Topic: General Cardiology

Abstract

Diastolic Function and Clinical Outcomes After Transcatheter Aortic Valve Replacement: PARTNER 2 SAPIEN 3 Registry.

Ong G, Pibarot P, Redfors B, Weissman NJ, ... Douglas PS, Hahn RT
Background
Few studies have evaluated if diastolic function could predict outcomes in patients with aortic stenosis.
Objectives
The authors aimed to assess the association between diastolic dysfunction (DD) and outcomes in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR).
Methods
Baseline, 30-day, and 1- and 2-year transthoracic echocardiograms from the PARTNER (Placement of Aortic Transcatheter Valves) 2 SAPIEN 3 registry were analyzed by a consortium of core laboratories and divided into the American Society of Echocardiography DD groups.
Results
Among the 1,750 included, 682 (54.4%) had grade 1 DD, 352 (28.1%) had grade 2 DD, 168 (13.4%) had grade 3 DD, and 51 (4.1%) had indeterminate DD grade. Incremental baseline grades of DD were associated with an increase in combined 1- and 2-year cardiovascular (CV) death/rehospitalization (all p < 0.002) and all-cause death at 2 years (p = 0.01) but not at 1 year. Improvement in DD grade/grade 1 DD at 30 days post-TAVR was seen in 70.8% patients. Patients with improvement in ≥1 grade of DD/grade 1 DD had reduced 1-year CV death/rehospitalization (p < 0.001) and increased 2-year survival (p = 0.01). Baseline grade 3 DD was a predictor of 1-year CV death/rehospitalization (hazard ratio: 2.73; 95% confidence interval: 1.07 to 6.98; p = 0.04). Improvement in DD grade/grade 1 DD at 30 days was protective for 1-year CV death/rehospitalizations (hazard ratio: 0.39; 95% confidence interval: 0.19 to 0.83; p = 0.01).
Conclusions
In the PARTNER 2 SAPIEN 3 registry, baseline DD was a predictor of up to 2 years clinical outcomes in patients who underwent TAVR. Improvement in DD grade at 30 days was associated with improvement in short-term clinical outcomes. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate [PARTNERII S3i]; NCT03222128; PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - High Risk and Nested Registry 7 [PII S3HR/NR7]; NCT03222141).

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

J Am Coll Cardiol: 21 Dec 2020; 76:2940-2951
Ong G, Pibarot P, Redfors B, Weissman NJ, ... Douglas PS, Hahn RT
J Am Coll Cardiol: 21 Dec 2020; 76:2940-2951 | PMID: 33334422
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Abstract

Evolution of antithrombotic therapy in patients undergoing percutaneous coronary intervention: a 40-year journey.

Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R

Since its introduction in 1977, percutaneous coronary intervention has become one of the most commonly performed therapeutic procedures worldwide. Such widespread diffusion, however, would have not been possible without a concomitant evolution of the pharmacotherapies associated with this intervention. Antithrombotic agents are fundamental throughout the management of patients undergoing coronary stent implantation, starting from the procedure itself to the long-term prevention of cardiovascular events. The last 40 years of interventional cardiology have seen remarkable improvements in both drug therapies and device technologies, which largely reflected a progressive understanding of the pathophysiological mechanisms of coronary artery disease, as well as procedure- and device-related adverse events. The purpose of this article is to provide an overview of the important milestones in antithrombotic pharmacology that have shaped clinical practice of today while also providing insights into knowledge gaps and future directions.

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

Eur Heart J: 25 Dec 2020; epub ahead of print
Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R
Eur Heart J: 25 Dec 2020; epub ahead of print | PMID: 33367641
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Abstract

Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission.

Wei AH, Döhner H, Pocock C, Montesinos P, ... Roboz GJ,
Background
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
Methods
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
Results
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
Conclusions
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 23 Dec 2020; 383:2526-2537
Wei AH, Döhner H, Pocock C, Montesinos P, ... Roboz GJ,
N Engl J Med: 23 Dec 2020; 383:2526-2537 | PMID: 33369355
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Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

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

Eur Heart J: 22 Dec 2020; epub ahead of print
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 22 Dec 2020; epub ahead of print | PMID: 33355356
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Abstract

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Aims 
There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.
Methods and results 
In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.
Conclusions 
In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.

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

Eur Heart J: 12 Jan 2021; epub ahead of print
Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Eur Heart J: 12 Jan 2021; epub ahead of print | PMID: 33438022
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Abstract

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, ... Broxmeyer HE, Zhang S
Background
Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.
Methods
We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.
Results
A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.
Conclusions
In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

Copyright © 2021 Massachusetts Medical Society.

N Engl J Med: 06 Jan 2021; 384:11-19
Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, ... Broxmeyer HE, Zhang S
N Engl J Med: 06 Jan 2021; 384:11-19 | PMID: 33406328
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Abstract

Incidence and Predictors of Out-of-Hospital Cardiac Arrest Within 90 Days After Myocardial Infarction.

Faxén J, Jernberg T, Hollenberg J, Gadler F, Herlitz J, Szummer K
Background
The risk of sudden cardiac death (SCD) is high early after myocardial infarction (MI). Current knowledge and guidelines mainly rely on results from older clinical trials and registry studies. Left ventricular ejection fraction (LVEF) alone has not been proven a reliable predictor of SCD.
Objectives
This study sought to identify the incidence and additional predictors of SCD early after MI in a contemporary nationwide setting.
Methods
The authors used data from SWEDEHEART, the Swedish Cardiopulmonary Resuscitation Registry, and the Swedish Pacemaker and Implantable Cardioverter-Defibrillator (ICD) Registry. Cases of MI, which had undergone coronary angiography and were discharged alive between 2009 to 2017 without a prior ICD, were followed up to 90 days. Cox regression models were used to assess associations between clinical parameters and out-of-hospital cardiac arrest (OHCA).
Results
Among 121,379 cases, OHCA occurred in 349 (0.29%) and non-OHCA death in 2,194 (1.8%). A total of 6 variables (male sex, diabetes, estimated glomerular filtration rate <30 ml/min/1.73 m, Killip class ≥II, new-onset atrial fibrillation/flutter, and impaired LVEF [reference ≥50%] categorized as 40% to 49%, 30% to 39%, and <30%) were identified as independent predictors, were assigned points, and were grouped into 3 categories, where the incidence of OHCA ranged from 0.12% to 2.0% and non-OHCA death from 0.76% to 11.7%. Stratified by LVEF <40% alone, the incidence of OHCA was 0.20% and 0.76% and for non-OHCA death 1.1% and 4.9%.
Conclusions
In this nationwide study, the incidence of OHCA within 90 days after MI was <0.3%. A total of 5 clinical parameters in addition to LVEF predicted OHCA and non-OHCA death better than LVEF alone.

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

J Am Coll Cardiol: 21 Dec 2020; 76:2926-2936
Faxén J, Jernberg T, Hollenberg J, Gadler F, Herlitz J, Szummer K
J Am Coll Cardiol: 21 Dec 2020; 76:2926-2936 | PMID: 33334420
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Abstract

Discriminatory cardiac arrest care? Patients with low socioeconomic status receive delayed cardiopulmonary resuscitation and are less likely to survive an in-hospital cardiac arrest.

Agerström J, Carlsson M, Bremer A, Herlitz J, Israelsson J, Årestedt K
Aims 
Individuals with low socioeconomic status (SES) face widespread prejudice in society. Whether SES disparities exist in treatment and survival following in-hospital cardiac arrest (IHCA) is unclear. The aim of the current retrospective registry study was to examine SES disparities in IHCA treatment and survival, assessing SES at the patient level, and adjusting for major demographic, clinical, and contextual factors.
Methods and results 
In total, 24 217 IHCAs from the Swedish Register of Cardiopulmonary Resuscitation were analysed. Education and income constituted SES proxies. Controlling for age, gender, ethnicity, comorbidity, heart rhythm, aetiology, hospital, and year, primary analyses showed that high (vs. low) SES patients were significantly less likely to receive delayed cardiopulmonary resuscitation (CPR) (highly educated: OR = 0.89, and high income: OR = 0.98). Furthermore, patients with high SES were significantly more likely to survive CPR (high income: OR = 1.02), to survive to hospital discharge with good neurological outcome (highly educated: OR = 1.27; high income: OR = 1.06), and to survive to 30 days (highly educated: OR = 1.21; and high income: OR = 1.05). Secondary analyses showed that patients with high SES were also significantly more likely to receive prophylactic heart rhythm monitoring (highly educated: OR = 1.16; high income: OR = 1.02), and this seems to partially explain the observed SES differences in CPR delay.
Conclusion 
There are clear SES differences in IHCA treatment and survival, even when controlling for major sociodemographic, clinical, and contextual factors. This suggests that patients with low SES could be subject to discrimination when suffering IHCA.

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

Eur Heart J: 20 Dec 2020; epub ahead of print
Agerström J, Carlsson M, Bremer A, Herlitz J, Israelsson J, Årestedt K
Eur Heart J: 20 Dec 2020; epub ahead of print | PMID: 33345270
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Abstract

Association of Age With 10-Year Outcomes After Coronary Surgery in the Arterial Revascularization Trial.

Gaudino M, Di Franco A, Flather M, Gerry S, ... Fremes SE, Taggart DP
Background
The association of age with the outcomes of bilateral internal thoracic arteries (BITAs) versus single internal thoracic arteries (SITAs) for coronary bypass grafting (CABG) remains to be determined.
Objectives
The purpose of this study was to evaluate the association between age and BITA versus SITA outcomes in the Arterial Revascularization Trial.
Methods
The primary endpoints were all-cause mortality and a composite of major adverse events, including all-cause mortality, myocardial infarction, or stroke. Secondary endpoints were bleeding complications and sternal wound complications up to 6 months after surgery. Multivariable fractional polynomials analysis and log-rank tests were used.
Results
Age did not affect any of the explored outcomes in the overall BITA versus SITA comparison in the intention-to-treat analysis and in the analysis based on the number of arterial grafts received. However, when the intention-to-treat analysis was restricted to the populations of patients between age 50 and 70 years, younger patients in the BITA arm had a significantly lower incidence of major adverse events (p = 0.03).
Conclusions
Our results suggest that BITA may improve long-term outcome in younger patients, although more randomized data are needed to confirm this hypothesis.

