, Bolger AF, ... American Heart Association Young Hearts Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiovascular and Stroke Nursing; and the Council on Quality of Care and Outcomes Research
Background
In 2007, the American Heart Association published updated evidence-based guidelines on the recommended use of antibiotic prophylaxis to prevent viridans group streptococcal (VGS) infective endocarditis (IE) in cardiac patients undergoing invasive procedures. The 2007 guidelines significantly scaled back the underlying conditions for which antibiotic prophylaxis was recommended, leaving only 4 categories thought to confer the highest risk of adverse outcome. The purpose of this update is to examine interval evidence of the acceptance and impact of the 2007 recommendations on VGS IE and, if needed, to make revisions based on this evidence.
Methods and results
A writing group was formed consisting of experts in prevention and treatment of infective endocarditis including members of the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics, in addition to the American Heart Association. MEDLINE database searches were done for English language articles on compliance with the recommendations in the 2007 guidelines and the frequency of and morbidity or mortality from VGS IE after publication of the 2007 guidelines. Overall, there was good general awareness of the 2007 guidelines but variable compliance with recommendations. There was no convincing evidence that VGS IE frequency, morbidity, or mortality has increased since 2007.
Conclusions
On the basis of a review of the available evidence, there are no recommended changes to the 2007 VGS IE prevention guidelines. We continue to recommend VGS IE prophylaxis only for categories of patients at highest risk for adverse outcome while emphasizing the critical role of good oral health and regular access to dental care for all. Randomized controlled studies to determine whether antibiotic prophylaxis is effective against VGS IE are needed to further refine recommendations.



Circulation: 14 Apr 2021:CIR0000000000000969; epub ahead of print
Wilson WR, Gewitz M, Lockhart PB, Bolger AF, ... American Heart Association Young Hearts Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Cardiovascular and Stroke Nursing; and the Council on Quality of Care and Outcomes Research
Circulation: 14 Apr 2021:CIR0000000000000969; epub ahead of print | PMID: 33853363
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Abstract

Very High Coronary Artery Calcium (≥1000) and Association With Cardiovascular Disease Events, Non-Cardiovascular Disease Outcomes, and Mortality: Results From MESA.

Peng AW, Dardari ZA, Blumenthal RS, Dzaye O, ... Page J, Blaha MJ
Background
There are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations.
Methods
Our study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).
Results
Compared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm2), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63-6.11), 7.57- (5.50-10.42), 4.86-(3.32-7.11), and 1.94-fold (1.57-2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25-2.16), 1.66- (1.22-2.25), 1.51- (1.03-2.23), and 1.34-fold (1.05-1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57-2.41) and 1.43-fold (1.12-1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups.
Conclusions
Individuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.



Circulation: 19 Apr 2021; 143:1571-1583
Peng AW, Dardari ZA, Blumenthal RS, Dzaye O, ... Page J, Blaha MJ
Circulation: 19 Apr 2021; 143:1571-1583 | PMID: 33650435
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Impact:
Abstract

Blood Pressure Effects of Sodium Reduction: Dose-Response Meta-Analysis of Experimental Studies.

Filippini T, Malavolti M, Whelton PK, Naska A, Orsini N, Vinceti M
Background
The relationship between dietary sodium intake and blood pressure (BP) has been tested in clinical trials and nonexperimental human studies, indicating a direct association. The exact shape of the dose-response relationship has been difficult to assess in clinical trials because of the lack of random-effects dose-response statistical models that can include 2-arm comparisons.
Methods
After performing a comprehensive literature search for experimental studies that investigated the BP effects of changes in dietary sodium intake, we conducted a dose-response meta-analysis using the new 1-stage cubic spline mixed-effects model. We included trials with at least 4 weeks of follow-up; 24-hour urinary sodium excretion measurements; sodium manipulation through dietary change or supplementation, or both; and measurements of systolic and diastolic BP at the beginning and end of treatment.
Results
We identified 85 eligible trials with sodium intake ranging from 0.4 to 7.6 g/d and follow-up from 4 weeks to 36 months. The trials were conducted in participants with hypertension (n=65), without hypertension (n=11), or a combination (n=9). Overall, the pooled data were compatible with an approximately linear relationship between achieved sodium intake and mean systolic as well as diastolic BP, with no indication of a flattening of the curve at either the lowest or highest levels of sodium exposure. Results were similar for participants with or without hypertension, but the former group showed a steeper decrease in BP after sodium reduction. Intervention duration (≥12 weeks versus 4 to 11 weeks), type of study design (parallel or crossover), use of antihypertensive medication, and participants\' sex had little influence on the BP effects of sodium reduction. Additional analyses based on the BP effect of difference in sodium exposure between study arms at the end of the trial confirmed the results on the basis of achieved sodium intake.
Conclusions
In this dose-response analysis of sodium reduction in clinical trials, we identified an approximately linear relationship between sodium intake and reduction in both systolic and diastolic BP across the entire range of dietary sodium exposure. Although this occurred independently of baseline BP, the effect of sodium reduction on level of BP was more pronounced in participants with a higher BP level.



Circulation: 19 Apr 2021; 143:1542-1567
Filippini T, Malavolti M, Whelton PK, Naska A, Orsini N, Vinceti M
Circulation: 19 Apr 2021; 143:1542-1567 | PMID: 33586450
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Impact:
Abstract

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD
Background
Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.
Objective
To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.
Design
New-user retrospective propensity score-matched cohort study.
Setting
U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.
Participants
Adults with valvular AF who were newly prescribed DOACs or warfarin.
Measurements
The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.
Results
Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).
Limitation
Relatively short follow-up; inability to ascertain disease severity.
Conclusion
In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.
Primary funding source
None.



Ann Intern Med: 29 Mar 2021; epub ahead of print
Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD
Ann Intern Med: 29 Mar 2021; epub ahead of print | PMID: 33780291
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Impact:
Abstract

Effect of Sleep Disturbances on Blood Pressure.

Makarem N, Alcántara C, Williams N, Bello NA, Abdalla M
This review summarizes recent literature addressing the association of short sleep duration, shift work, and obstructive sleep apnea with hypertension risk, blood pressure (BP) levels, and 24-hour ambulatory BP. Observational studies demonstrate that subjectively assessed short sleep increases hypertension risk, though conflicting results are observed in studies of objectively assessed short sleep. Intervention studies demonstrate that mild and severe sleep restriction are associated with higher BP. Rotating and night shift work are associated with hypertension as shift work may exacerbate the detrimental impact of short sleep on BP. Further, studies demonstrate that shift work may increase nighttime BP and reduce BP control in patients with hypertension. Finally, moderate to severe obstructive sleep apnea is associated with hypertension, particularly resistant hypertension. Obstructive sleep apnea is also associated with abnormal 24-hour ambulatory BP profiles, including higher daytime and nighttime BP, nondipping BP, and a higher morning surge. Continuous positive airway pressure treatment may lower BP and improve BP dipping. In conclusion, efforts should be made to educate patients and health care providers about the importance of identifying and treating sleep disturbances for hypertension prevention and management. Empirically supported sleep health interventions represent a critical next step to advance this research area and establish causality.



Hypertension: 29 Apr 2021; 77:1036-1046
Makarem N, Alcántara C, Williams N, Bello NA, Abdalla M
Hypertension: 29 Apr 2021; 77:1036-1046 | PMID: 33611935
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Impact:
Abstract

Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: A Milestone Achieved.

Sarafidis P, Papadopoulos CE, Kamperidis V, Giannakoulas G, Doumas M
Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population.



Hypertension: 28 Mar 2021:HYPERTENSIONAHA12117005; epub ahead of print
Sarafidis P, Papadopoulos CE, Kamperidis V, Giannakoulas G, Doumas M
Hypertension: 28 Mar 2021:HYPERTENSIONAHA12117005; epub ahead of print | PMID: 33775130
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Impact:
Abstract

Effect of Intensive Blood Pressure Control on Aortic Stiffness in the SPRINT-HEART.

Upadhya B, Pajewski NM, Rocco MV, Hundley WG, ... Kitzman DW, SPRINT Research Group
In a subgroup of 337 participants (mean age 64±9 years; 45% women) from the SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive treatment (target systolic blood pressure <120 mm Hg) versus standard treatment (<140 mm Hg), we examined the effect of intensive blood pressure lowering on indexes of aortic stiffness. Carotid-femoral pulse wave velocity, a validated global measure of aortic stiffness, was measured by echo-guided Doppler at baseline and 18-month follow-up visit. Aortic elastance, distensibility, and compliance were measured by cardiac magnetic resonance imaging. During follow-up, the intensive treatment produced a mean between-group reduction in systolic blood pressure of 12.7 mm Hg (95% CI, 11.1-14.3 mm Hg). During follow-up, intensive treatment significantly attenuated the increase in carotid-femoral pulse wave velocity compared with standard treatment (adjusted follow-up least square mean=9.0 m/s [95% CI, 8.7-9.3] versus 10.0 m/s [9.6-10.3]; P<0.001), an effect that persisted even after adjusting for mean arterial pressure. Intensive treatment also decreased the aortic elastance index (least square mean, 1.38 mm Hg/mL per m2 [95% CI, 1.34-1.41] versus 1.48 mm Hg/mL per m2 [95% CI, 1.44-1.51], P=0.002) compared with standard treatment. No significant between-group differences were observed for aortic distensibility and compliance. We conclude that intensive treatment significantly attenuated increases in carotid-femoral pulse wave velocity and aortic elastance index. Attenuation of increases in aortic stiffness may be one of the mechanisms contributing to the benefit of intensive blood pressure treatment observed in SPRINT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.



Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016676; epub ahead of print
Upadhya B, Pajewski NM, Rocco MV, Hundley WG, ... Kitzman DW, SPRINT Research Group
Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016676; epub ahead of print | PMID: 33775127
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Impact:
Abstract

Prenatal Testosterone Associates With Blood Pressure in Young Adults: A Prospective Cohort Study.

Le-Ha C, Beilin LJ, Burrows S, Keelan JA, Hickey M, Mori TA
Preclinical evidence suggests that adult blood pressure (BP) may be modified by the prenatal endocrine environment. Specifically, in several animal models, higher prenatal testosterone exposure increases the risk of hypertension in later life. We investigated the prospective association between prenatal testosterone levels (as measured in umbilical cord blood) and BP at 20 to 27 years in 434 participants from the Raine Study. As expected, median bioavailable testosterone, the fraction of total testosterone either free or bound to serum albumin, was higher in males than females (0.12 [Q1-Q3, 0.09-0.19] versus 0.07 [Q1-Q3, 0.05-0.1] nmol/L; P<0.001). Mean (SD) systolic BP was 122.9 (±12.3) and 110.9 (±9.5) mm Hg at age 20 years and 122.4 (±11) and 111.2 (±9.1) mm Hg at 27 years in males and females, respectively. Using hierarchical mixed-effects models, higher cord blood bioavailable testosterone concentrations were associated with higher levels of systolic BP (P=0.007) and diastolic BP (P=0.002) in young adults at 20 and 27 years, after adjusting for change in BP over time and potential confounders. In these models, one SD increase in bioavailable testosterone equated to a 1 mm Hg increase in systolic BP (regression coefficient, 11.1 [95% CI, 4.1-21.11]) and diastolic BP (regression coefficient, 10.15 [95% CI, 3.67-15.93]). There was no significant difference detected between males and females in the association between bioavailable testosterone and adult BP. These data from a large unselected population indicate that higher fetal testosterone levels in late pregnancy are associated with higher BP in young adulthood.



Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016256; epub ahead of print
Le-Ha C, Beilin LJ, Burrows S, Keelan JA, Hickey M, Mori TA
Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016256; epub ahead of print | PMID: 33775121
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Impact:
Abstract

Pregnancy Outcomes and Blood Pressure Visit-to-Visit Variability and Level in Three Less-Developed Countries.

Magee LA, Bone J, Owasil SB, Singer J, ... von Dadelszen P, CLIP Study Group
In pregnancy in well-resourced settings, limited data suggest that higher blood pressure (BP) visit-to-visit variability may be associated with adverse pregnancy outcomes. Included were pregnant women in 22 intervention clusters of the CLIP (Community-Level Interventions for Preeclampsia) cluster randomized trials, who had received at least 2 prenatal contacts from a community health worker, including standardized BP measurement. Mixed-effects adjusted logistic regression assessed relationships between pregnancy outcomes and both BP level (median [interquartile range]) and visit-to-visit variability (SD and average real variability [ARV], adjusted for BP level), among all women and those who became hypertensive. The primary outcome was the CLIP composite of maternal and perinatal mortality and morbidity. Among 17 770 pregnancies, higher systolic and diastolic BP levels were associated with increased odds of the composite outcome per 5 mm Hg increase in BP (odds ratio [OR], 1.05 [95% CI, 1.03-1.07] and OR, 1.08 [1.06-1.11], respectively). Higher BP visit-to-visit variability was associated with increased odds, per a SD increase in BP variability measure, of (1) hypertension (systolic: OR, 2.09 [1.98-2.21] for SD and 1.52 [1.45-1.60] for ARV; diastolic: OR, 2.70 [2.54-2.87] for SD and 1.86 [1.76-1.96] for ARV); and (2) the composite outcome (systolic: OR, 1.10 [1.06-1.14] for SD and 1.06 [1.02-1.10] for ARV; diastolic: OR, 1.07 [1.03-1.11] for SD and 1.06 [1.02-1.09] for ARV). In 3 less-developed countries, higher BP level and visit-to-visit variability predicted adverse pregnancy outcomes, providing an opportunity for high-definition medicine.



Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016851; epub ahead of print
Magee LA, Bone J, Owasil SB, Singer J, ... von Dadelszen P, CLIP Study Group
Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016851; epub ahead of print | PMID: 33775120
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Impact:
Abstract

Blood Pressure Levels in Young Adulthood and Midlife Stroke Incidence in a Diverse Cohort.

Gerber Y, Rana JS, Jacobs DR, Yano Y, ... Lewis CE, Sidney S
We examined the longitudinal association between blood pressure (BP) and stroke incidence in young and middle-aged adults. BP measured during 9 examinations of the CARDIA study (Coronary Artery Risk Development in Young Adults) from 1985-1986 to 2015-2016 was used to classify participants (n=5079) according to the 2017 Hypertension Clinical Practice Guidelines. We used the highest BP obtained through the third examination (1990-1991) to define baseline BP categories; time-dependent categories (accounting for change in BP over time) were determined incorporating follow-up measurements. BP groups at ages 30 and 40 years were also defined. Stroke events were adjudicated until 2018. Mean age at baseline was 29.8 years. Stroke occurred in 100 participants. Stroke incidence (per 100 000 person-years) was higher (P<0.001) in Black (120 [95% CI, 95-149]) versus White (29 [95% CI, 18-46]) participants. After adjustment with Cox models for sociodemographic and cardiovascular risk factors, stage 2 hypertension was associated with a higher risk of stroke at baseline (hazard ratio, 3.72 [95% CI, 2.12-6.54]), as a time-dependent variable (hazard ratio, 5.84 [95% CI, 3.43-9.95]), at age 30 (hazard ratio, 4.14 [95% CI, 2.19-7.82]) and at age 40 (hazard ratio, 5.59 [95% CI, 3.35-9.31]), compared with normal BP. Elevated BP and stage 1 hypertension showed more modest increases in risk. As a continuous variable, systolic BP ≥90 mm Hg at age 40 was directly associated with stroke risk. These findings call for primordial prevention strategies to reduce population BP levels among young and middle-aged adults, particularly in Black young adults given ≈4-fold higher stroke incidence, including within values traditionally considered to be normal.



Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016535; epub ahead of print
Gerber Y, Rana JS, Jacobs DR, Yano Y, ... Lewis CE, Sidney S
Hypertension: 28 Mar 2021:HYPERTENSIONAHA12016535; epub ahead of print | PMID: 33775116
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Impact:
Abstract

High Cardiovascular Risk in Older Men With Severe Peripheral Artery Calcification on High-Resolution Peripheral QCT Scans: The STRAMBO Study.

Szulc P, Planckaert C, Foesser D, Patsch J, Chapurlat R
Objective
Arterial calcification is associated with high cardiovascular risk. Our aim was to assess the utility of peripheral arterial calcification (PAC) in distal forearm and distal leg for the prediction of acute coronary syndrome (ACS) and major adverse cardiovascular event in older men. Approach and
Results:
In 815 home-dwelling older men, PAC was assessed on the scans of distal forearm and leg obtained by high-resolution peripheral quantitative computed tomography. PAC score (0-12) was calculated on the basis of the number and severity in small peripheral arteries. The information on ACS and major adverse cardiovascular event was collected prospectively for 8 years. PAC severity increased with age and body mass index (P<0.001). Median PAC score was higher in men with ischemic heart disease or pharmacologically treated diabetes (P<0.001). After adjustment for confounders, the risk of ACS was higher in men with severe PAC (6+) versus men with lower PAC (0-5; HR, 3.86 [95% CI, 1.65-9.02], P<0.005). After adjustment for confounders, the risk of major adverse cardiovascular event was higher in men with severe PAC (6+) versus men with lower PAC (HR, 2.58 [95% CI, 1.41-4.72], P<0.005). In men who did not have cardiovascular risk factors, severe PAC was associated with higher risk of ACS, for example, in men who did not self-report ischemic heart disease (HR, 6.62 [95% CI, 2.16-20.23], P<0.001).
Conclusions
Severe PAC is associated with higher risk of ACS and major adverse cardiovascular event in older home-dwelling men, also in men without known ischemic heart disease. Incidentally found severe PAC can be a serious warning indicating high cardiovascular risk.



Arterioscler Thromb Vasc Biol: 31 Mar 2021:ATVBAHA120315289; epub ahead of print
Szulc P, Planckaert C, Foesser D, Patsch J, Chapurlat R
Arterioscler Thromb Vasc Biol: 31 Mar 2021:ATVBAHA120315289; epub ahead of print | PMID: 33792348
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Impact:
Abstract

Per-Particle Triglyceride-Rich Lipoproteins Imply Higher Myocardial Infarction Risk Than Low-Density Lipoproteins: Copenhagen General Population Study.

Johansen MØ, Vedel-Krogh S, Nielsen SF, Afzal S, Smith GD, Nordestgaard BG
Objective
ApoB (Apolipoprotein B)-containing triglyceride-rich lipoproteins and LDL (low-density lipoproteins) are each causal for myocardial infarction and atherosclerotic cardiovascular disease; however, the relative importance is unknown. We tested the hypothesis that for the same number of nonfasting apoB-containing particles from smaller LDL through to larger triglyceride-rich lipoproteins, the risk of myocardial infarction is similar. Approach and
Results:
We included 29 039 individuals with no history of myocardial infarction nested within 109 751 individuals from the Copenhagen General Population Study. Particle number of apoB-containing lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy. During a mean follow-up of 10 years, 2309 individuals developed myocardial infarction. Multivariable-adjusted hazard ratios for myocardial infarction per 1×1015 particles were higher with larger size and more triglyceride content of apoB-containing lipoproteins using ten different subfractions, ranging from 11 (95% CI, 5.6-22) for extra extra large VLDL (very-low-density lipoproteins) to 1.06 (1.05-1.07) for extra small VLDL to 1.02 (1.01-1.02) for IDL (intermediate-density lipoproteins), through to 1.01 (1.01-1.01) for small LDL. When combining the particle number of 6 VLDL subfractions and combining IDL and 3 LDL subfractions, hazard ratios for myocardial infarction per 1×1017 particles were 3.5 (2.7-4.5) for VLDL and 1.3 (1.2-1.4) for IDL and LDL combined.
Conclusions
For the same number of apoB-containing particles (1×1017 particles/L), the hazard ratio for myocardial infarction was 3.5-fold for VLDL and 1.3-fold for IDL and LDL combined. Biological implications include that VLDL particles are more atherogenic than LDL particles and clinically that VLDL and LDL should be measured separately.



Arterioscler Thromb Vasc Biol: 07 Apr 2021:ATVBAHA120315639; epub ahead of print
Johansen MØ, Vedel-Krogh S, Nielsen SF, Afzal S, Smith GD, Nordestgaard BG
Arterioscler Thromb Vasc Biol: 07 Apr 2021:ATVBAHA120315639; epub ahead of print | PMID: 33827253
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Impact:
Abstract

Antihypertensive Class and Cardiovascular Outcomes in Patients With HIV and Hypertension.

Rethy LB, Feinstein MJ, Achenbach CJ, Townsend RR, ... Shah SJ, Cohen JB
Given unique pathways contributing to hypertension among people with HIV, we sought to determine whether antihypertensive class was associated with cardiovascular disease (CVD) events among people with HIV. Among veterans with HIV and incident hypertension (2000-2018), we used propensity-score matching to evaluate risk of (1) incident/recurrent CVD or death, (2) incident CVD, and (3) incident heart failure by antihypertensive class. In supplementary analyses, we performed stratified analyses by race and chronic kidney disease status. Among 8041 veterans, 24% were initiated on ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blocker) monotherapy, 23% on thiazide/thiazide-like diuretic monotherapy, 13% on β-blocker monotherapy, and 11% on calcium channel blocker monotherapy. Over a median of 6.5 years, 25% experienced a CVD event. β-blockers, but not calcium channel blockers or diuretics, were associated with an increased risk of incident CVD compared with ACEs/ARBs (hazard ratio [95% CI], β-blockers 1.90 [1.24-2.89]; calcium channel blockers 1.02 [0.77-1.34]; diuretics 1.06 [0.86-1.31]); similar hazard ratio were noted for incident/recurrent CVD or death. In veterans without chronic kidney disease, ACE inhibitor/ARBs were associated with a lower risk of incident heart failure compared with all other classes (hazard ratio [95% CI]: β-blockers, 1.52 [1.11-2.09]; calcium channel blockers 1.48 [1.00-2.19]; diuretics 1.52 [1.07-2.16]). In conclusion, we observed high rates of CVD events in people with HIV with hypertension and a high prevalence of β-blocker use for initial hypertension management, even among those without indications. Our findings highlight the potential harm associated with β-blockers and the possible benefit associated with ACE inhibitor/ARBs for hypertension management in people with HIV. Prospective and randomized trials are needed to confirm these findings.