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

J Am Coll Cardiol: 04 Jan 2021; 77:18-26
Gaudino M, Di Franco A, Flather M, Gerry S, ... Fremes SE, Taggart DP
J Am Coll Cardiol: 04 Jan 2021; 77:18-26 | PMID: 33413936
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Abstract

Transcatheter Replacement of Transcatheter Versus Surgically Implanted Aortic Valve Bioprostheses.

Landes U, Sathananthan J, Witberg G, De Backer O, ... Leon MB, Webb JG
Background
Surgical aortic valve replacement and transcatheter aortic valve replacement (TAVR) are now both used to treat aortic stenosis in patients in whom life expectancy may exceed valve durability. The choice of initial bioprosthesis should therefore consider the relative safety and efficacy of potential subsequent interventions.
Objectives
The aim of this study was to compare TAVR in failed transcatheter aortic valves (TAVs) versus surgical aortic valves (SAVs).
Methods
Data were collected on 434 TAV-in-TAV and 624 TAV-in-SAV consecutive procedures performed at centers participating in the Redo-TAVR international registry. Propensity score matching was applied, and 330 matched (165:165) patients were analyzed. Principal endpoints were procedural success, procedural safety, and mortality at 30 days and 1 year.
Results
For TAV-in-TAV versus TAV-in-SAV, procedural success was observed in 120 (72.7%) versus 103 (62.4%) patients (p = 0.045), driven by a numerically lower frequency of residual high valve gradient (p = 0.095), ectopic valve deployment (p = 0.081), coronary obstruction (p = 0.091), and conversion to open heart surgery (p = 0.082). Procedural safety was achieved in 116 (70.3%) versus 119 (72.1%) patients (p = 0.715). Mortality at 30 days was 5 (3%) after TAV-in-TAV and 7 (4.4%) after TAV-in-SAV (p = 0.570). At 1 year, mortality was 12 (11.9%) and 10 (10.2%), respectively (p = 0.633). Aortic valve area was larger (1.55 ± 0.5 cm vs. 1.37 ± 0.5 cm; p = 0.040), and the mean residual gradient was lower (12.6 ± 5.2 mm Hg vs. 14.9 ± 5.2 mm Hg; p = 0.011) after TAV-in-TAV. The rate of moderate or greater residual aortic regurgitation was similar, but mild aortic regurgitation was more frequent after TAV-in-TAV (p = 0.003).
Conclusions
In propensity score-matched cohorts of TAV-in-TAV versus TAV-in-SAV patients, TAV-in-TAV was associated with higher procedural success and similar procedural safety or mortality.

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

J Am Coll Cardiol: 04 Jan 2021; 77:1-14
Landes U, Sathananthan J, Witberg G, De Backer O, ... Leon MB, Webb JG
J Am Coll Cardiol: 04 Jan 2021; 77:1-14 | PMID: 33413929
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Abstract

Low-density lipoprotein cholesterol reduction and statin intensity in myocardial infarction patients and major adverse outcomes: a Swedish nationwide cohort study.

Schubert J, Lindahl B, Melhus H, Renlund H, ... Jernberg T, Hagström E
Aims
Clinical trials have demonstrated that a reduction in low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular (CV) events. This has, however, not yet been shown in a real-world setting. We aimed to investigate the association between LDL-C changes and statin intensity with prognosis after a myocardial infarction (MI).
Methods and results
Patients admitted with MI were followed for mortality and major CV events. Changes in LDL-C between the MI and a 6- to 10-week follow-up visit were analysed. The associations between quartiles of LDL-C change and statin intensity with outcomes were assessed using adjusted Cox regression analyses. A total of 40 607 patients were followed for a median of 3.78 years. The median change in LDL-C was a 1.20 mmol/L reduction. Patients with larger LDL-C reduction (1.85 mmol/L, 75th percentile) compared with a smaller reduction (0.36 mmol/L, 25th percentile) had lower hazard ratios (HR) for all outcomes (95% confidence interval): composite of CV mortality, MI, and ischaemic stroke 0.77 (0.70-0.84); all-cause mortality 0.71 (0.63-0.80); CV mortality 0.68 (0.57-0.81); MI 0.81 (0.73-0.91); ischaemic stroke 0.76 (0.62-0.93); heart failure hospitalization 0.73 (0.63-0.85), and coronary artery revascularization 0.86 (0.79-0.94). Patients with ≥50% LDL-C reduction using high-intensity statins at discharge had a lower incidence of all outcomes compared with those using a lower intensity statin.
Conclusions
Larger early LDL-C reduction and more intensive statin therapy after MI were associated with a reduced hazard of all CV outcomes and all-cause mortality. This supports clinical trial data suggesting that earlier lowering of LDL-C after an MI confers the greatest benefit.

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

Eur Heart J: 23 Dec 2020; epub ahead of print
Schubert J, Lindahl B, Melhus H, Renlund H, ... Jernberg T, Hagström E
Eur Heart J: 23 Dec 2020; epub ahead of print | PMID: 33367526
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Abstract

Prognostic value of peak stress cardiac power in patients with normal ejection fraction undergoing exercise stress echocardiography.

Anand V, Kane GC, Scott CG, Pislaru SV, ... Pellikka PA, Pislaru C
Aims 
Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF.
Methods and results 
We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6-8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4-0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results.
Conclusion 
The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

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

Eur Heart J: 29 Dec 2020; epub ahead of print
Anand V, Kane GC, Scott CG, Pislaru SV, ... Pellikka PA, Pislaru C
Eur Heart J: 29 Dec 2020; epub ahead of print | PMID: 33377479
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Abstract

Diet-Derived Circulating Antioxidants and Risk of Coronary Heart Disease: A Mendelian Randomization Study.

Luo J, le Cessie S, van Heemst D, Noordam R
Background
Previously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation.
Objectives
The purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR).
Methods
Single-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed.
Results
Among an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels.
Conclusions
Evidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD.

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

J Am Coll Cardiol: 04 Jan 2021; 77:45-54
Luo J, le Cessie S, van Heemst D, Noordam R
J Am Coll Cardiol: 04 Jan 2021; 77:45-54 | PMID: 33413940
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Abstract

A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans.

Abohashem S, Osborne MT, Dar T, Naddaf N, ... Rajagopalan S, Tawakol A
Aims 
Air pollution [i.e. particulate matter with diameter <2.5 μm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE.
Methods and results 
Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual\'s home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE.
Conclusions 
Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

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: 10 Jan 2021; epub ahead of print
Abohashem S, Osborne MT, Dar T, Naddaf N, ... Rajagopalan S, Tawakol A
Eur Heart J: 10 Jan 2021; epub ahead of print | PMID: 33428721
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Abstract

Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia.

Pérez de Isla L, Watts GF, Alonso R, Díaz-Díaz JL, ... López-Miranda J, Mata P
Aims
Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.
Methods and results
SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78-18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20-12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event.
Conclusion
The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.ClinicalTrials.gov number NCT02693548.

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: 11 Jan 2021; epub ahead of print
Pérez de Isla L, Watts GF, Alonso R, Díaz-Díaz JL, ... López-Miranda J, Mata P
Eur Heart J: 11 Jan 2021; epub ahead of print | PMID: 33437997
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Abstract

Aortic Valve Replacement in Low-Risk Patients With Severe Aortic Stenosis Outside Randomized Trials.

Alperi A, Voisine P, Kalavrouziotis D, Dumont E, ... Mohammadi S, Rodés-Cabau J
Background
Recent randomized trials including low-risk patients showed positive results for transcatheter aortic valve replacement (TAVR) compared to surgical aortic valve replacement (SAVR), but patients with non-tricuspid aortic valve (NTAV), severe coronary artery disease (SevCAD), and those requiring concomitant mitral/tricuspid valve (CMTV) or concomitant ascending aorta replacement (CAAR) interventions were excluded.
Objectives
This study sought to evaluate the presence and impact of the main clinical variables not evaluated in TAVR versus SAVR trials (NTAV, SevCAD, and CMTV or CAAR intervention) in a large series of consecutive low-risk patients with severe aortic stenosis (SAS) undergoing SAVR.
Methods
Single-center study including consecutive patients with SAS and low surgical risk (Society of Thoracic Surgeons score of <4%) undergoing SAVR. Baseline, procedural characteristics, and 30-day outcomes were prospectively collected.
Results
Of 6,772 patients with SAS who underwent SAVR between 2000 and 2019, 5,310 (78.4%) exhibited a low surgical risk (mean Society of Thoracic Surgeons score: 1.94 ± 0.87%). Of these, 2,165 patients (40.8%) had at least 1 of the following: NTAV (n = 1,468, 27.6%), SevCAD (n = 307, 5.8%), CMTV (n = 306, 5.8%), and CAAR (n = 560, 10.5%). The 30-day mortality and stroke rates for the overall low-risk SAS cohort were 1.9% and 2.4%, respectively. The mortality rate was similar in the SevCAD (2.6%) and CAAR (2.1%) groups versus the rest of the cohort (odds ratio [OR]: 1.79; 95% confidence interval [CI]: 0.85 to 3.75, and OR: 1.64; 95% CI: 0.88 to 3.05, respectively), lower in the NTAV group (0.9%; OR: 0.42; 95% CI: 0.22 to 0.81), and higher in the CMTV group (5.9%; OR: 2.61; 95% CI: 1.51 to 4.5).
Conclusions
In a real-world setting, close to one-half of the low-risk patients with SAS undergoing SAVR exhibited at least 1 major criterion not evaluated in TAVR versus SAVR randomized trials. Clinical outcomes were better than or similar to those predicted by surgical scores in all groups but those patients requiring CMTV intervention. These results may help determine the impact of implementing the results of TAVR-SAVR trials in real practice and may inform future trials in specific groups.

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

J Am Coll Cardiol: 18 Jan 2021; 77:111-123
Alperi A, Voisine P, Kalavrouziotis D, Dumont E, ... Mohammadi S, Rodés-Cabau J
J Am Coll Cardiol: 18 Jan 2021; 77:111-123 | PMID: 33446305
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Abstract

VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration.

Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Background
Recent discoveries have indicated that, in the developing heart, sinus venosus and endocardium provide major sources of endothelium for coronary vessel growth that supports the expanding myocardium. Here we set out to study the origin of the coronary vessels that develop in response to vascular endothelial growth factor B (VEGF-B) in the heart and the effect of VEGF-B on recovery from myocardial infarction.
Methods
We used mice and rats expressing a VEGF-B transgene, VEGF-B-gene-deleted mice and rats, apelin-CreERT, and natriuretic peptide receptor 3-CreERT recombinase-mediated genetic cell lineage tracing and viral vector-mediated VEGF-B gene transfer in adult mice. Left anterior descending coronary vessel ligation was performed, and 5-ethynyl-2\'-deoxyuridine-mediated proliferating cell cycle labeling; flow cytometry; histological, immunohistochemical, and biochemical methods; single-cell RNA sequencing and subsequent bioinformatic analysis; microcomputed tomography; and fluorescent- and tracer-mediated vascular perfusion imaging analyses were used to study the development and function of the VEGF-B-induced vessels in the heart.
Results
We show that cardiomyocyte overexpression of VEGF-B in mice and rats during development promotes the growth of novel vessels that originate directly from the cardiac ventricles and maintain connection with the coronary vessels in subendocardial myocardium. In adult mice, endothelial proliferation induced by VEGF-B gene transfer was located predominantly in the subendocardial coronary vessels. Furthermore, VEGF-B gene transduction before or concomitantly with ligation of the left anterior descending coronary artery promoted endocardium-derived vessel development into the myocardium and improved cardiac tissue remodeling and cardiac function.
Conclusions
The myocardial VEGF-B transgene promotes the formation of endocardium-derived coronary vessels during development, endothelial proliferation in subendocardial myocardium in adult mice, and structural and functional rescue of cardiac tissue after myocardial infarction. VEGF-B could provide a new therapeutic strategy for cardiac neovascularization after coronary occlusion to rescue the most vulnerable myocardial tissue.



Circulation: 04 Jan 2021; 143:65-77
Räsänen M, Sultan I, Paech J, Hemanthakumar KA, ... Kivelä R, Alitalo K
Circulation: 04 Jan 2021; 143:65-77 | PMID: 33203221
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Abstract

Comparison of Self-Expanding Bioprostheses for Transcatheter Aortic Valve Replacement in Patients With Symptomatic Severe Aortic Stenosis: SCOPE 2 Randomized Clinical Trial.

Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D
Background
Few randomized trials have compared bioprostheses for transcatheter aortic valve replacement, and no trials have compared bioprostheses with supra-annular design. The SCOPE 2 trial (Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation 2) was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut bioprostheses for transcatheter aortic valve replacement.
Methods
SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years old with an indication for transfemoral transcatheter aortic valve replacement as agreed by the heart team were randomly assigned to receive treatment with either the ACURATE neo (n=398) or the CoreValve Evolut bioprostheses (n=398). The primary end point, powered for noninferiority of the ACURATE neo bioprosthesis, was all-cause death or stroke at 1 year. The key secondary end point, powered for superiority of the ACURATE neo bioprosthesis, was new permanent pacemaker implantation at 30 days.
Results
Among 796 randomized patients (mean age, 83.2±4.3 years; mean Society of Thoracic Surgeons Predicted Risk of Mortality score, 4.6±2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary end point occurred in 15.8% of patients in the ACURATE neo group and in 13.9% of patients in the CoreValve Evolut group (absolute risk difference, 1.8%, upper 1-sided 95% confidence limit, 6.1%; =0.0549 for noninferiority). The 30-day rates of new permanent pacemaker implantation were 10.5% in the ACURATE neo group and 18.0% in the CoreValve Evolut group (absolute risk difference, -7.5% [95% CI, -12.4 to -2.60]; =0.0027). No significant differences were observed in the components of the primary end point. Cardiac death at 30 days (2.8% versus 0.8%; =0.03) and 1 year (8.4% versus 3.9%; =0.01), and moderate or severe aortic regurgitation at 30 days (10% versus 3%; =0.002) were significantly increased in the ACURATE neo group.
Conclusions
Transfemoral transcatheter aortic valve replacement with the self-expanding ACURATE neo did not meet noninferiority compared with the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and it was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192813.



Circulation: 21 Dec 2020; 142:2431-2442
Tamburino C, Bleiziffer S, Thiele H, Scholtz S, ... Hengstenberg C, Capodanno D
Circulation: 21 Dec 2020; 142:2431-2442 | PMID: 33054367
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Abstract

Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

Peterson BE, Bhatt DL, Steg PG, Miller M, ... Ballantyne CM,
Background
Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations.
Methods
REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
Results
A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; <0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; <0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; <0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; =0.0005).
Conclusions
Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.



Circulation: 04 Jan 2021; 143:33-44
Peterson BE, Bhatt DL, Steg PG, Miller M, ... Ballantyne CM,
Circulation: 04 Jan 2021; 143:33-44 | PMID: 33148016
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Impact:
Abstract

Primary Results From the Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction (UNTOUCHED) Trial.

Gold MR, Lambiase PD, El-Chami MF, Knops RE, ... Boersma LVA,
Background
The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms.
Methods
Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points.
Results
S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%.
Conclusions
This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379.



Circulation: 04 Jan 2021; 143:7-17
Gold MR, Lambiase PD, El-Chami MF, Knops RE, ... Boersma LVA,
Circulation: 04 Jan 2021; 143:7-17 | PMID: 33073614
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Abstract

Current Indications for Transcatheter Mitral Valve Replacement Using Transcatheter Aortic Valves: Valve-in-Valve, Valve-in-Ring, and Valve-in-Mitral Annulus Calcification.

Urena M, Vahanian A, Brochet E, Ducrocq G, Iung B, Himbert D

Use of transcatheter mitral valve replacement (TMVR) using transcatheter aortic valves in clinical practice is limited to patients with failing bioprostheses and rings or mitral valve disease associated with severe mitral annulus calcification. Whereas the use of valve-in-valve TMVR appears to be a reasonable alternative to surgery in patients at high surgical risk, much less evidence supports valve-in-ring and valve-in-mitral annulus calcification interventions. Data on the results of TMVR in these settings are derived from small case series or voluntary registries. This review summarizes the current evidence on TMVR using transcatheter aortic valves in clinical practice from the characteristics of the TMVR candidates, screening process, performance of the procedure, and description of current results and future perspectives. TMVR using dedicated devices in native noncalcified mitral valve diseases is beyond the scope of the article.



Circulation: 11 Jan 2021; 143:178-196
Urena M, Vahanian A, Brochet E, Ducrocq G, Iung B, Himbert D
Circulation: 11 Jan 2021; 143:178-196 | PMID: 33428433
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Abstract

Clinical Efficacy and Safety of Alirocumab after Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial.

Schwartz GG, Steg PG, Bhatt DL, Bittner VA, ... Szarek M, ODYSSEY OUTCOMES Committees and Investigators

Recent international guidelines have lowered recommended target levels of low-density lipoprotein-cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below conventional targets. Inferences from prior analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score matching (PSM) analysis of the ODYSSEY OUTCOMES trial which compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment.Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25-50 (n=3692) or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence, using 1:1 PSM.Across achieved LDL-C strata of the alirocumab group patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After PSM, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio (HR), 95% confidence interval (CI), and absolute risk reduction (ARR, number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (HR, 0.74; 95% CI, 0.62 to 0.89; ARR, 0.92) or 25-50 mg/dL (HR, 0.74; 95% CI, 0.64 to 0.87; ARR, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (HR, 0.87; 95% CI, 0.73 to 1.04; ARR, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL.After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL did not appear to derive further reduction in the risk of MACE compared to those who achieved LDL-C levels of 25-50 mg/dL.URL: https://www.clinicaltrials.gov Unique identifier: NCT01663402.



Circulation: 12 Jan 2021; epub ahead of print
Schwartz GG, Steg PG, Bhatt DL, Bittner VA, ... Szarek M, ODYSSEY OUTCOMES Committees and Investigators
Circulation: 12 Jan 2021; epub ahead of print | PMID: 33438437
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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

After heart transplantation, Endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive and its conventional histologic interpretation has limitations. This is a validation study to assesses the performance of a sensitive blood biomarker- percent donor-derived cell-free DNA (%ddcfDNA) - for detection of AR in cardiac transplant recipients.This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data was collected to define AR, its two 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 to controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.The study included 171 subjects with median post-transplant follow-up of 17.7 months (IQR: 12.1-23.6), with 1,392 EMBx, and 1,834 ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (0.03-0.21) by 28 days. %ddcfDNA increased again with AR compared to controls values (0.38, IQR=0.31-0.83, vs. 0.03, IQR=0.01-0.14 p<0.001). The rise was detected 0.5 and 3.2 months before histopathological diagnosis of ACR and AMR. The area-under-the- receiver-operator characteristics curve (AUROC) for AR was 0.92. A 0.25 %ddcfDNA threshold had a negative predictive value (NPV) for AR of 99% and would have safely eliminated 81% of EMBx. %ddcfDNA showed distinctive characteristics comparing AMR to ACR, included 5-fold higher levels (pAMR ≥2 1.68, IQR=0.49-2.79 vs. ACR grade ≥2R 0.34, IQR=0.28-0.72), higher AUROC (0.95 vs. 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.%ddcfDNA detected AR with a high AUROC and NPV. 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 heart transplant patients and paves the way for a clinical utility study.URL: http://clinicaltrials.gov Unique Identifier: NCT02423070.



Circulation: 12 Jan 2021; epub ahead of print
Agbor-Enoh S, Shah P, Tunc I, Hsu S, ... Valantine HA, GRAfT Investigators
Circulation: 12 Jan 2021; epub ahead of print | PMID: 33435695
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Abstract

Association of Body Mass Index and Age With Morbidity and Mortality in Patients Hospitalized With COVID-19: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry.