Hypertension: 04 Apr 2021:HYPERTENSIONAHA12016263; epub ahead of print
Rethy LB, Feinstein MJ, Achenbach CJ, Townsend RR, ... Shah SJ, Cohen JB
Hypertension: 04 Apr 2021:HYPERTENSIONAHA12016263; epub ahead of print | PMID: 33813847
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Impact:
Abstract

Impact of the 2017 American Academy of Pediatrics\' Clinical Practice Guideline on the Identification and Risk Stratification of Youth at Increased Cardiovascular Disease Risk.

Brady TM, Altemose K, Urbina EM
The updated clinical practice guideline (CPG) published by the American Academy of Pediatrics in 2017 introduced significant changes to the diagnostic and evaluative approach towards children with elevated blood pressure. The goals of this review were to summarize the current evidence regarding the impact of the new CPG on the identification and risk stratification of children at increased cardiovascular disease risk. Universally, the new CPG definitions of abnormal blood pressure led to more children classified as having a hypertensive blood pressure when compared with alternative definitions. Youth who moved to a higher blood pressure stage with the CPG typically had worse cardiometabolic profiles and more comorbidites. The association of CPG-defined hypertension and concurrent intermediate cardiovascular disease outcomes such as left ventricular hypertrophy and increased pulse wave velocity remains unclear; however, longitudinal data suggests an improved identification of those at greatest risk for adult cardiovascular disease with the CPG definitions. The majority of studies reviewed used blood pressure from one encounter, not replicate blood pressures from multiple visits, to define an abnormal or hypertensive blood pressure. Therefore, future studies investigating the prevalence of confirmed hypertension and the association between confirmed hypertension and outcomes are needed to optimally characterize the performance of the new CPG on identifying children at cardiovascular disease risk.



Hypertension: 04 Apr 2021:HYPERTENSIONAHA12114585; epub ahead of print
Brady TM, Altemose K, Urbina EM
Hypertension: 04 Apr 2021:HYPERTENSIONAHA12114585; epub ahead of print | PMID: 33813845
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Impact:
Abstract

Relationship Between Blood Pressure and Incident Cardiovascular Disease: Linear and Nonlinear Mendelian Randomization Analyses.

Malik R, Georgakis MK, Vujkovic M, Damrauer SM, ... Dichgans M, Gill D
Observational studies exploring whether there is a nonlinear effect of blood pressure on cardiovascular disease (CVD) risk are hindered by confounding. This limitation can be overcome by leveraging randomly allocated genetic variants in nonlinear Mendelian randomization analyses. Based on their association with blood pressure traits in a genome-wide association study of 299 024 European ancestry individuals, we selected 253 genetic variants to proxy the effect of modifying systolic and diastolic blood pressure. Considering the outcomes of incident coronary artery disease, stroke and the combined outcome of CVD, linear and nonlinear Mendelian randomization analyses were performed on 255 714 European ancestry participants without a history of CVD or antihypertensive medication use. There was no evidence favoring nonlinear relationships of genetically proxied systolic and diastolic blood pressure with the cardiovascular outcomes over linear relationships. For every 10-mm Hg increase in genetically proxied systolic blood pressure, risk of incident CVD increased by 49% (hazard ratio, 1.49 [95% CI, 1.38-1.61]), with similar estimates obtained for coronary artery disease (hazard ratio, 1.50 [95% CI, 1.38-1.63]) and stroke (hazard ratio, 1.44 [95% CI, 1.22-1.70]). Genetically proxied blood pressure had a similar relationship with CVD in men and women. These findings provide evidence to support that even for individuals who do not have elevated blood pressure, public health interventions achieving persistent blood pressure reduction will be of considerable benefit in the primary prevention of CVD.



Hypertension: 04 Apr 2021:HYPERTENSIONAHA12016534; epub ahead of print
Malik R, Georgakis MK, Vujkovic M, Damrauer SM, ... Dichgans M, Gill D
Hypertension: 04 Apr 2021:HYPERTENSIONAHA12016534; epub ahead of print | PMID: 33813844
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Impact:
Abstract

Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease.

Levin MG, Klarin D, Walker VM, Gill D, ... Voight BF, Damrauer SM
Objective
We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease. Approach and
Results:
Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16-1.25] per 10 mm Hg increase, P=1×10-24; diastolic BP OR, 1.27 [1.18-1.35], P=4×10-11; MAP OR, 1.26 [1.19-1.33], P=6×10-16; pulse pressure OR, 1.31 [1.24-1.39], P=9×10-23). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of Ors, 1.06 [1.0-1.12], P=0.04; MAP ratio of OR, 1.15 [1.06-1.26], P=8.6×10-4; diastolic BP ratio of OR, 1.21 [1.08-1.35], P=6.9×10-4). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17-1.35], P=3×10-10; MAP OR, 1.14 [1.06-1.23], P=2×10-4). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via β-blocker (OR, 0.74 per 10 mm Hg decrease in SBP [95% CI, 0.65-0.84]; P=5×10-6), loop diuretic (OR, 0.66 [0.48-0.91], P=0.01), and thiazide diuretic (OR, 0.57 [0.41-0.79], P=6×10-4) associated variants were protective of PAD.
Conclusions
Higher BP is likely to cause PAD. BP-lowering through β blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.



Arterioscler Thromb Vasc Biol: 14 Apr 2021:ATVBAHA120315482; epub ahead of print
Levin MG, Klarin D, Walker VM, Gill D, ... Voight BF, Damrauer SM
Arterioscler Thromb Vasc Biol: 14 Apr 2021:ATVBAHA120315482; epub ahead of print | PMID: 33853351
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Impact:
Abstract

Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement: How Would You Manage This Patient With Severe Aortic Stenosis? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Reynolds EE, Baron SJ, Kaneko T, Libman H
Aortic stenosis (AS) is common, especially among the elderly. Left untreated, severe symptomatic AS is typically fatal. Surgical aortic valve replacement (SAVR) was the standard of care until transcatheter aortic valve replacement (TAVR) was shown to have lower mortality rates in patients at the highest surgical risk and was recommended for this group in the 2014 American Heart Association/American College of Cardiology (AHA/ACC) guidelines. In the 2017 AHA/ACC focused update, evidence of benefit and noninferiority extended the use of TAVR to intermediate-risk patients. More recent studies suggest potential benefit to low-risk patients, although no published guidelines yet recommend the use of TAVR for this population. An advantage of SAVR is a 30-year experience with valve durability, but SAVR may have higher rates of perioperative death and a slower return of quality of life. Although TAVR has less than 10-year experience with valve durability, it has lower or noninferior primary end points, such as mortality and stroke, and fewer periprocedural complications among anatomically permissive patients. Here, a cardiologist and a cardiothoracic surgeon debate the risks and benefits of TAVR versus SAVR for a patient with severe symptomatic AS who is at low risk for surgical death.



Ann Intern Med: 30 Mar 2021; 174:521-528
Reynolds EE, Baron SJ, Kaneko T, Libman H
Ann Intern Med: 30 Mar 2021; 174:521-528 | PMID: 33844572
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Impact:
Abstract

Risk of left atrial appendage thrombus and stroke in patients with atrial fibrillation and mitral regurgitation.

Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Objective
To investigate the association of mitral regurgitation (MR) on thromboembolic risk of patients with non-valvular atrial fibrillation (NVAF) undergoing transoesophageal echocardiography (TEE)-guided cardioversion.
Methods
Data for consecutive patients who underwent TEE-guided cardioversion for NVAF between 2000 and 2012 were analysed. MR severity was assessed by Doppler echocardiography and classified as ≤mild, moderate or severe. Left atrial appendage emptying velocities were averaged for five consecutive cycles. Multivariable regression models were used to identify independent predictors of left atrial appendage thrombus (LAAT) and stroke.
Results
2950 patients (age, 69.3±12.2 years, 67% men) were analysed. 2173 (73.7%) had ≤mild MR; 631 (21.4%), moderate MR; and 146 (4.9%), severe MR. Patients with moderate (age, 72.4±10.7 years) and severe (age, 72.8±12.1 years) MR were older than those with ≤mild MR (age, 68.2±12.5 years). The prevalence of LAAT was 1.5% (n=43). CHA2DS2-VASc scores (≤mild MR, 3.0±1.6; moderate MR, 3.5±1.5; severe MR, 3.9±1.5; p<0.001) and heart failure frequency (≤mild MR, 38.4%; moderate MR, 48.0%; severe MR, 69.2%; p<0.001) were increasingly higher with greater MR severity. Multivariable logistic regression analysis showed no association of moderate MR (OR 0.77, 95% CI 0.38 to 1.56) or severe MR (OR 0.55, 95% CI 0.21 to 1.49) with LAAT. During a mean follow-up of 7.3±5.1 years (median 7.5, IQR, 2.7-10.9), 216 patients had an ischaemic stroke. Adjusted Cox regression analysis showed no significant association of moderate MR (HR 1.22, 95% CI 0.88 to 1.68) or severe MR (HR 0.73, 95% CI 0.31 to 1.46) with stroke.
Conclusions
Among patients with NVAF, the presence or severity of MR was not associated with a decreased risk of LAAT or stroke.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 24 Mar 2021; epub ahead of print
Melduni R, Nkomo VT, Wysokinski W, Gersh BJ, ... Oh JK, Lee HC
Heart: 24 Mar 2021; epub ahead of print | PMID: 33766985
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Impact:
Abstract

Prognostic implications of left atrial dilation in aortic regurgitation due to bicuspid aortic valve.

Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Objective
To investigate the prognostic value of left atrial volume index (LAVI) in patients with moderate to severe aortic regurgitation (AR) and bicuspid aortic valve (BAV).
Methods
554 individuals (45 (IQR 33-57) years, 80% male) with BAV and moderate or severe AR were selected from an international, multicentre registry. The association between LAVI and the combined endpoint of all-cause mortality or aortic valve surgery was investigated with Cox proportional hazard regression analyses.
Results
Dilated LAVI was observed in 181 (32.7%) patients. The mean indexed aortic annulus, sinus of Valsalva, sinotubular junction and ascending aorta diameters were 13.0±2.0 mm/m2, 19.4±3.7 mm/m2, 16.5±3.8 mm/m2 and 20.4±4.5 mm/m2, respectively. After a median follow-up of 23 (4-82) months, 272 patients underwent aortic valve surgery (89%) or died (11%). When compared with patients with normal LAVI (<35 mL/m2), those with a dilated LAVI (≥35 mL/m2) had significantly higher rates of aortic valve surgery or mortality (43% and 60% vs 23% and 36%, at 1 and 5 years of follow-up, respectively, p<0.001). Dilated LAVI was independently associated with reduced event-free survival (HR=1.450, 95% CI 1.085 to 1.938, p=0.012) after adjustment for LV ejection fraction, aortic root diameter, LV end-diastolic diameter and LV end-systolic diameter.
Conclusions
In this large, multicentre registry of patients with BAV and moderate to severe AR, left atrial dilation was independently associated with reduced event-free survival. The role of this parameter for the risk stratification of individuals with significant AR merits further investigation.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 07 Apr 2021; epub ahead of print
Butcher SC, Fortuni F, Kong W, Vollema EM, ... Bax JJ, Delgado V
Heart: 07 Apr 2021; epub ahead of print | PMID: 33833069
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Impact:
Abstract

Anxa1 in smooth muscle cells protects against acute aortic dissection.

Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Aims
Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signaling system that protects AAD progression exists, remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD.
Methods and results
We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas.
Conclusions
Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents acute aortic dissection by inhibiting vascular smooth muscle cell phenotype switching, suggesting that Anxa1 signaling may be a potential target for AAD pharmacological therapy.
Translational perspective
Our studies herein may lead to a paradigm shift for pharmacologic therapy towards acute aortic dissection. Through careful examination of the pathological changes that occur during AAD onset in experimental animal models, we demonstrated that VSMC phenotype switching plays a critical role in the development of AAD. Inhibition of VSMC phenotype switching and its attendant impacts on aortic function may be a viable approach for future treatment. Toward that end, our studies highlighted the protective benefit of Anxa1 and its mimetic peptide Ac2-26 in AAD through prevention of the switching of VSMC to a synthetic phenotype.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions please email: [email protected]

Cardiovasc Res: 22 Mar 2021; epub ahead of print
Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Cardiovasc Res: 22 Mar 2021; epub ahead of print | PMID: 33757117
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Abstract

Continuous electrocardiography for detecting atrial fibrillation beyond 1 year after stroke in primary care.

Lyckhage LF, Hansen ML, Toft JC, Larsen SL, ... Ali AM, Wienecke T
Background:
and purpose
The diagnostic benefit of using continuous ECG (cECG) for poststroke atrial fibrillation (AF) screening in a primary care setting is unclear. We aimed to assess the diagnostic yield from screening patients who previously had a stroke with a 7-day Holter monitor.
Methods
Patients older than 49 years, naive to AF, with an ischaemic stroke over 1 year before enrolment were included. In a primary care setting, all patients were screened for AF using pulse palpation, 12-lead ECG and 7-day Holter monitoring. Further, NT-proBNP was determined at baseline.
Results
7-day Holter monitoring uncovered AF in 17 of 366 patients (4.6% (95% CI 2.7 to 7.3)). The number needed to screen was 22 patients (14-37). 12-lead ECG uncovered AF in 3 patients (0.82% (95% CI 0.17 to 2.4)), and 122 patients had irregular pulse during pulse palpation (33.5% (95% CI 28.7 to 38.2)). When using 7-day Holter monitoring as reference standard, the sensitivity of pulse palpation and 12-lead ECG was 47% (95% CI 23% to 72%) and 18% (95% CI 4% to 43%). High levels (≥400 pg/mL) of NT-proBNP versus low levels (≤200 pg/mL) were not associated with AF in the univariate analysis nor when adjusted for age (OR 2.4 (95% CI 0.5 to 8.4) and 1.6 (95% CI 0.3 to 6.0)).
Conclusions
A relevant proportion of patients with stroke more than 1 year before inclusion were diagnosed with AF through 7-day Holter monitoring. Given the low sensitivities of pulse palpation and 12-lead ECG, additional cECG may be considered during poststroke primary care follow-up.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:635-641
Lyckhage LF, Hansen ML, Toft JC, Larsen SL, ... Ali AM, Wienecke T
Heart: 30 Mar 2021; 107:635-641 | PMID: 32620555
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Impact:
Abstract

Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics.

Swerdlow DI, Rider DA, Yavari A, Lindholm MW, Campion GV, Nissen SE
Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein (a) Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that lipoprotein(a) is an important genetically-determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure and peripheral vascular disease. Accordingly, the need for specific lipoprotein(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining \'high risk\' is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine (GalNAc)-conjugated gene silencing therapeutics such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable lipoprotein(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of lipoprotein(a) across the cardiovascular disease spectrum, examine the role of established lipid modifying therapies in lowering lipoprotein(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing lipoprotein(a)-related disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 24 Mar 2021; epub ahead of print
Swerdlow DI, Rider DA, Yavari A, Lindholm MW, Campion GV, Nissen SE
Cardiovasc Res: 24 Mar 2021; epub ahead of print | PMID: 33769464
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Impact:
Abstract

Single high-sensitivity troponin levels to assess patients with potential acute coronary syndromes.

Barnes C, Fatovich DM, Macdonald SPJ, Alcock RF, ... Schultz CJ, Hillis GS
Objective
We tested the hypothesis that patients with a potential acute coronary syndrome (ACS) and very low levels of high-sensitivity cardiac troponin I can be efficiently and safely discharged from the emergency department after a single troponin measurement.
Methods
This prospective cohort study recruited 2255 consecutive patients aged ≥18 years presenting to the Emergency Department, Royal Perth Hospital, Western Australia, with chest pain without high-risk features but requiring the exclusion of ACS. Patients were managed using a guideline-recommended pathway or our novel Single Troponin Accelerated Triage (STAT) pathway. The primary outcome was the percentage of patients discharged in <3 hours. Secondary outcomes included the duration of observation and death or acute myocardial infarction in the next 30 days.
Results
The study enrolled 1131 patients to the standard cohort and 1124 to the STAT cohort. Thirty-eight per cent of the standard cohort were discharged directly from emergency department compared with 63% of the STAT cohort (p<0.001). The median duration of observation was 4.3 (IQR 3.3-7.1) hours in the standard cohort and 3.6 (2.6-5.4) hours in the STAT cohort (p<0.001), with 21% and 38% discharged in <3 hours, respectively (p<0.001). No patients discharged directly from the emergency department died or suffered an acute myocardial infarction within 30 days in either cohort.
Conclusions
Among low-risk patients with a potential ACS, a pathway which incorporates early discharge based on a single very low level of high-sensitivity cardiac troponin increases the proportion of patients discharged directly from the emergency department, reduces length of stay and is safe.
Trial registration number
ACTRN12618000797279.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:721-727
Barnes C, Fatovich DM, Macdonald SPJ, Alcock RF, ... Schultz CJ, Hillis GS
Heart: 29 Apr 2021; 107:721-727 | PMID: 33436490
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Impact:
Abstract

Guideline-Driven Management of Hypertension: An Evidence-Based Update.

Carey RM, Wright JT, Taler SJ, Whelton PK
Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.



Circ Res: 01 Apr 2021; 128:827-846
Carey RM, Wright JT, Taler SJ, Whelton PK
Circ Res: 01 Apr 2021; 128:827-846 | PMID: 33793326
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Impact:
Abstract

Recreational substance use among patients with premature atherosclerotic cardiovascular disease.

Mahtta D, Ramsey D, Krittanawong C, Al Rifai M, ... Petersen LA, Virani SS
Objective
Despite an upsurge in the incidence of atherosclerotic cardiovascular diseases (ASCVD) among young adults, the attributable risk of recreational substance use among young patients has been incompletely evaluated. We evaluated the association of all recreational substances with premature and extremely premature ASCVD.
Methods
In a cross-sectional analysis using the 2014-2015 nationwide Veterans Affairs Healthcare database and the Veterans wIth premaTure AtheroscLerosis (VITAL) registry, patients were categorised as having premature, extremely premature or non-premature ASCVD. Premature ASCVD was defined as having first ASCVD event at age <55 years for men and <65 years for women. Extremely premature was defined as having first ASCVD event at age <40 years while non-premature ASCVD was defined as having first ASCVD event at age ≥55 years for men and ≥65 years for women. Patients with premature ASCVD (n=135 703) and those with extremely premature ASCVD (n=7716) were compared against patients with non-premature ASCVD (n=1 112 455). Multivariable logistic regression models were used to study the independent association of all recreational substances with premature and extremely premature ASCVD.
Results
Compared with patients with non-premature ASCVD, patients with premature ASCVD had a higher use of tobacco (62.9% vs 40.6%), alcohol (31.8% vs 14.8%), cocaine (12.9% vs 2.5%), amphetamine (2.9% vs 0.5%) and cannabis (12.5% vs 2.7%) (p<0.01 for all comparisons). In adjusted models, the use of tobacco (OR 1.97, 95% CI 1.94 to 2.00), alcohol (OR 1.50, 95% CI 1.47 to 1.52), cocaine (OR 2.44, 95% CI 2.38 to 2.50), amphetamine (OR 2.74, 95% CI 2.62 to 2.87), cannabis (OR 2.65, 95% CI 2.59 to 2.71) and other drugs (OR 2.53, 95% CI 2.47 to 2.59) was independently associated with premature ASCVD. Patients with polysubstance use had a graded response with the highest risk (~9-fold) of premature ASCVD among patients with use of ≥4 recreational substances. Similar trends were observed among patients with extremely premature ASCVD. Gender interactions with substance use were significant (p-interaction <0.05), with recreational substance use and premature ASCVD showing stronger associations among women than in men with premature ASCVD.
Conclusions
All subgroups of recreational substances were independently associated with a higher likelihood of premature and extremely premature ASCVD. Recreational substance use confers a greater magnitude of risk for premature ASCVD among women. A graded response relationship exists between increasing number of recreational substances used and higher likelihood of early-onset ASCVD.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:650-656
Mahtta D, Ramsey D, Krittanawong C, Al Rifai M, ... Petersen LA, Virani SS
Heart: 30 Mar 2021; 107:650-656 | PMID: 33589427
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Impact:
Abstract

Relative survival after aortic valve surgery in patients with bicuspid aortic valves.

Glaser N, Jackson V, Eriksson P, Sartipy U, Franco-Cereceda A
Objectives
The objective of this cohort study was to analyse long-term relative survival in patients with bicuspid aortic valve (BAV) who underwent aortic valve surgery.
Methods
We studied 865 patients with BAVs who participated in three prospective cohort studies of elective, open-heart, aortic valve surgery at the Karolinska University Hospital, Stockholm, Sweden, between 2007 and 2020. The expected survival for the age, sex and calendar year-matched general Swedish population was obtained from the Human Mortality Database. The Ederer II method was used to calculate relative survival, which was used as an estimate of cause-specific survival.
Results
No differences were found in the observed versus expected survival at 1, 5, 10 or 12 years: 99%, 94%, 83% and 76% vs 99%, 93%, 84% and 80%, respectively. The relative survival at 1, 5, 10 and 12 years was 100% (95% CI 99% to 100%), 101% (95% CI 99% to 103%), 99% (95% CI 95% to 103%) and 95% (95% CI 87% to 102%), respectively. The relative survival at the end of follow-up tended to be lower for women than men (86% vs 95%). The mean follow-up was 6.3 years (maximum 13.3 years).
Conclusions
The survival of patients with BAV following aortic valve surgery was excellent and similar to that of the general population. Our results suggest that the timing of surgery according to current guidelines is correct and provide robust long-term survival rates, as well as important information about the natural history of BAV in patients following aortic valve surgery.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Heart: 22 Mar 2021; epub ahead of print
Glaser N, Jackson V, Eriksson P, Sartipy U, Franco-Cereceda A
Heart: 22 Mar 2021; epub ahead of print | PMID: 33622679
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Impact:
Abstract

Severe alpha-1-antitrypsin deficiency increases the risk of venous thromboembolism.