Hendren NS, de Lemos JA, Ayers C, Das SR, ... Neeland IJ, Grodin JL
Background
Obesity may contribute to adverse outcomes in coronavirus disease 2019 (COVID-19). However, studies of large, broadly generalizable patient populations are lacking, and the effect of body mass index (BMI) on COVID-19 outcomes- particularly in younger adults-remains uncertain.
Methods
We analyzed data from patients hospitalized with COVID-19 at 88 US hospitals enrolled in the American Heart Association\'s COVID-19 Cardiovascular Disease Registry with data collection through July 22, 2020. BMI was stratified by World Health Organization obesity class, with normal weight prespecified as the reference group.
Results
Obesity, and, in particular, class III obesity, was overrepresented in the registry in comparison with the US population, with the largest differences among adults ≤50 years. Among 7606 patients, in-hospital death or mechanical ventilation occurred in 2109 (27.7%), in-hospital death in 1302 (17.1%), and mechanical ventilation in 1602 (21.1%). After multivariable adjustment, classes I to III obesity were associated with higher risks of in-hospital death or mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09-1.51], 1.57 [1.29-1.91], 1.80 [1.47-2.20], respectively), and class III obesity was associated with a higher risk of in-hospital death (hazard ratio, 1.26 [95% CI, 1.00-1.58]). Overweight and class I to III obese individuals were at higher risk for mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09-1.51], 1.54 [1.29-1.84], 1.88 [1.52-2.32], and 2.08 [1.68-2.58], respectively). Significant BMI by age interactions were seen for all primary end points (-interaction<0.05 for each), such that the association of BMI with death or mechanical ventilation was strongest in adults ≤50 years, intermediate in adults 51 to 70 years, and weakest in adults >70 years. Severe obesity (BMI ≥40 kg/m) was associated with an increased risk of in-hospital death only in those ≤50 years (hazard ratio, 1.36 [1.01-1.84]). In adjusted analyses, higher BMI was associated with dialysis initiation and with venous thromboembolism but not with major adverse cardiac events.
Conclusions
Obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if young (age ≤50 years). Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals regardless of age.



Circulation: 11 Jan 2021; 143:135-144
Hendren NS, de Lemos JA, Ayers C, Das SR, ... Neeland IJ, Grodin JL
Circulation: 11 Jan 2021; 143:135-144 | PMID: 33200947
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Abstract

Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation.

Aeschbacher S, Blum S, Meyre PB, Coslovsky M, ... Kühne M,

The association of blood pressure (BP) and hypertension with the presence of different types of brain lesions in patients with atrial fibrillation is unclear. BP values were obtained in a multicenter cohort of patients with atrial fibrillation. Systolic and diastolic BP was categorized in predefined groups. All patients underwent brain magnetic resonance imaging and neurocognitive testing. Brain lesions were classified as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, or white matter lesions. White matter lesions were graded according to the Fazekas scale. Overall, 1738 patients with atrial fibrillation were enrolled in this cross-sectional analysis (mean age, 73 years, 73% males). Mean BP was 135/79 mm Hg, and 67% of participants were taking BP-lowering treatment. White matter lesions Fazekas ≥2 were found in 54%, large noncortical or cortical infarcts in 22%, small noncortical infarcts in 21%, and microbleeds in 22% of patients, respectively. Compared with patients with systolic BP <120 mm Hg, the adjusted odds ratios (95% CI) for Fazekas≥2 was 1.25 (0.94-1.66), 1.41 (1.03-1.93), and 2.54 (1.65-3.95) among patients with systolic BP of 120 to 140, 140 to 160, and ≥160 mm Hg ( for linear trend<0.001). Per 5 mm Hg increase in systolic and diastolic BP, the adjusted β-coefficient (95% CI) for log-transformed white matter lesions was 0.04 (0.02-0.05), <0.001 and 0.04 (0.01-0.06), =0.004. Systolic BP was associated with small noncortical infarcts (odds ratios [95% CI] per 5 mm Hg 1.05 [1.01-1.08], =0.006), microbleeds were associated with hypertension, but large noncortical or cortical infarcts were not associated with BP or hypertension. After multivariable adjustment, BP and hypertension were not associated with neurocognitive function. Among patients with atrial fibrillation, BP is strongly associated with the presence and extent of white matter lesions, but there is no association with large noncortical or cortical infarcts. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.



Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016025; epub ahead of print
Aeschbacher S, Blum S, Meyre PB, Coslovsky M, ... Kühne M,
Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016025; epub ahead of print | PMID: 33356398
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Abstract

Genetically Predicted Blood Pressure and Risk of Atrial Fibrillation.

Hyman MC, Levin MG, Gill D, Walker VM, ... Marchlinski FE, Damrauer SM

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; =1×10; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; =3×10; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; =0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; =8×10) and β-blockers (OR, 0.61 [95% CI, 0.46-0.81]; =6×10) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016191; epub ahead of print
Hyman MC, Levin MG, Gill D, Walker VM, ... Marchlinski FE, Damrauer SM
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016191; epub ahead of print | PMID: 33390040
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Abstract

Aortic Pulse Wave Velocity Predicts Cardiovascular Events and Mortality in Patients Undergoing Coronary Angiography: A Comparison of Invasive Measurements and Noninvasive Estimates.

Hametner B, Wassertheurer S, Mayer CC, Danninger K, Binder RK, Weber T

Aortic pulse wave velocity (PWV) is directly related to arterial stiffness. Different methods for the determination of PWV coexist. The aim of this prospective study was to evaluate the prognostic value of PWV in high-risk patients with suspected coronary artery disease undergoing invasive angiography and to compare 3 different methods for assessing PWV. In 1040 patients, invasive PWV (iPWV) was measured during catheter pullback. Additionally, PWV was estimated with a model incorporating age, central systolic blood pressure, and pulse waveform characteristics obtained from noninvasive measurements (estimated PWV). As a third method, PWV was calculated with a formula solely based on age and blood pressure (formula-based PWV). Survival analysis was based on continuous PWV as well as using cutoff values. After a median follow-up duration of 1565 days, 24% of the patients reached the combined end point (cardiovascular events or mortality). Cox proportional hazard ratios per 1 SD were 1.35 for iPWV, 1.37 for estimated PWV, and 1.28 for formula-based PWV (<0.0001 for all 3 methods) in univariate analysis, remaining statistically significant after comprehensive multivariable adjustments. In a model including a modified risk score for coronary artery disease, iPWV and estimated PWV remained borderline significant. The net reclassification improvement was significant for iPWV (0.173), formula-based PWV (0.181), and estimated PWV (0.230). All 3 methods for the determination of PWV predicted cardiovascular events and mortality in patients with suspected coronary artery disease. This indicates that iPWV as well as both noninvasive estimation methods are suitable for the assessment of arterial stiffness, bearing in mind their individual characteristics.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12015336; epub ahead of print
Hametner B, Wassertheurer S, Mayer CC, Danninger K, Binder RK, Weber T
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12015336; epub ahead of print | PMID: 33390046
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Abstract

Association of Fatal and Nonfatal Cardiovascular Outcomes With 24-Hour Mean Arterial Pressure.

Melgarejo JD, Yang WY, Thijs L, Li Y, ... Zhang ZY,

Major adverse cardiovascular events are closely associated with 24-hour blood pressure (BP). We determined outcome-driven thresholds for 24-hour mean arterial pressure (MAP), a BP index estimated by oscillometric devices. We assessed the association of major adverse cardiovascular events with 24-hour MAP, systolic BP (SBP), and diastolic BP (DBP) in a population-based cohort (n=11 596). Statistics included multivariable Cox regression and the generalized R statistic to test model fit. Baseline office and 24-hour MAP averaged 97.4 and 90.4 mm Hg. Over 13.6 years (median), 2034 major adverse cardiovascular events occurred. Twenty-four-hour MAP levels of <90 (normotension, n=6183), 90 to <92 (elevated MAP, n=909), 92 to <96 (stage-1 hypertension, n=1544), and ≥96 (stage-2 hypertension, n=2960) mm Hg yielded equivalent 10-year major adverse cardiovascular events risks as office MAP categorized using 2017 American thresholds for office SBP and DBP. Compared with 24-hour MAP normotension, hazard ratios were 0.96 (95% CI, 0.80-1.16), 1.32 (1.15-1.51), and 1.77 (1.59-1.97), for elevated and stage-1 and stage-2 hypertensive MAP. On top of 24-hour MAP, higher 24-hour SBP increased, whereas higher 24-hour DBP attenuated risk (<0.001). Considering the 24-hour measurements, R statistics were similar for SBP (1.34) and MAP (1.28), lower for DBP than for MAP (0.47), and reduced to null, if the base model included SBP and DBP; if the ambulatory BP indexes were dichotomized according to the 2017 American guideline and the proposed 92 mm Hg for MAP, the R values were 0.71, 0.89, 0.32, and 0.10, respectively. In conclusion, the clinical application of 24-hour MAP thresholds in conjunction with SBP and DBP refines risk estimates.



Hypertension: 30 Dec 2020; 77:39-48
Melgarejo JD, Yang WY, Thijs L, Li Y, ... Zhang ZY,
Hypertension: 30 Dec 2020; 77:39-48 | PMID: 33296250
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Abstract

Adverse Health Outcomes Associated With Refractory and Treatment-Resistant Hypertension in the Chronic Renal Insufficiency Cohort.

Buhnerkempe MG, Prakash V, Botchway A, Adekola B, ... Ricardo AC, Flack JM

Refractory hypertension (RfH) is a severe phenotype of antihypertension treatment failure. Treatment-resistant hypertension (TRH), a less severe form of difficult-to-treat hypertension, has been associated with significantly worse health outcomes. However, no studies currently show how health outcomes may worsen upon progression to RfH. RfH and TRH were studied in 3147 hypertensive participants in the CRIC (Chronic Renal Insufficiency Cohort study). The hypertensive phenotype (ie, no TRH or RfH, TRH, or RfH) was identified at the baseline visit, and health outcomes were monitored at subsequent visits. Outcome risk was compared using Cox proportional hazards models with time-varying covariates. A total of 136 (4.3%) individuals were identified with RfH at baseline. After adjusting for participant characteristics, individuals with RfH had increased risk for the composite renal outcome across all study years (50% decline in estimated glomerular filtration rate or end-stage renal disease; hazard ratio for study years 0-10=1.73 [95% CI, 1.42-2.11]) and the composite cardiovascular disease outcome during later study years (stroke, myocardial infarction, or congestive heart failure; hazard ratio for study years 0-3=1.25 [0.91-1.73], for study years 3-6=1.50 [0.97-2.32]), and for study years 6-10=2.72 [1.47-5.01]) when compared with individuals with TRH. There was no significant difference in all-cause mortality between those with refractory versus TRH. We provide the first evidence that RfH is associated with worse long-term health outcomes compared with TRH.



Hypertension: 30 Dec 2020; 77:72-81
Buhnerkempe MG, Prakash V, Botchway A, Adekola B, ... Ricardo AC, Flack JM
Hypertension: 30 Dec 2020; 77:72-81 | PMID: 33161774
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Abstract

Cost-Effectiveness of Initiating Pharmacological Treatment in Stage One Hypertension Based on 10-Year Cardiovascular Disease Risk: A Markov Modeling Study.

Constanti M, Floyd CN, Glover M, Boffa R, Wierzbicki AS, McManus RJ

Antihypertensive drug treatment is cost-effective for adults at high risk of developing cardiovascular disease (CVD). However, the cost-effectiveness in people with stage 1 hypertension (140-159 mm Hg systolic blood pressure) at lower CVD risk remains unclear. The objective was to establish the 10-year CVD risk threshold where initiating antihypertensive drug treatment for primary prevention in adults, with stage 1 hypertension, becomes cost-effective. A lifetime horizon Markov model compared antihypertensive drug versus no treatment, using a UK National Health Service perspective. Analyses were conducted for groups ranging between 5% and 20% 10-year CVD risk. Health states included no CVD event, CVD and non-CVD death, and 6 nonfatal CVD morbidities. Interventions were compared using cost-per-quality-adjusted life-years. The base-case age was 60, with analyses repeated between ages 40 and 75. The model was run separately for men and women, and threshold CVD risk assessed against the minimum plausible risk for each group. Treatment was cost-effective at 10% CVD risk for both sexes (incremental cost-effectiveness ratio £10 017/quality-adjusted life-year [$14 542] men, £8635/QALY [$12 536] women) in the base-case. The result was robust in probabilistic and deterministic sensitivity analyses but was sensitive to treatment effects. Treatment was cost-effective for men regardless of age and women aged >60. Initiating treatment in stage 1 hypertension for people aged 60 is cost-effective regardless of 10-year CVD risk. For other age groups, it is also cost-effective to treat regardless of risk, except in younger women.



Hypertension: 20 Dec 2020:HYPERTENSIONAHA12014913; epub ahead of print
Constanti M, Floyd CN, Glover M, Boffa R, Wierzbicki AS, McManus RJ
Hypertension: 20 Dec 2020:HYPERTENSIONAHA12014913; epub ahead of print | PMID: 33342242
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Abstract

Association of Cumulative Systolic Blood Pressure With Long-Term Risk of Cardiovascular Disease and Healthy Longevity: Findings From the Lifetime Risk Pooling Project Cohorts.

Reges O, Ning H, Wilkins JT, Wu CO, ... Lloyd-Jones DM, Allen NB

Hypertension is a major risk factor for cardiovascular disease (CVD), but previous studies have mostly been limited to a single exam, a single cohort, a short follow-up period, or a limited number of outcomes. This study aimed to assess the association of 10-year cumulative systolic blood pressure (BP) in middle age with long-term risk of any CVD, coronary heart disease, stroke, heart failure, all-cause mortality, and healthy longevity. Individuals (11 502) from 5 racially/ethnically diverse US community-based cohorts were included in this study once they met all the inclusion criteria: ≥10 year of observation in the included cohort, aged 45 to 60 years, free of CVD, and had ≥3 visits with BP exams over the preceding 10 years. For each participant, systolic BP level was predicted for each year of the 10-year prior inclusion, based on the available exams (median of 4.0; spread over, 9.1 [range, 7.2-10] years). Lower 10-year cumulative systolic BP was associated with 4.1 years longer survival and 5.4 years later onset of CVD, resulting in living longer life with a shorter period with morbidity. Models adjusted for sociodemographic characteristics, cardiovascular risk factors, and index systolic BP demonstrated associations of 10-year cumulative systolic BP (per 130 mm Hg×year change, the threshold for stage-1 hypertension) with CVD (hazard ratio [HR], 1.28 [95% CI, 1.20-1.36]), coronary heart disease (HR, 1.29 [95% CI, 1.19-1.40]), stroke (HR, 1.33 [95% CI, 1.20-1.47]), heart failure (HR, 1.12 [95% CI, 1.02-1.23]), and all-cause mortality (HR, 1.21 [95% CI, 1.14-1.29]). These findings emphasize the importance of 10-year cumulative systolic BP as a risk factor to CVD, above and beyond current systolic BP.



Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015650; epub ahead of print
Reges O, Ning H, Wilkins JT, Wu CO, ... Lloyd-Jones DM, Allen NB
Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015650; epub ahead of print | PMID: 33342241
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Impact:
Abstract

Applicability of Blood Pressure-Lowering Drug Trials to Real-World Patients With Cardiovascular Disease.

Bonekamp NE, Spiering W, Nathoe HM, Kappelle LJ, ... Westerink J,

This study aimed to assess applicability of blood pressure-lowering drug trials to real-world secondary preventive care. We applied the eligibility criteria of the landmark blood pressure-lowering drug trials (EUROPA, PEACE, HOPE-peripheral arterial disease [PAD], PRoFESS, and PROGRESS) to patients with coronary artery disease (CAD; n=5155), peripheral arterial disease (PAD; n=1487), and cerebrovascular disease (n=2515) participating in the UCC-SMART cohort. Baseline differences according to trial eligibility were assessed. Differences in risk of all-cause mortality and a composite of cardiovascular death, myocardial infarction, and stroke (major adverse cardiovascular event) were calculated using Cox proportional hazard models, adjusted for age, sex, and cardiovascular risk factors. Seventy-five percent of UCC-SMART patients with CAD would have been eligible for EUROPA, 84% for PEACE, 59% of patients with PAD for HOPE-PAD, 17% of patients with cerebrovascular disease for PRoFESS, and 100% for PROGRESS. Eligible patients were older (average difference ranging 1.4-14.6 years across trials). Eligible patients with CAD were at lower risk of major adverse cardiovascular event after adjustment for age, sex, and cardiovascular risk factors in PEACE (hazard ratio, 0.65 [95% CI, 0.53-0.79]) and of mortality in both EUROPA (hazard ratio, 0.72 [95% CI, 0.62-0.82]) and PEACE (0.63 [95% CI, 0.51-0.78]). Adjusted mortality and major adverse cardiovascular event risks were not different between eligible and ineligible patients with PAD and cerebrovascular disease in HOPE-PAD, PRoFESS, and PROGRESS. The majority of real-world patients with CAD, PAD, or cerebrovascular disease would be eligible for landmark trials on blood pressure-lowering drugs. Patients with CAD ineligible for the EUROPA and PEACE trials are at higher adjusted mortality and major adverse cardiovascular event risks, which may limit applicability of their results to ineligible patients.



Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015965; epub ahead of print
Bonekamp NE, Spiering W, Nathoe HM, Kappelle LJ, ... Westerink J,
Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015965; epub ahead of print | PMID: 33342237
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Abstract

Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.

Clark CE, Warren FC, Boddy K, McDonagh STJ, ... Aboyans V, Campbell JL

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.



Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015997; epub ahead of print
Clark CE, Warren FC, Boddy K, McDonagh STJ, ... Aboyans V, Campbell JL
Hypertension: 20 Dec 2020:HYPERTENSIONAHA12015997; epub ahead of print | PMID: 33342236
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Abstract

Ambulatory Blood Pressure Monitoring to Predict Response to Renal Denervation: A Post Hoc Analysis of the RADIANCE-HTN SOLO Study.

Gosse P, Cremer A, Kirtane AJ, Lobo MD, ... Liu Y, Azizi M

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP <130 mm Hg (RDN: 22/64 versus sham: 7/58); meaningful with 24-hour SBP reduction ≥10 mm Hg (RDN: 24/64, sham: 7/58); and extreme with 24-hour SBP reduction above mean+2 SD of the SBP decrease in the sham group, that is, ≥16.5 mm Hg (RDN: 10/64 versus sham: 2/58). The predictive criteria reported above were tested for sensitivity, specificity, and positive and negative predictive values. The predictive value varied according to the definition of response, with the clinical definition being strongly influenced by regression to the mean. Baseline nighttime SBP and its variability, especially when combined, offered good specificity (>90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02649426.



Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016292; epub ahead of print
Gosse P, Cremer A, Kirtane AJ, Lobo MD, ... Liu Y, Azizi M
Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016292; epub ahead of print | PMID: 33356403
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Abstract

Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials.

Gill D, Cameron AC, Burgess S, Li X, ... Dawson J, Tzoulaki I

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10-1.30]; =4×10), peripheral artery disease (1.12 [95% CI, 1.03-1.21]; =9×10), and stroke (1.11 [95% CI, 1.05-1.18]; =2×10). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, -2.55 mm Hg [95% CI, -4.06 to -1.05]; =1×10) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22-0.73]; =3×10) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44-1.03]; =0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.



Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016547; epub ahead of print
Gill D, Cameron AC, Burgess S, Li X, ... Dawson J, Tzoulaki I
Hypertension: 27 Dec 2020:HYPERTENSIONAHA12016547; epub ahead of print | PMID: 33356394
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Abstract

Pregnancy and Preeclampsia Are Associated With Acute Adverse Peripheral Arterial Events.