Basil N, Ekström M, Piitulainen E, Lindberg A, ... Jehpsson L, Tanash H
Background
Severe Alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is associated with increased risk of liver disease and chronic obstructive pulmonary disease (COPD), but the risk of venous thromboembolism (VTE) is unknown. Our aim was to evaluate the risk of VTE in individuals with severe AATD compared with control subjects from the general population.
Methods
Individuals with severe AATD (n=1577) were recruited from the Swedish national AATD register. Control subjects (n=5969) were selected from the OLIN (Obstructive lung disease in Northern Sweden) studies, that include a random general population sample. Longitudinal data on VTE and diagnoses were obtained from the Swedish National Patient Registry. Associations were analyzed using multivariable Cox regression.
Results
At inclusion, 46% of the AATD individuals and 53% of the controls were never-smokers. COPD was present in 46% of the AATD individuals compared with 4% of the controls. During a median follow-up of 18 years, 116 (7%) of the AATD individuals and 89 (1%) of the control subjects developed VTE, unadjusted hazard ratio (HR) 6.5 (95% CI, 4.9-8.6). Risk factors for incident VTE were male gender, age, COPD, cancer and liver disease. Adjusting for these factors, the AATD individuals had a significantly higher risk of incident VTE, adjusted HR 4.2 (95% CI 2.9-6.2) as compared with the controls.
Conclusion
Subjects with severe AATD have considerably increased risk of developing VTE compared with the general population, even after accounting for risk factors. This calls for optimized risk factor management and clinical follow-up of this patient group.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 23 Mar 2021; epub ahead of print
Basil N, Ekström M, Piitulainen E, Lindberg A, ... Jehpsson L, Tanash H
J Thromb Haemost: 23 Mar 2021; epub ahead of print | PMID: 33763945
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Impact:
Abstract

Arterial Stiffness and Cardiovascular Risk in Hypertension.

Boutouyrie P, Chowienczyk P, Humphrey JD, Mitchell GF
Arterial stiffness, a leading marker of risk in hypertension, can be measured at material or structural levels, with the latter combining effects of the geometry and composition of the wall, including intramural organization. Numerous studies have shown that structural stiffness predicts outcomes in models that adjust for conventional risk factors. Elastic arteries, nearer to the heart, are most sensitive to effects of blood pressure and age, major determinants of stiffness. Stiffness is usually considered as an index of vascular aging, wherein individuals excessively affected by risk factor exposure represent early vascular aging, whereas those resistant to risk factors represent supernormal vascular aging. Stiffness affects the function of the brain and kidneys by increasing pulsatile loads within their microvascular beds, and the heart by increasing left ventricular systolic load; excessive pressure pulsatility also decreases diastolic pressure, necessary for coronary perfusion. Stiffness promotes inward remodeling of small arteries, which increases resistance, blood pressure, and in turn, central artery stiffness, thus creating an insidious feedback loop. Chronic antihypertensive treatments can reduce stiffness beyond passive reductions due to decreased blood pressure. Preventive drugs, such as lipid-lowering drugs and antidiabetic drugs, have additional effects on stiffness, independent of pressure. Newer anti-inflammatory drugs also have blood pressure independent effects. Reduction of stiffness is expected to confer benefit beyond the lowering of pressure, although this hypothesis is not yet proven. We summarize different steps for making arterial stiffness measurement a keystone in hypertension management and cardiovascular prevention as a whole.



Circ Res: 01 Apr 2021; 128:864-886
Boutouyrie P, Chowienczyk P, Humphrey JD, Mitchell GF
Circ Res: 01 Apr 2021; 128:864-886 | PMID: 33793325
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Impact:
Abstract

Hypertension and Prohypertensive Antineoplastic Therapies in Cancer Patients.

van Dorst DCH, Dobbin SJH, Neves KB, Herrmann J, ... Danser AHJ, Lang NN
The development of a wide range of novel antineoplastic therapies has improved the prognosis for patients with a wide range of malignancies, which has increased the number of cancer survivors substantially. Despite the oncological benefit, cancer survivors are exposed to short- and long-term adverse cardiovascular toxicities associated with anticancer therapies. Systemic hypertension, the most common comorbidity among cancer patients, is a major contributor to the increased risk for developing these adverse cardiovascular events. Cancer and hypertension have common risk factors, have overlapping pathophysiological mechanisms and hypertension may also be a risk factor for some tumor types. Many cancer therapies have prohypertensive effects. Although some of the mechanisms by which these antineoplastic agents lead to hypertension have been characterized, further preclinical and clinical studies are required to investigate the exact pathophysiology and the optimal management of hypertension associated with anticancer therapy. In this way, monitoring and management of hypertension before, during, and after cancer treatment can be improved to minimize cardiovascular risks. This is vital to optimize cardiovascular health in patients with cancer and survivors, and to ensure that advances in terms of cancer survivorship do not come at the expense of increased cardiovascular toxicities.



Circ Res: 01 Apr 2021; 128:1040-1061
van Dorst DCH, Dobbin SJH, Neves KB, Herrmann J, ... Danser AHJ, Lang NN
Circ Res: 01 Apr 2021; 128:1040-1061 | PMID: 33793337
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Impact:
Abstract

Safety, efficacy and impact on frailty of mini-invasive radial balloon aortic valvuloplasty.

Tumscitz C, Di Cesare A, Balducelli M, Piva T, ... Campo G, Biscaglia S
Objective
The study was designed to: (1) confirm safety and feasibility of mini-invasive radial balloon aortic valvuloplasty (BAV); (2) assess its impact in terms of quality of life and frailty; and (3) evaluate whether changes in frailty after BAV are associated with death in patients undergoing transcatheter aortic valve implantation (TAVI).
Methods
330 patients undergoing BAV in 16 Italian centres were prospectively included. The primary endpoint was the occurrence of major and minor Valve Academic Research Consortium (VARC)-2 bleeding. Secondary endpoints were scales of quality of life, frailty, evaluated at baseline and 30 days, and their relationship with the occurrence of all-cause death.
Results
BAV was performed by radial access in 314 (95%) patients. No VARC-2 major and six (1.8%) VARC-2 minor bleedings occurred in the study population. Quality of life, as well as frailty status, significantly improved 30 days after BAV. At 1 year, patients undergoing TAVI with baseline essential frailty toolset (EFT) <3 or achieving an EFT <3 after BAV had a comparable occurrence of all-cause death (15% vs 19%, p=0.58). On the contrary, patients with EFT ≥3 at 30 days despite BAV showed the worst prognosis (all-cause death: 40% vs 15% and 19%, p=0.006 and p=0.05, respectively).
Conclusions
Mini-invasive radial BAV is safe, feasible and associated with a low rate of vascular complications. Patients improving EFT 30 days after BAV showed a favourable outcome after TAVI.
Trial registration number
NCT03087552.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 23 Mar 2021; epub ahead of print
Tumscitz C, Di Cesare A, Balducelli M, Piva T, ... Campo G, Biscaglia S
Heart: 23 Mar 2021; epub ahead of print | PMID: 33627400
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Impact:
Abstract

Hospital variation of 30-day readmission rate following transcatheter aortic valve implantation.

Ando T, Ashraf S, Kuno T, Briasoulis A, ... Grines C, Malik A
Objectives
Thirty-day readmission rate is one of the hospital quality metrics. Outcomes of transcatheter aortic valve implantation (TAVI) have improved significantly, but it remains unclear whether hospital-level variance in 30-day readmission rate exists in the contemporary TAVI era.
Methods
From the 2017 US Nationwide Readmission Database, endovascular TAVI were identified. The unadjusted 30-day readmission rate and 30-day risk-standardised readmission rate (RSRR) were calculated and we then conducted model testing to determine the relative contribution of hospital characteristics, patient-level covariates and economic status to the variation in readmission rates observed between the hospitals.
Results
A total of 44 899 TAVI from 338 hospitals were identified. The range of unadjusted 30-day readmission rate and 30-day RSRR was 2.0%-33.3% and 9.4%-15.3%, respectively. Median 30-day RSRR was 11.8% and there was a significant hospital-level variation (median OR 1.22, 95% CI 1.16 to 1.32, p<0.01) and this was similar in both readmissions caused due to major cardiac and non-cardiac conditions. Patient, hospital and economic factors accounted for 9.6%, 1.9% and 3.8% of the variability in hospital readmission rate, respectively.
Conclusions
There was significant hospital-level variation in 30-day RSRR following TAVI. Further measures are required to mitigate this variance in the readmission rate.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 23 Mar 2021; epub ahead of print
Ando T, Ashraf S, Kuno T, Briasoulis A, ... Grines C, Malik A
Heart: 23 Mar 2021; epub ahead of print | PMID: 33627399
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Impact:
Abstract

Increased risk of infective endocarditis after traumatic skin wound.

Ohbe H, Iwagami M, Sasabuchi Y, Yasunaga H
Objective
Current data suggest that a history of traumatic open skin wounds may be a risk factor for infectious endocarditis, with limited evidence. We tested the hypothesis that traumatic skin wound is a risk factor for infectious endocarditis.
Methods
Using the Japan Medical Data Center (JMDC) database (4 650 927 people aged 20-64 years, 2012-2018) and the Kumamoto database (493 414 people aged ≥65 years, 2012-2017), we conducted nested case-control and self-controlled case series (SCCS) analyses.
Results
In the JMDC database, 544 cases hospitalised for infective endocarditis (IE) were matched with 2091 controls; 2.8% of cases and 0.5% of controls were exposed to traumatic skin wounds in the previous 1-4 weeks, with an adjusted OR of 4.31 (95% CI 1.74 to 10.7). In the Kumamoto database, 4.0% (27/670) of cases and 1.1% (29/2581) of controls were exposed to traumatic skin wounds in the previous 1-4 weeks, with an adjusted OR of 4.15 (95% CI 2.04 to 8.46). In the SCCS, the incidence rate ratios for IE were 2.61 (95% CI 1.67 to 4.09), 1.73 (95% CI 1.01 to 2.94), 1.19 (95% CI 0.63 to 2.27) and 1.52 (95% CI 0.82 to 2.74) for the Kumamoto database and 3.78 (95% CI 2.07 to 6.92), 1.58 (95% CI 0.64 to 3.89), 1.60 (95% CI 0.65 to 3.94) and 1.29 (95% CI 0.47 to 3.53) for the JMDC database at 1-4, 5-8, 9-12 and 13-16 weeks after traumatic skin wound, respectively, compared with the baseline period.
Conclusions
This study suggests that traumatic skin wound is a risk factor for IE 1-4 weeks after the wound.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 24 Mar 2021; epub ahead of print
Ohbe H, Iwagami M, Sasabuchi Y, Yasunaga H
Heart: 24 Mar 2021; epub ahead of print | PMID: 33632746
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Impact:
Abstract

Newly diagnosed diabetes and outcomes after acute myocardial infarction in young adults.