DeCarlo C, Boitano LT, Molina RL, Weinberg I, ... Eagleton MJ, Dua A
Objective
Acute peripheral arterial events, such as aortic dissection, carotid artery dissection, vertebral artery dissection, and ruptured renoviseral aneurysms, have been reported during pregnancy in case series, but there is a paucity of population-based data. This study sought to establish pregnancy and preeclampsia as risk factors for acute peripheral arterial events. Approach and
Results:
All women who gave birth between 1998 and 2020 within a multicenter health care system were identified. Births that occurred in women <18 or >50 years of age were excluded. Primary outcome was any acute peripheral arterial event that was symptomatic or required intervention. Cox regression model was used to evaluate the association between vascular events and pregnancy as a time-varying covariate. The pregnancy exposure period was from the estimated date of conception to 3 months postpartum. There were 277 697 pregnancies (81.3% deliveries, 17.0% abortions, and 1.7% ectopics) among 176 635 women with 1.68 million patient-years of total follow-up (median, 7.9 years; interquartile range, 2.4-16.2). Preeclampsia complicated 5.3% of pregnancies; 67 790 of 225 763 (30.0%) deliveries were delivered by cesarean. Ninety-six acute arterial events occurred during follow-up, of which 24 occurred during pregnancy, including the postpartum period. Pregnancy (hazard ratio, 1.85 [95% CI, 1.01-3.38]; =0.046) and preeclampsia (hazard ratio, 10.9 [95% CI, 5.24-22.7]; <0.001) were significant independent predictors of acute arterial events.
Conclusions
While taking into account limitations from estimating conception and outcome dates, pregnancy, especially when complicated by preeclampsia, is associated with an increased risk of acute peripheral arterial events.



Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:526-533
DeCarlo C, Boitano LT, Molina RL, Weinberg I, ... Eagleton MJ, Dua A
Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:526-533 | PMID: 33054392
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Abstract

Clinical Evaluation of the Polygenetic Background of Blood Pressure in the Population-Based Setting.

Giontella A, Sjögren M, Lotta LA, Overton JD, ... Fava C, Melander O

The clinical value of the polygenetic component of blood pressure (BP) is commonly questioned. We evaluated a genetic risk score for BP (BP-GRS), based on the most recently published genome-wide association studies variants that were significantly associated with either systolic BP or diastolic BP, for prediction of hypertension and cardiovascular end points. The genotyping was performed in 2 urban-based prospective cohorts: the Malmö Diet and Cancer (n=29 295) and the Malmö Preventive Project (n=9367) and a weighted BP-GRS based on 858 SNPs was calculated. At baseline, we found a difference of 9.0 mm Hg (systolic BP) and 4.8 mm Hg (diastolic BP) between the top and the bottom quartile of BP-GRS. In Malmö Preventive Project, the top versus bottom quartile of BP-GRS was associated with a doubled risk of incident hypertension (odds ratio, 2.05 [95% CI, 1.75-2.39], =1.4×10), a risk higher than that of body mass index, as evaluated in quartiles. In Malmö Diet and Cancer, significant association was found between the age and sex-adjusted BP-GRS and the incidence of total cardiovascular events, stroke, coronary artery disease, heart failure, atrial fibrillation, and total mortality. Most of these associations remained significant after adjusting for traditional risk factors, including hypertension. BP-GRS could contribute predictive information regarding future hypertension, with an effect size comparable to other well-known risk factors such as obesity, and predicts cardiovascular events. Given that the exposure to high polygenetic risk starts at birth, we suggest that the BP-GRS might be useful to identify children or adolescents who would benefit from early hypertension screening and treatment.



Hypertension: 30 Dec 2020; 77:169-177
Giontella A, Sjögren M, Lotta LA, Overton JD, ... Fava C, Melander O
Hypertension: 30 Dec 2020; 77:169-177 | PMID: 33222547
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Abstract

Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank.

Patel AP, Wang M, Pirruccello JP, Ellinor PT, ... Kathiresan S, Khera AV
Objective
Lp(a) (lipoprotein[a]) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD), and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address 3 areas of uncertainty: (1) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (2) variation of risk across racial and clinical subgroups; (3) clinical importance of a high lipoprotein(a) threshold to guide therapy. Approach and
Results:
Relationship of lipoprotein(a) to incident ASCVD was studied in 460 506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22 401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6-74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95% CI, 1.10-1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race-median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar-hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with preexisting ASCVD and associated with hazard ratios of 1.50 (95% CI, 1.44-1.56) and 1.16 (95% CI, 1.05-1.27), respectively.
Conclusions
Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.



Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:465-474
Patel AP, Wang M, Pirruccello JP, Ellinor PT, ... Kathiresan S, Khera AV
Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:465-474 | PMID: 33115266
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Abstract

Human Aortic Valve Interstitial Cells Display Proangiogenic Properties During Calcific Aortic Valve Disease.

Gendron N, Rosa M, Blandinieres A, Sottejeau Y, ... Susen S, Smadja DM
Objective
The study\'s aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and
Results:
VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VIC) mesenchymal-like phenotype was confirmed by CD90/CD73/CD44 expression and multipotent-like differentiation ability. When VIC were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VIC and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VIC-conditioned media and confirmed at the mRNA level in VIC compared with control VIC. Conditioned media from VIC induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VIC involvement in angiogenesis by a VEGF-A dependent mechanism.
Conclusions
We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VIC in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.



Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:415-429
Gendron N, Rosa M, Blandinieres A, Sottejeau Y, ... Susen S, Smadja DM
Arterioscler Thromb Vasc Biol: 30 Dec 2020; 41:415-429 | PMID: 33147990
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Impact:
Abstract

Adding Home and/or Ambulatory Blood Pressure to Office Blood Pressure for Cardiovascular Risk Prediction.

Mancia G, Facchetti R, Seravalle G, Cuspidi C, Corrao G, Grassi G

Home and 24-hour blood pressure (BP and BP) are believed to improve the prognostic value of office BP (BP) alone, but the evidence has limitations such as that (1) these 3 BPs are characterized by multicollinearity and (2) the procedures adopted do not allow quantification of the prognostic advantage. One thousand eight hundred thirty-three individuals belonging to the PAMELA (Pressioni Arteriose Monitorate e Loro Associazioni) were followed for 16 years. Prediction of cardiovascular and all-cause mortality was determined via the goodness of fit of individual data (Cox model), the area underlying the receiving operator curves and the net reclassification improvement of cardiovascular and all-cause mortality risk. Calculations were made for BP alone and after addition of BP, BP, or both, limited to their residual portion which was found to be unexplained by, and thus independent on, BP. With all methods addition of residual out-of-office systolic or diastolic BP to BP significantly improved cardiovascular and all-cause mortality prediction. The improvement was more consistent when BP rather than BP was added to BP and, compared with BP plus BP, no better prediction was found when addition was extended to BP. With all additions, however, the improvement was quantitatively modest, which was the case also when data were separately analyzed in younger and older individuals or in dippers and nondippers. Thus, addition of out-of-office to BP improves prediction of cardiovascular risk, even when data analysis avoids previous limitations. The improvement appears to be limited, however, which raises the question of the advantage to recommend their extended use in clinical practice.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016303; epub ahead of print
Mancia G, Facchetti R, Seravalle G, Cuspidi C, Corrao G, Grassi G
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016303; epub ahead of print | PMID: 33390055
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Impact:
Abstract

Blood Pressure and Risk of Cardiovascular Disease in UK Biobank: A Mendelian Randomization Study.

Wan EYF, Fung WT, Schooling CM, Au Yeung SL, ... Wong ICK, Lam CLK

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25-1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15-1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24-1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14-1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24-1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12-1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016138; epub ahead of print
Wan EYF, Fung WT, Schooling CM, Au Yeung SL, ... Wong ICK, Lam CLK
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016138; epub ahead of print | PMID: 33390054
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Abstract

Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements.

Picone DS, Schultz MG, Armstrong MK, Black JA, ... Sharman JE,

Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016109; epub ahead of print
Picone DS, Schultz MG, Armstrong MK, Black JA, ... Sharman JE,
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12016109; epub ahead of print | PMID: 33390047
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Abstract

Developmental and Early Life Origins of Cardiometabolic Risk Factors: Novel Findings and Implications.

Lurbe E, Ingelfinger J

The intent of this review is to critically consider the data that support the concept of programming and its implications. Birth weight and growth trajectories during childhood are associated with cardiometabolic disease in adult life. Both extremes, low and high birth weight coupled with postnatal growth increase the early presence of cardiometabolic risk factors and vascular imprinting, crucial elements of this framework. Data coming from epigenetics, proteomics, metabolomics, and microbiota added relevant information and contribute to better understanding of mechanisms as well as development of biomarkers helping to move forward to take actions. Research has reached a stage in which sufficiently robust data calls for new initiatives focused on early life. Prevention starting early in life is likely to have a very large impact on reducing disease incidence and its associated effects at the personal, economic, and social levels.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12014592; epub ahead of print
Lurbe E, Ingelfinger J
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12014592; epub ahead of print | PMID: 33390043
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Abstract

Aortic Stiffness, Central Blood Pressure, and Pulsatile Arterial Load Predict Future Thoracic Aortic Aneurysm Expansion.

Boczar KE, Boodhwani M, Beauchesne L, Dennie C, ... Wells GA, Coutinho T

Thoracic aortic aneurysm is a disease associated with high morbidity and mortality. Clinically useful strategies for medical management of thoracic aortic aneurysm are critically needed. To address this need, we sought to determine the role of aortic stiffness and pulsatile arterial load on future aneurysm expansion. One hundred five consecutive, unoperated subjects with thoracic aortic aneurysm were recruited and prospectively followed. By combining arterial tonometry with echocardiography, we estimated measures of aortic stiffness, central blood pressure, steady, and pulsatile arterial load at baseline. Aneurysm size was measured at baseline and follow-up with imaging; growth was calculated in mm/y. Stepwise multivariable linear regression assessed associations of arterial stiffness and load measures with aneurysm growth after adjusting for potential confounders. Mean±SD age, baseline aneurysm size, and follow-up time were 62.6±11.4 years, 46.24±3.84 mm, and 2.92±1.01 years, respectively. Aneurysm growth rate was 0.43±0.37 mm/y. After correcting for multiple comparisons, higher central systolic (β±SE: 0.026±0.009, =0.007), and pulse pressures (β±SE: 0.032±0.009, =0.0002), carotid-femoral pulse wave velocity (β±SE: 0.032±0.011, =0.005), amplitudes of the forward (β±SE: 0.044±0.012, =0.0003) and reflected (β±SE: 0.060±0.020, =0.003) pressure waves, and lower total arterial compliance (β±SE: -0.086±0.032, =0.009) were independently associated with future aneurysm growth. Measures of aortic stiffness and pulsatile hemodynamics are independently associated with future thoracic aortic aneurysm growth and provide novel insights into disease activity. Our findings highlight the role of central hemodynamic assessment to tailor novel risk assessment and therapeutic strategies to patients with thoracic aortic aneurysm.