Ding Q, Spatz ES, Lipska KJ, Lin H, ... Bueno H, Krumholz HM
Objective
To examine prevalence and characteristics of newly diagnosed diabetes (NDD) in younger adults hospitalised with acute myocardial infarction (AMI) and investigate whether NDD is associated with health status and clinical outcomes over 12-month post-AMI.
Methods
In individuals (18-55 years) admitted with AMI, without established diabetes, we defined NDD as (1) baseline or 1-month HbA1c≥6.5%; (2) discharge diabetes diagnosis or (3) diabetes medication initiation within 1 month. We compared baseline characteristics of NDD, established diabetes and no diabetes, and their associations with baseline, 1-month and 12-month health status (angina-specific and non-disease specific), mortality and in-hospital complications.
Results
Among 3501 patients in Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients study, 14.5% met NDD criteria. Among 508 patients with NDD, 35 (6.9%) received discharge diagnosis, 91 (17.9%) received discharge diabetes education and 14 (2.8%) initiated pharmacological treatment within 1 month. NDD was more common in non-White (OR 1.58, 95% CI 1.23 to 2.03), obese (OR 1.72, 95% CI 1.39 to 2.12), financially stressed patients (OR 1.27, 95% CI 1.02 to 1.58). Compared with established diabetes, NDD was independently associated with better disease-specific health status and quality of life (p≤0.04). No significant differences were found in unadjusted in-hospital mortality and complications between NDD and established or no diabetes.
Conclusions
NDD was common among adults≤55 years admitted with AMI and was more frequent in non-White, obese, financially stressed individuals. Under 20% of patients with NDD received discharge diagnosis or initiated discharge diabetes education or pharmacological treatment within 1 month post-AMI. NDD was not associated with increased risk of worse short-term health status compared with risk noted for established diabetes.
Trial registration number
NCT00597922.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:657-666
Ding Q, Spatz ES, Lipska KJ, Lin H, ... Bueno H, Krumholz HM
Heart: 30 Mar 2021; 107:657-666 | PMID: 33082173
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Impact:
Abstract

Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants.

Adam L, Feller M, Syrogiannouli L, Del-Giovane C, ... Rodondi N, SWISS-AF Investigators
Objective
Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs.
Methods
We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the β-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel\'s c-statistics for model discrimination.
Results
We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80).
Conclusion
In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination.

© 2021 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 30 Mar 2021; 19:931-940
Adam L, Feller M, Syrogiannouli L, Del-Giovane C, ... Rodondi N, SWISS-AF Investigators
J Thromb Haemost: 30 Mar 2021; 19:931-940 | PMID: 33501722
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Impact:
Abstract

Racial differences in management and outcomes of acute myocardial infarction during COVID-19 pandemic.

Rashid M, Timmis A, Kinnaird T, Curzen N, ... Gale CP, Mamas M
Objective
There are concerns that healthcare and outcomes of black, Asian and minority ethnic (BAME) communities are disproportionately impacted by the COVID-19 pandemic. We investigated admission rates, treatment and mortality of BAME with acute myocardial infarction (AMI) during COVID-19.
Methods
Using multisource national healthcare records, patients hospitalised with AMI in England during 1 February-27 May 2020 were included in the COVID-19 group, whereas patients admitted during the same period in the previous three consecutive years were included in a pre-COVID-19 group. Multilevel hierarchical regression analyses were used to quantify the changes in-hospital and 7-day mortality in BAME compared with whites.
Results
Of 73 746 patients, higher proportions of BAME patients (16.7% vs 10.1%) were hospitalised with AMI during the COVID-19 period compared with pre-COVID-19. BAME patients admitted during the COVID-19 period were younger, male and likely to present with ST-elevation acute myocardial infarction. COVID-19 BAME group admitted with non-ST-elevation acute myocardial infarction less frequently received coronary angiography (86.1% vs 90.0%, p<0.001) and had a longer median delay to reperfusion (4.1 hours vs 3.7 hours, p<0.001) compared with whites. BAME had higher in-hospital (OR 1.68, 95% CI 1.27 to 2.28) and 7-day mortality (OR 1.81 95% CI 1.31 to 2.19) during COVID-19 compared with pre-COVID-19 period.
Conclusion
In this multisource linked cohort study, compared with whites, BAME patients had proportionally higher hospitalisation rates with AMI, less frequently received guidelines indicated care and had higher early mortality during COVID-19 period compared with pre-COVID-19 period. There is a need to develop clinical pathways to achieve equity in the management of these vulnerable populations.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:734-740
Rashid M, Timmis A, Kinnaird T, Curzen N, ... Gale CP, Mamas M
Heart: 29 Apr 2021; 107:734-740 | PMID: 33685933
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Impact:
Abstract

Association of cardiovascular health and incident atrial fibrillation in elderly population.

Lee JH, Yang PS, Yu HT, Kim TH, ... Lee MH, Joung B
Objective
To evaluate whether baseline and changes in cardiovascular health (CVH) were related to incident atrial fibrillation (AF) risk in the elderly population.
Methods
From the Korea National Health Insurance Service-Senior cohort, we included 208 598 participants without prior AF (median age: 70 (IQR 66-74) years; 90 916 (43.6%) men) who underwent national health check-ups between 1 January 2005 and 31 December 2012. Using the six metrics of the American Heart Association, participants were categorised as having low, moderate and high CVH.
Results
Over a median follow-up of 7.2 years, 7818 cases of incident AF occurred. In multivariable analysis, moderate (HR: 0.90; 95% CI: 0.86 to 0.94) and high (HR: 0.81; 95% CI: 0.73 to 0.91) CVH status at baseline were associated with a lower risk of incident AF. However, in 109 695 participants with changes in CVH between the first and second check-ups, the direction of change in CVH scores showed no consistent association with future AF incidence. In newly diagnosed participants with AF, the incidence of the composite outcome (stroke, major bleeding and all-cause death) decreased with every 1-point increase in the baseline CVH score (HR: 0.94; 95% CI: 0.89 to 0.99).
Conclusions
In the general elderly population, better baseline CVH metrics were associated with lower incident AF risk. In participants with newly diagnosed AF, better CVH was also associated with lower incidence of future composite outcomes. However, the direction of change in CVH status within 2 years showed an inconsistent influence on incident AF risk.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 01 Apr 2021; epub ahead of print
Lee JH, Yang PS, Yu HT, Kim TH, ... Lee MH, Joung B
Heart: 01 Apr 2021; epub ahead of print | PMID: 33811131
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Impact:
Abstract

Predictive models for cardiovascular and kidney outcomes in patients with type 2 diabetes: systematic review and meta-analyses.

Buchan TA, Malik A, Chan C, Chambers J, ... Guyatt G, Foroutan F
Objective
To inform a clinical practice guideline (BMJ Rapid Recommendations) considering sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists for treatment of adults with type 2 diabetes, we summarised the available evidence regarding the performance of validated risk models on cardiovascular and kidney outcomes in these patients.
Methods
We systematically searched bibliographic databases in January 2020 to identify observational studies evaluating risk models for all-cause and cardiovascular mortality, heart failure (HF) hospitalisations, end-stage kidney disease (ESKD), myocardial infarction (MI) and ischaemic stroke in ambulatory adults with type 2 diabetes. Using a random effects model, we pooled discrimination measures for each model and outcome, separately, and descriptively summarised calibration plots, when available. We used the Prediction Model Risk of Bias Assessment Tool to assess risk of bias of each included study and the Grading of Recommendations, Assessment, Development, and Evaluation approach to evaluate our certainty in the evidence.
Results
Of 22 589 publications identified, 15 observational studies reporting on seven risk models proved eligible. Among the seven models with >1 validation cohort, the Risk Equations for Complications of Type 2 Diabetes (RECODe) had the best calibration in primary studies and the highest pooled discrimination measures for the following outcomes: all-cause mortality (C-statistics 0.75, 95% CI 0.70 to 0.80; high certainty), cardiovascular mortality (0.79, 95% CI 0.75 to 0.84; low certainty), ESKD (0.73, 95% CI 0.52 to 0.94; low certainty), MI (0.72, 95% CI 0.69 to 0.74; moderate certainty) and stroke (0.71, 95% CI 0.68 to 0.74; moderate certainty). This model does not, however, predict risk of HF hospitalisations.
Conclusion
Of available risk models, RECODe proved to have satisfactory calibration in primary validation studies and acceptable discrimination superior to other models, though with high risk of bias in most primary studies.
Trial registration number
CRD42020168351.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 07 Apr 2021; epub ahead of print
Buchan TA, Malik A, Chan C, Chambers J, ... Guyatt G, Foroutan F
Heart: 07 Apr 2021; epub ahead of print | PMID: 33833070
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Impact:
Abstract

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation.

Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Aims
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.
Methods/results
We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.
Conclusion
Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:713-720
Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Heart: 29 Apr 2021; 107:713-720 | PMID: 32938772
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Impact:
Abstract

Cardiogenetics: genetic testing in the diagnosis and management of patients with aortic disease.

Thakker PD, Braverman AC
Thoracic aortic aneurysm and aortic dissection have a potent genetic underpinning with 20% of individuals having an affected relative. Heritable thoracic aortic diseases (HTAD) may be classified as syndromic (including Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome and others) or non-syndromic (without recognisable phenotypes) and relate to pathogenic variants in multiple genes affecting extracellular matrix proteins, transforming growth factor-beta (TGF-β) signalling and smooth muscle contractile function. Clinical and imaging characteristics may heighten likelihood of an underlying HTAD. HTAD should be investigated in individuals with thoracic aortic aneurysm or aortic dissection, especially when occurring in younger individuals, in those with phenotypic features and in those with a family history of aneurysm disease. Screening family members for aneurysm disease is important. Consultation with a medical geneticist and genetic testing of individuals at increased risk for HTAD is recommended. Medical management and prophylactic aortic surgical thresholds are informed by an accurate clinical and molecular diagnosis.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:619-626
Thakker PD, Braverman AC
Heart: 30 Mar 2021; 107:619-626 | PMID: 33334864
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Impact:
Abstract

Socioeconomic disparities in prehospital factors and survival after out-of-hospital cardiac arrest.

Møller S, Wissenberg M, Starkopf L, Kragholm K, ... Torp-Pedersen C, Gerds TA
Objective
It remains unknown whether patient socioeconomic factors affect interventions and survival after out-of-hospital cardiac arrest (OHCA), and whether a socioeconomic effect on bystander interventions affects survival. Therefore, this study examined patient socioeconomic disparities in prehospital factors and survival.
Methods
From the Danish Cardiac Arrest Registry, patients with OHCA ≥30 years were identified, 2001-2014, and divided into quartiles of household income (highest, high, low, lowest). Associations between income and bystander cardiopulmonary resuscitation (CPR) and 30-day survival with bystander CPR as mediator were analysed by logistic regression and mediation analysis in private witnessed, public witnessed, private unwitnessed and public unwitnessed arrests, adjusted for confounders.
Results
We included 21 480 patients. Highest income patients were younger, had higher education and were less comorbid relative to lowest income patients. They had higher odds for bystander CPR with the biggest difference in private unwitnessed arrests (OR 1.74, 95% CI 1.47 to 2.05). For 30-day survival, the biggest differences were in public witnessed arrests with 26.0% (95% CI 22.4% to 29.7%) higher survival in highest income compared with lowest income patients. Had bystander CPR been the same for lowest income as for highest income patients, then survival would be 25.3% (95% CI 21.5% to 29.0%) higher in highest income compared with lowest income patients, resulting in elimination of 0.79% (95% CI 0.08% to 1.50%) of the income disparity in survival. Similar trends but smaller were observed in low and high-income patients, the other three subgroups and with education instead of income. From 2002 to 2014, increases were observed in both CPR and survival in all income groups.
Conclusion
Overall, lower socioeconomic status was associated with poorer prehospital factors and survival after OHCA that was not explained by patient or cardiac arrest-related factors.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:627-634
Møller S, Wissenberg M, Starkopf L, Kragholm K, ... Torp-Pedersen C, Gerds TA
Heart: 30 Mar 2021; 107:627-634 | PMID: 33419881
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Impact:
Abstract

Tyrosine kinase inhibitors in chronic myeloid leukaemia and emergent cardiovascular disease.