Hypertension: 30 Dec 2020; 77:126-134
Boczar KE, Boodhwani M, Beauchesne L, Dennie C, ... Wells GA, Coutinho T
Hypertension: 30 Dec 2020; 77:126-134 | PMID: 33249858
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Abstract

Ambulatory Blood Pressure Monitoring to Diagnose and Manage Hypertension.

Huang QF, Yang WY, Asayama K, Zhang ZY, ... O\'Brien E, Staessen JA

This review portrays how ambulatory blood pressure (BP) monitoring was established and recommended as the method of choice for the assessment of BP and for the rational use of antihypertensive drugs. To establish much-needed diagnostic ambulatory BP thresholds, initial statistical approaches evolved into longitudinal studies of patients and populations, which demonstrated that cardiovascular complications are more closely associated with 24-hour and nighttime BP than with office BP. Studies cross-classifying individuals based on ambulatory and office BP thresholds identified white-coat hypertension, an elevated office BP in the presence of ambulatory normotension as a low-risk condition, whereas its counterpart, masked hypertension, carries a hazard almost as high as ambulatory combined with office hypertension. What clinically matters most is the level of the 24-hour and the nighttime BP, while other BP indexes derived from 24-hour ambulatory BP recordings, on top of the 24-hour and nighttime BP level, add little to risk stratification or hypertension management. Ambulatory BP monitoring is cost-effective. Ambulatory and home BP monitoring are complimentary approaches. Their interchangeability provides great versatility in the clinical implementation of out-of-office BP measurement. We are still waiting for evidence from randomized clinical trials to prove that out-of-office BP monitoring is superior to office BP in adjusting antihypertensive drug treatment and in the prevention of cardiovascular complications. A starting research line, the development of a standardized validation protocol for wearable BP monitoring devices, might facilitate the clinical applicability of ambulatory BP monitoring.



Hypertension: 03 Jan 2021:HYPERTENSIONAHA12014591; epub ahead of print
Huang QF, Yang WY, Asayama K, Zhang ZY, ... O'Brien E, Staessen JA
Hypertension: 03 Jan 2021:HYPERTENSIONAHA12014591; epub ahead of print | PMID: 33390042
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Abstract

Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients.

Semenzato L, Botton J, Drouin J, Baricault B, ... Dray-Spira R, Zureik M

After initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations. We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs). Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020. We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias. The primary end point was time to hospitalization for COVID-19. The secondary end point was time to intubation/death during a hospital stay for COVID-19. In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19. ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65-0.83] and 0.84 [0.76-0.93], respectively) and a lower risk of intubation/death. Risks were slightly lower for ACE inhibitor users than for ARB users. This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs. These results, if confirmed, tend to contradict previous hypotheses and raise new hypotheses.



Hypertension: 10 Jan 2021:HYPERTENSIONAHA12016314; epub ahead of print
Semenzato L, Botton J, Drouin J, Baricault B, ... Dray-Spira R, Zureik M
Hypertension: 10 Jan 2021:HYPERTENSIONAHA12016314; epub ahead of print | PMID: 33423528
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Abstract

Association of Blood Pressure Variability and Diuretics With Cardiovascular Events in Patients With Chronic Kidney Disease Stages 1-5.

Gregg LP, Hedayati SS, Yang H, Van Buren PN, ... Winkelmayer WC, Alvarez CA

Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events in the general population. Data are scarce in chronic kidney disease. We hypothesized that BPV would be associated with cardiovascular outcomes, death, and end-stage kidney disease (ESKD) and that diuretics would modify these associations in patients with chronic kidney disease. We studied US Veterans with nondialysis chronic kidney disease stages 1-5 and hypertension on nondiuretic antihypertensive monotherapy. At the time of second antihypertensive agent prescription, we propensity-matched for exposure to a loop or thiazide diuretic versus any other antihypertensive. BPV was defined as the coefficient of variation of systolic blood pressure over 6 months after second agent prescription. Cox proportional hazards regression measured associations of BPV with a primary cardiovascular event composite (fatal or nonfatal myocardial infarction or ischemic stroke; heart failure hospitalization). Secondary outcomes included all-cause death, each primary outcome component, end-stage kidney disease, and cardiovascular death. There were 31 394 participants in each group. BPV was associated with composite cardiovascular events, hazard ratio (95% CI) at second, third, fourth, and fifth versus first quintile: 1.79 (1.53-2.11), 2.32 (1.99-2.71), 2.60 (2.24-3.02), and 3.12 (2.68-3.62). Diuretics attenuated associations between the fourth and fifth BPV quintiles with composite events (=0.03 and 0.04, respectively). BPV was associated with all secondary outcomes except end-stage kidney disease, with no diuretic interactions. BPV was associated with cardiovascular events and death but not end-stage kidney disease in patients with chronic kidney disease, with attenuated associations with cardiovascular events in the diuretic-treated group at high BPV quintiles. Future studies should investigate whether other antihypertensive classes modify these risks.



Hypertension: 10 Jan 2021:HYPERTENSIONAHA12016117; epub ahead of print
Gregg LP, Hedayati SS, Yang H, Van Buren PN, ... Winkelmayer WC, Alvarez CA
Hypertension: 10 Jan 2021:HYPERTENSIONAHA12016117; epub ahead of print | PMID: 33423525
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Abstract

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

Wallentin L, Eriksson N, Olszowka M, Grammer TB, ... Åberg M, Siegbahn A
Background
Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.
Methods and findings
The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapladIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973) carried most prognostic information. The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.
Conclusions
Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.
Trial registration
ClinicalTrials.gov NCT00799903.



PLoS Med: 12 Jan 2021; 18:e1003513
Wallentin L, Eriksson N, Olszowka M, Grammer TB, ... Åberg M, Siegbahn A
PLoS Med: 12 Jan 2021; 18:e1003513 | PMID: 33439866
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Abstract

Aortic Regurgitation Is Associated With Ascending Aortic Remodeling in the Nondilated Aorta.

Balint B, Federspiel JM, Schwab T, Ehrlich T, Ramsthaler F, Schäfers HJ
Objective
The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and
Results:
Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas (=0.005) but not AS-aortas (=0.23). This pathological remodeling included mucoid extracellular matrix accumulation (=0.005), elastin loss (=0.003), elastin fragmentation (=0.008), and decreased expression of fibrillin (=0.003) and collagen (=0.008). Furthermore, endothelial nitric oxide synthase expression was decreased in the intima (=0.0008) and in vasa vasorum (=0.004) of AR-aortas but not AS-aortas (all >0.05). Likewise, subendothelial apoptosis was increased in AR-aortas (=0.03) but not AS-aortas (=0.50).
Conclusions
AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR.



Arterioscler Thromb Vasc Biol: 13 Jan 2021:ATVBAHA120315739; epub ahead of print
Balint B, Federspiel JM, Schwab T, Ehrlich T, Ramsthaler F, Schäfers HJ
Arterioscler Thromb Vasc Biol: 13 Jan 2021:ATVBAHA120315739; epub ahead of print | PMID: 33441026
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Abstract

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses.

Sun L, Pennells L, Kaptoge S, Nelson CP, ... Inouye M, Di Angelantonio E
Background
Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD.
Methods and findings
Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009-0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40-75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.
Conclusions
Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.



PLoS Med: 30 Dec 2020; 18:e1003498
Sun L, Pennells L, Kaptoge S, Nelson CP, ... Inouye M, Di Angelantonio E
PLoS Med: 30 Dec 2020; 18:e1003498 | PMID: 33444330
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Abstract

Effects of Intensive Blood Pressure Treatment on Orthostatic Hypotension : A Systematic Review and Individual Participant-based Meta-analysis.

Juraschek SP, Hu JR, Cluett JL, Ishak A, ... Wright JT, Mukamal KJ
Background
Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH).
Purpose
To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults.
Data sources
MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions.
Study selection
Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing.
Data extraction
2 investigators independently abstracted articles and rated risk of bias.
Data synthesis
5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH ( for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged.
Limitations
Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available.
Conclusion
Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension.
Primary funding source
National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).



Ann Intern Med: 30 Dec 2020; 174:58-68
Juraschek SP, Hu JR, Cluett JL, Ishak A, ... Wright JT, Mukamal KJ
Ann Intern Med: 30 Dec 2020; 174:58-68 | PMID: 32909814
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Abstract

Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation.

Qi XY, Vahdahi Hassani F, Hoffmann D, Xiao J, ... Dobrev D, Nattel S

The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca regulates gene-expression, but the nature and significance of nuclear Ca-changes in AF are largely unknown.To elucidate mechanisms by which AF alters atrial cardiomyocyte (CM) nuclear Ca ([Ca]) and Ca/calmodulin-dependent protein kinase-II (CaMKII)-related signaling. Atrial CMs were isolated from control and AF-dogs (kept in AF by atrial tachypacing [600 bpm x 1 week]). [Ca] and cytosolic [Ca] (Ca]) were recorded via confocal microscopy. Diastolic [Ca] was greater than [Ca] under control conditions, while resting [Ca] was similar to [Ca]; both diastolic and resting [Ca] increased with AF. Inositol-trisphosphate-receptor (IPR) stimulation produced larger [Ca] increases in AF versus control CMs, and IPR-blockade suppressed the AF-related [Ca]-differences. AF upregulated nuclear protein-expression of IPR-type 1 (IPR1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot), while decreasing the nuclear/cytosolic expression-ratio for histone deacetylase type-4 (HDAC4). Isolated atrial CMs tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca] changes and L-type calcium current (ICaL) decreases versus 1-Hz-paced CMs; these changes were prevented by IP3R knockdown with short-interfering RNA directed against IPR1. Nuclear/cytosolic HDAC4 expression-ratio was decreased by 3-Hz pacing, while nuclear CaMKII and HDAC4 phosphorylation were increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IPR-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial CMs from AF patients, nuclear IPR1-expression was significantly increased, with decreased nuclear/non-nuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by Luciferase assay) and was downregulated in AF atrial CMs; microRNA-26a silencing reproduced AF-induced IP3R1 upregulation and nuclear diastolic Ca-loading.AF increases atrial CM nucleoplasmic Ca-handling by IPR1-upregulation involving miR-26a, leading to enhanced IPR1-CaMKII-HDAC4 signaling and I-downregulation.