Leong D, Aghel N, Hillis C, Siegal D, ... Pond G, Seow H
Objectives
(1) Describe how the risk of major adverse cardiovascular events (MACE) in individuals with chronic myeloid leukaemia (CML) has evolved; (2) evaluate the risk of MACE associated with the prescription of different CML tyrosine kinase inhibitors (TKI).
Methods
A population-based retrospective study including all patients (n=4238) diagnosed with CML in Ontario, Canada between 1986 and 2017 and and age-matched and sex-matched individuals who received healthcare but who did not have CML (controls: n=42 380). The cohort was divided into those entering before 2001 vs from 2001 onwards (when TKIs were introduced). We developed competing risks models to compare time-to-event in CML cases versus controls. We adjusted for baseline comorbidities and present subdistribution HRs and 95% CIs. The relationship between TKI use and MACE was assessed by logistic regression.
Results
Before 2001 and from 2001 on, patients with CML had a higher crude incidence of MACE than patients without CML (19.8 vs 15.3 and 20.3 vs 12.6 per 1000 person-years, respectively). After adjustment for cardiovascular risk factors, patients with CML had a lower subdistribution hazard for MACE (0.59, 95% CI 0.46 to 0.76) before 2001; but from 2001, the adjusted subdistribution HR for MACE (1.27, 95% CI 0.96 to 1.43) was similar to age-matched and sex-matched patients. The incidence (9.3 vs 13.8 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.43, 95% CI 0.36 to 0.52) were lower in patients with CML than controls before 2001. From 2001 on, the incidence (6.3 vs 5.4 per 1000 person-years) and subdistribution hazard for cardiovascular death (0.99, 95% CI 0.84 to 1.18) were similar to age-matched and sex-matched patients without CML with a higher risk of cerebrovascular events (8.6 vs 5.6 per 1000 person-years; 1.35, 95% CI 1.00 to 1.83) and peripheral arterial events (6.9 vs 3.0 per 1000 person-years; 1.66 95% CI, 1.15 to 2.39) in patients with CML than patients without CML. Compared with imatinib, there was no difference in the risk of MACE among those prescribed dasatinib (OR 0.67, 95% CI 0.41 to 1.10) or nilotinib (OR 1.22, 95% CI 0.70 to 1.97).
Conclusions
In a contemporary CML population, the risk of MACE and cardiovascular death is at least as high as among age-matched and sex-matched patients without CML and may be higher for cerebrovascular and peripheral arterial events. No difference in the risk of MACE between imatinib, dasatinib and nilotinib was observed.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; 107:667-673
Leong D, Aghel N, Hillis C, Siegal D, ... Pond G, Seow H
Heart: 30 Mar 2021; 107:667-673 | PMID: 33419879
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Impact:
Abstract

Addition of cystatin C predicts cardiovascular death better than creatinine in intensive care.

Helmersson-Karlqvist J, Lipcsey M, Ärnlöv J, Bell M, ... Dardashti A, Larsson A
Objective
Decreased kidney function increases cardiovascular risk and predicts poor survival. Estimated glomerular filtration rate (eGFR) by creatinine may theoretically be less accurate in the critically ill. This observational study compares long-term cardiovascular mortality risk by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; Caucasian, Asian, paediatric and adult cohort (CAPA) cystatin C equation and the CKD-EPI combined creatinine/cystatin C equation.
Methods
The nationwide study includes 22 488 intensive care patients in Uppsala, Karolinska and Lund University Hospitals, Sweden, between 2004 and 2015. Creatinine and cystatin C were analysed with accredited methods at admission. Reclassification and model discrimination with C-statistics was used to compare creatinine and cystatin C for cardiovascular mortality prediction.
Results
During 5 years of follow-up, 2960 (13 %) of the patients died of cardiovascular causes. Reduced eGFR was significantly associated with cardiovascular death by all eGFR equations in Cox regression models. In each creatinine-based GFR category, 17%, 19% and 31% reclassified to a lower GFR category by cystatin C. These patients had significantly higher cardiovascular mortality risk, adjusted HR (95% CI), 1.55 (1.38 to 1.74), 1.76 (1.53 to 2.03) and 1.44 (1.11 to 1.86), respectively, compared with patients not reclassified. Harrell\'s C-statistic for cardiovascular death for cystatin C, alone or combined with creatinine, was 0.73, significantly higher than for creatinine (0.71), p<0.001.
Conclusions
A single cystatin C at admission to the intensive care unit added significant predictive value to creatinine for long-term cardiovascular death risk assessment. Cystatin C, alone or in combination with creatinine, should be used for estimating GFR for long-term risk prediction in critically ill.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 31 Mar 2021; epub ahead of print
Helmersson-Karlqvist J, Lipcsey M, Ärnlöv J, Bell M, ... Dardashti A, Larsson A
Heart: 31 Mar 2021; epub ahead of print | PMID: 33795382
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Impact:
Abstract

Role of beta blockers following percutaneous coronary intervention for acute coronary syndrome.

Peck KY, Andrianopoulos N, Dinh D, Roberts L, ... Freeman M, Teh AW
Aims
There is a paucity of evidence supporting routine beta blocker (BB) use in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). The aim of this study was to evaluate BB use post PCI and its association with mortality. Furthermore, the study aimed to evaluate the association between BB and mortality in the subgroups of patients with left ventricular ejection fraction (LVEF) <35%, LVEF 35%-50% and LVEF >50%.
Methods
Using a large PCI registry, data from patients with ACS between January 2005 and June 2017 who were alive at 30 days were analysed. Those patients taking BB at 30 days were compared with those who were not taking BB. The primary outcome was all-cause mortality. The mean follow-up was 5.3±3.5 years.
Results
Of the 17 562 patients, 83.3% were on BB. Mortality was lower in the BB group (13.1% vs 19.5%, p=0.0001). Multivariable Cox proportional hazards model showed that BB use was associated with lower overall mortality (adjusted HR 0.87, 95% CI 0.78 to 0.97, p=0.014). In the subgroup analysis, BB use was associated with reduced mortality in LVEF <35% (adjusted HR 0.63, 95% CI 0.44 to 0.91, p=0.013), LVEF 35%-50% (adjusted HR 0.80, 95% CI 0.68 to 0.95, p=0.01), but not LVEF >50% (adjusted HR 1.03, 95% CI 0.87 to 1.21, p=0.74).
Conclusion
BB use remains high and is associated with reduced mortality. This reduction in mortality is primarily seen in those with reduced ejection fraction, but not in those with preserved ejection fraction.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:728-733
Peck KY, Andrianopoulos N, Dinh D, Roberts L, ... Freeman M, Teh AW
Heart: 29 Apr 2021; 107:728-733 | PMID: 32887736
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Impact:
Abstract

Racial, ethnic and socioeconomic disparities in patients undergoing left atrial appendage closure.

Sparrow R, Sanjoy S, Choi YH, Elgendy IY, ... Mamas MA, Bagur R
Objective
This manuscript aims to explore the impact of race/ethnicity and socioeconomic status on in-hospital complication rates after left atrial appendage closure (LAAC).
Methods
The US National Inpatient Sample was used to identify hospitalisations for LAAC between 1 October 2015 to 31 December 2018. These patients were stratified by race/ethnicity and quartiles of median neighbourhood income. The primary outcome was the occurrence of in-hospital major adverse events, defined as a composite of postprocedural bleeding, cardiac and vascular complications, acute kidney injury and ischaemic stroke.
Results
Of 6478 unweighted hospitalisations for LAAC, 58% were male and patients of black, Hispanic and \'other\' race/ethnicity each comprised approximately 5% of the cohort. Adjusted by the older Americans population, the estimated number of LAAC procedures was 69.2/100 000 for white individuals, as compared with 29.5/100 000 for blacks, 47.2/100 000 for Hispanics and 40.7/100 000 for individuals of \'other\' race/ethnicity. Black patients were ~5 years younger but had a higher comorbidity burden. The primary outcome occurred in 5% of patients and differed significantly between racial/ethnic groups (p<0.001) but not across neighbourhood income quartiles (p=0.88). After multilevel modelling, the overall rate of in-hospital major adverse events was higher in black patients as compared with whites (OR: 1.60, 95% CI 1.22 to 2.10, p<0.001); however, the incidence of acute kidney injury was higher in Hispanics (OR: 2.19, 95% CI 1.52 to 3.17, p<0.001). No significant differences were found in adjusted overall in-hospital complication rates between income quartiles.
Conclusion
In this study assessing racial/ethnic disparities in patients undergoing LAAC, minorities are under-represented, specifically patients of black race/ethnicity. Compared with whites, black patients had higher comorbidity burden and higher rates of in-hospital complications. Lower socioeconomic status was not associated with complication rates.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 31 Mar 2021; epub ahead of print
Sparrow R, Sanjoy S, Choi YH, Elgendy IY, ... Mamas MA, Bagur R
Heart: 31 Mar 2021; epub ahead of print | PMID: 33795381
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Impact:
Abstract

Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.

Packard C, Chapman MJ, Sibartie M, Laufs U, Masana L
Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of \'lower is better\'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 31 Mar 2021; epub ahead of print
Packard C, Chapman MJ, Sibartie M, Laufs U, Masana L
Heart: 31 Mar 2021; epub ahead of print | PMID: 33795379
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Abstract

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

Chung MK, Zidar DA, Bristow MR, Cameron SJ, ... Barnard J, Loscalzo J
A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.



Circ Res: 15 Apr 2021; 128:1214-1236
Chung MK, Zidar DA, Bristow MR, Cameron SJ, ... Barnard J, Loscalzo J
Circ Res: 15 Apr 2021; 128:1214-1236 | PMID: 33856918
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Abstract

Counterpoint: challenges and limitations of transcatheter aortic valve implantation for aortic regurgitation.

Huded CP, Allen KB, Chhatriwalla AK
Transcatheter aortic valve implantation (TAVI) for isolated aortic regurgitation (AR) comprises <1.0% of all TAVI procedures performed in the USA. In this manuscript, we review the challenges, evidence and future directions of TAVI for isolated AR. There are no randomised clinical trials or mid-term data evaluating TAVI for isolated AR, and no commercially available devices are approved for this indication. Challenges in performing TAVI for isolated AR as opposed to aortic stenosis (AS) include: lack of a calcified anchoring zone for valve deployment, large and dynamic size of the aortic annulus and high stroke volume (during systole) and regurgitant volume (during diastole) across the aortic annulus during each cardiac cycle. Observational studies have shown that outcomes of TAVI for AR are worse than outcomes of TAVI for AS. However, newer generation TAVI devices may perform better than older generation devices in patients with AR. Two emerging valves (the JenaValve and the J-Valve) are designed with mechanisms to anchor in a non-calcified annulus, and these valves have shown promise for AR. Data on these devices are limited, and clinical investigation is ongoing. Randomised clinical trials are needed to establish TAVI as a safe and effective treatment for isolated AR.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Apr 2021; epub ahead of print
Huded CP, Allen KB, Chhatriwalla AK
Heart: 15 Apr 2021; epub ahead of print | PMID: 33863760
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Abstract

Point: patients with native aortic regurgitation can be treated with transcatheter aortic valve implantation.

Khan SA, Baron SJ
Approximately 2% of people between the ages of 70 and 83 suffer from moderate or greater aortic regurgitation (AR) in the United States. Left untreated, this disease is progressive and fatal; however, up to 8% of patients with AR, who meet the criteria for surgical intervention, do not receive treatment. As such, there is a pressing need to address the lack of treatment options for the thousands of patients with AR who meet a class I indication for aortic valve replacement but who still do not receive surgery. The advent of transcatheter aortic valve implantation (TAVI) has significantly altered the paradigm of treatment for valvular heart disease and is now a well-established therapeutic option for patients with severe aortic stenosis. While transcatheter devices dedicated for the treatment of AR are under investigation, they are not commercially available at this time. Nevertheless, there is a growing body of data that demonstrate acceptable safety and efficacy for the off-label use of current TAVI devices for the treatment of severe AR. Given the dearth of treatment options for inoperable patients with severe AR, available TAVI devices should be considered for this patient population.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Apr 2021; epub ahead of print
Khan SA, Baron SJ
Heart: 15 Apr 2021; epub ahead of print | PMID: 33863759
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Abstract

Optimising cardiovascular care of patients with multiple myeloma.

Fontes Oliveira M, Naaktgeboren WR, Hua A, Ghosh AK, ... Hallam S, Manisty C
Multiple myeloma (MM) is the third most common haematological malignancy, with increasing prevalence over recent years. Advances in therapy have improved survival, changing the clinical course of MM into a chronic condition and meaning that management of comorbidities is fundamental to improve clinical outcomes. Cardiovascular (CV) events affect up to 7.5% of individuals with MM, due to a combination of patient, disease and treatment-related factors and adversely impact survival. MM typically affects older people, many with pre-existing CV risk factors or established CV disease, and the disease itself can cause renal impairment, anaemia and hyperviscosity, which exacerabate these further. Up to 15% of patients with MM develop systemic amyloidosis, with prognosis determined by the extent of cardiac involvement. Management of MM generally involves administration of multiple treatment lines over several years as disease progresses, with many drug classes associated with adverse CV effects including high rates of venous and arterial thrombosis alongside heart failure. Recommendations for holistic management of patients with MM now include routine baseline risk stratification including ECG and echocardiography and administration of thromboprophylaxis drugs for patients treated with immunomodulatory drugs. Close surveillance of high-risk patients with collaboration between haematology and cardiology is required, with prompt investigation in the event of CV symptoms, in order to identify and treat complications early. Decisions regarding discontinuation of cardiotoxic therapies should be made in a multidisciplinary setting, taking into account the severity of the complication, prognosis, expected benefits and the availability of effective alternatives.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 04 Apr 2021; epub ahead of print
Fontes Oliveira M, Naaktgeboren WR, Hua A, Ghosh AK, ... Hallam S, Manisty C
Heart: 04 Apr 2021; epub ahead of print | PMID: 33820757
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Abstract

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

Dörr K, Kammer M, Reindl-Schwaighofer R, Lorenz M, ... Erben RG, Oberbauer R
Rationale: Left ventricular hypertrophy (LVH) is highly prevalent in patients with chronic kidney disease and increases their risk of cardiac events and mortality. Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels, which are associated with the development of LVH, rise progressively with declining renal function. Objective: To determine whether FGF23 suppression by calcimimetic therapy may reduce LVH progression in comparison to FGF23 elevation under vitamin D analogs at equal PTH suppression under either therapy as well as tight volume control.
Methods and results:
We conducted a single-blinded trial with 1:1 block randomization to investigate the effect of the intravenous treatment with etelcalcetide (ETL) versus alfacalcidol (ALFA) on LVH progression in 62 maintenance hemodialysis patients with secondary hyperparathyroidism and LVH. In the intention-to-treat analysis of 59 patients, the mean difference in the change of left ventricular mass index (LVMI) determined by cardiac magnetic resonance imaging from baseline to 12 months of treatment was -6.9 g/m² (95% confidence interval [CI] -12.6 to -1.2, p=0.022) in the ETL compared to the ALFA group. The effect estimate was -8.2 g/m² (95% CI -14 to -2.4) in the per-protocol analysis on 52 patients. The trajectories of PTH, phosphate and Klotho were similar in both groups throughout follow-up. FGF23 levels, which showed a strong positive association with LVMI, were decreasing under ETL and increasing under ALFA at similar PTH suppression. Mild hypocalcemia was the most common adverse event under ETL. Blood pressure and the distribution of antihypertensive medications were similar between groups. Conclusions: In this trial we were able to show that FGF23 suppression by ETL inhibited the progression of LVH compared to ALFA in hemodialysis patients. A successful prevention of increasing hypertrophy may reduce the risk of sudden cardiac death in this population.




Circ Res: 06 Apr 2021; epub ahead of print
Dörr K, Kammer M, Reindl-Schwaighofer R, Lorenz M, ... Erben RG, Oberbauer R
Circ Res: 06 Apr 2021; epub ahead of print | PMID: 33825489
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Abstract

J-curve relationship between admission SBP and 2-year cardiovascular mortality in older patients admitted for acute coronary syndrome.

Jiang C, Wu S, Wang M, Zhao X, Li H
Objective
To investigate the relationship between admission SBP and subsequent cardiovascular and all-cause mortality in older patients hospitalized for acute coronary syndrome (ACS).
Methods
This is a retrospective observational study. Data from the CBD Bank (Cardiovascular Center Beijing Friendship Hospital Database Bank) were used to analyze the cardiovascular and all-cause mortality during hospitalization and over the follow-up period in relation to admission SBP among patients aged at least 65 years admitted for ACS from December 2012 through July 2019. Results were presented according to SBP quartiles: Q1, less than 120 mmHg; Q2, from 120 to 129 mmHg; Q3, from 130 to 143 mmHg; and Q4, at or above 144 mmHg.
Results
A total of 6785 patients were included in this cohort study. Mean (SD) patient age was 74.0 (6.5) years, and 47.6% were women. Mean (SD) follow-up time was 2.54 (1.82) years. A nonlinear relation was observed between SBP at admission and cardiovascular and all-cause mortality during hospitalization and over the follow-up period using restricted cubic splines. After adjustment for potential confounders, patients in Q1 had higher risk for 2-year cardiovascular death by Cox proportional hazard model compared with patients in Q2 [hazard ratio, 1.58; 95% confidence interval (CI), 1.12-2.21, P = 0.009], whereas patients in Q3 or Q4 exhibited a trend towards increased risk for 2-year cardiovascular death (hazard ratio, 1.33, 95% CI, 0.95-1.86, P = 0.094, for Q3 vs. Q2; and hazard ratio, 1.28, 95% CI, 0.91-1.82, P = 0.160, for Q4 vs. Q2). Meanwhile, when compared with patients in Q1, patients in Q2 had lower risk for 2-year cardiovascular death (hazard ratio, 0.64; 95% CI, 0.45-0.89, P = 0.009) whereas patients in Q3 or Q4 had similar risk for cardiovascular death (hazard ratio, 0.85, 95% CI, 0.63-1.14, P = 0.272, for Q3 vs. Q1; and hazard ratio, 0.82, 95% CI, 0.59-1.13, P = 0.221, for Q4 vs. Q1). However, low-admission SBP was not an independent predictor of 2-year all-cause mortality in this population.
Conclusion
Among patients aged at least 65 years admitted for ACS, there is a J-curve relationship between supine admission SBP and risk for 2-year cardiovascular death, with a nadir at 120-129 mmHg.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.

J Hypertens: 30 Apr 2021; 39:926-934
Jiang C, Wu S, Wang M, Zhao X, Li H
J Hypertens: 30 Apr 2021; 39:926-934 | PMID: 33201050
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Abstract

Automated blood pressure measurement in atrial fibrillation: validation process modification and evaluation of a novel professional device which detects atrial fibrillation and adapts its blood pressure measurement algorithm.

Stergiou GS, Kyriakoulis KG, Bountzona I, Menti A, ... Kalogeropoulos P, Kollias A
Objectives
Blood pressure (BP) measurement in atrial fibrillation (AF) patients is problematic and automated monitors are regarded as inaccurate. The optimal procedure for validating BP monitors in AF is questionable. This study evaluated the accuracy of a novel professional oscillometric upper-arm cuff device (Microlife WatchBP Office), which has an algorithm for detecting AF and then applies an AF-specific BP measurement algorithm. BP variability, which is inherently increased in AF patients, was considered in the analysis.
Methods
Subjects with sustained AF were included in a validation study using the same arm sequential measurement method of the Universal Standard (ISO 81060-2:2018) for special populations. Analysis was performed in all subjects and separately in those with and without high reference BP variability (>12/8 mmHg SBP/DBP).
Results
Thirty-five subjects with 105 paired test/reference BP measurements were included (mean age 76.3 ± 8.4 years, reference SBP/DBP 128.2 ± 19.5/72.5 ± 12.1 mmHg, pulse rate 68.3 ± 14.9 bpm). Validation Criterion 1 (mean difference ± SD) was 0.0 ± 7.7/0.2 ± 7.0 mmHg in all 105 BP pairs (threshold ≤5 ± 8 mmHg). Criterion 1 was 0.5 ± 6.1/-0.2 ± 6.8 mmHg in 18 subjects (54 BP pairs) with low reference BP variability and -0.6 ± 9.2/0.6 ± 7.3 mmHg in 17 (51 pairs) with high variability. Criterion 1 did not differ in pulse rate < 70 vs. ≥ 70 bpm Validation Criterion 2 (SD of differences for 35 individuals) was 5.38/6.20 mmHg (SBP/DBP; threshold ≤6.95/6.95).
Conclusion
A technology which detects AF and activates an AF-specific BP measurement algorithm introduces a challenging solution for clinical practice. Validation of BP monitors in AF patients should not ignore their inherently high BP variability.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 31 Mar 2021; 39:614-620
Stergiou GS, Kyriakoulis KG, Bountzona I, Menti A, ... Kalogeropoulos P, Kollias A
J Hypertens: 31 Mar 2021; 39:614-620 | PMID: 33060450
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