Circ Res: 29 Dec 2020; epub ahead of print
Qi XY, Vahdahi Hassani F, Hoffmann D, Xiao J, ... Dobrev D, Nattel S
Circ Res: 29 Dec 2020; epub ahead of print | PMID: 33375812
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Abstract

Stroke risk prediction in patients with atrial fibrillation with and without rheumatic heart disease.

Benz AP, Healey JS, Chin A, Commerford P, ... Yusuf S, Connolly SJ
Aims
Patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), especially mitral stenosis, are assumed to be at high risk of stroke, irrespective of other factors. We aimed to re-evaluate stroke risk factors in a contemporary cohort of AF patients.
Methods and results
We analyzed data of 15,400 AF patients presenting to an emergency department and who were enrolled in the global RE-LY AF registry, representing 47 countries from all inhabited continents. Follow-up occurred at 1 year after enrollment. A total of 1,788 (11.6%) patients had RHD. These patients were younger (51.4 ± 15.7 vs. 67.8 ± 13.6 years), more likely to be female (66.2% vs. 44.7%) and had a lower mean CHA2DS2-VASc score (2.1 ± 1.7 vs. 3.7 ± 2.2) as compared to patients without RHD (all p < 0.001). Significant mitral stenosis (average mean transmitral gradient 11.5 ± 6.5 mmHg) was the predominant valve lesion in those with RHD (59.6%). Patients with RHD had a higher baseline rate of anticoagulation use (60.4% vs. 45.2%, p < 0.001). Unadjusted stroke rates at 1 year were 2.8% and 4.1% for patients with and without RHD, respectively. The performance of the CHA2DS2-VASc score was modest in both groups (stroke at 1 year, c-statistics 0.69, 95% confidence interval [CI] 0.60-0.78 and 0.63, 95% CI 0.61-0.66, respectively). In the overall cohort, advanced age, female sex, prior stroke, tobacco use and non-use of anticoagulation were predictors for stroke (all p < 0.05). Mitral stenosis was not associated with stroke risk (adjusted odds ratio 1.07, 95% CI 0.67-1.72, p = 0.764).
Conclusions
The performance of the CHA2DS2-VASc score was modest in AF patients both with and without RHD. In this cohort, moderate-to-severe mitral stenosis was not an independent risk factor for stroke.
Translational perspective
Based on studies conducted several decades ago, the presence of moderate-to-severe mitral stenosis has been associated with a very high risk of stroke in patients with AF. Our results, based on a large, global sample of contemporary patients with AF that contained a significant proportion of individuals with RHD, challenge the assumption that mitral stenosis is a major, independent risk factor for stroke. The performance of the widely used CHA2DS2-VASc score was modest in both patients with and without RHD. At least one ongoing randomized trial is evaluating the optimal antithrombotic strategy in patients with AF and RHD.

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

Cardiovasc Res: 01 Jan 2021; epub ahead of print
Benz AP, Healey JS, Chin A, Commerford P, ... Yusuf S, Connolly SJ
Cardiovasc Res: 01 Jan 2021; epub ahead of print | PMID: 33386845
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Abstract

Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study.

Feijen EAM, van Dalen EC, van der Pal HJH, Reulen RC, ... Kremer LCM,
Objective
In this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study.
Methods
Eight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3-5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors.
Results
Overall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14-30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)).
Conclusions
In this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.

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

Heart: 30 Dec 2020; 107:33-40
Feijen EAM, van Dalen EC, van der Pal HJH, Reulen RC, ... Kremer LCM,
Heart: 30 Dec 2020; 107:33-40 | PMID: 32826285
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Abstract

Cardiovascular outcomes of pregnancy in Turner syndrome.

Grewal J, Valente AM, Egbe AC, Wu FM, ... Roos-Hesselink JW,
Objectives
Women with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease.
Methods
Retrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005-2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period.
Results
Sixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%).
Conclusions
This study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

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

Heart: 30 Dec 2020; 107:61-66
Grewal J, Valente AM, Egbe AC, Wu FM, ... Roos-Hesselink JW,
Heart: 30 Dec 2020; 107:61-66 | PMID: 32669396
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Impact:
Abstract

Different DOACs Control Inflammation in Cardiac Ischemia-Reperfusion Differently.

Gadi I, Fatima S, Elwakiel A, Nazir S, ... Isermann B, Shahzad K

While thrombin is the key protease in thrombus formation, other coagulation proteases, such as fXa or activated protein C (aPC), independently modulate intracellular signaling via partially distinct receptors.To study the differential effects of fXa or fIIa inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury (IRI).Mice were treated with a direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses that induced comparable anticoagulant effects ex vivo and in vivo (tail bleeding assay and FeCl3-induced thrombosis). Myocardial IRI was induced via LAD ligation. We determined infarct size and in vivo aPC generation, analyzed gene expression by RNAseq, and performed immunoblotting and ELISA. The signaling-only 3K3A-aPC variant and inhibitory antibodies that blocked all or only the anticoagulant function of aPC were used to determine the role of aPC. Doses of fIIai and fXai that induced comparable anticoagulant effects resulted in a comparable reduction in infarct size. However, unbiased gene expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai but not fIIai inhibited sterile inflammation by reducing the expression of proinflammatory cytokines (IL-1beta, IL-6, and TNFalpha) as well as NF-κB and inflammasome activation. This anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post myocardial IRI. Mechanistically, in vivo aPC generation was higher with fXai than with fIIai. Inhibition of the anticoagulant and signaling properties of aPC abolished the anti-inflammatory effect associated with fXai, while inhibiting only the anticoagulant function of aPC had no effect. Combining 3K3A-aPC with fIIai reduced the inflammatory response, mimicking the fXai-associated effect.We showed that specific inhibition of coagulation via DOACs had differential effects on gene expression and inflammation, despite comparable anticoagulant effects and infarct sizes. Targeting individual coagulation proteases induces specific cellular responses unrelated to their anticoagulant effect.



Circ Res: 22 Dec 2020; epub ahead of print
Gadi I, Fatima S, Elwakiel A, Nazir S, ... Isermann B, Shahzad K
Circ Res: 22 Dec 2020; epub ahead of print | PMID: 33353373
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Abstract

Predicting sudden cardiac death in adults with congenital heart disease.

Oliver JM, Gallego P, Gonzalez AE, Avila P, ... Bermejo J,
Objectives
To develop, calibrate, test and validate a logistic regression model for accurate risk prediction of sudden cardiac death (SCD) and non-fatal sudden cardiac arrest (SCA) in adults with congenital heart disease (ACHD), based on baseline lesion-specific risk stratification and individual\'s characteristics, to guide primary prevention strategies.
Methods
We combined data from a single-centre cohort of 3311 consecutive ACHD patients (50% male) at 25-year follow-up with 71 events (53 SCD and 18 non-fatal SCA) and a multicentre case-control group with 207 cases (110 SCD and 97 non-fatal SCA) and 2287 consecutive controls (50% males). Cumulative incidences of events up to 20 years for specific lesions were determined in the prospective cohort. Risk model and its 5-year risk predictions were derived by logistic regression modelling, using separate development (18 centres: 144 cases and 1501 controls) and validation (two centres: 63 cases and 786 controls) datasets.
Results
According to the combined SCD/SCA cumulative 20 years incidence, a lesion-specific stratification into four clusters-very-low (<1%), low (1%-4%), moderate (4%-12%) and high (>12%)-was built. Multivariable predictors were lesion-specific cluster, young age, male sex, unexplained syncope, ischaemic heart disease, non-life threatening ventricular arrhythmias, QRS duration and ventricular systolic dysfunction or hypertrophy. The model very accurately discriminated (C-index 0.91; 95% CI 0.88 to 0.94) and calibrated (p=0.3 for observed vs expected proportions) in the validation dataset. Compared with current guidelines approach, sensitivity increases 29% with less than 1% change in specificity.
Conclusions
Predicting the risk of SCD/SCA in ACHD can be significantly improved using a baseline lesion-specific stratification and simple clinical variables.

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

Heart: 30 Dec 2020; 107:67-75
Oliver JM, Gallego P, Gonzalez AE, Avila P, ... Bermejo J,
Heart: 30 Dec 2020; 107:67-75 | PMID: 32546506
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Abstract

Prognostic value of electrocardiographic abnormalities in adults from the Brazilian longitudinal study of adults\' health.

Pinto-Filho MM, Brant LC, Dos Reis RP, Giatti L, ... Barreto SM, Ribeiro ALP
Objective
Cardiovascular diseases (CVDs) are highly preventable non-communicable diseases. ECG is a potential tool for risk stratification with respect to CVD. Our aim was to evaluate ECG\'s role in all-cause and cardiovascular mortality prediction.
Methods
Participants from the Brazilian Longitudinal Study of Adult Health, free of known CVD at baseline were included. A 12-lead ECG was obtained at baseline (2008-2010). Participants were followed up to 2018 by annual interviews. Deaths were independently reviewed. Cox as well as Fine and Grey multivariable regression models were applied to evaluate if the presence of any major electrocardiographic abnormality (MEA), defined according to the Minnesota Code system, would predict total and cardiovascular deaths. We also evaluated the Net Reclassification Index of adding MEA to the Systematic Coronary Risk Evaluation (SCORE).
Results
The 13 428 participants (median age 51 years, 45% men) were followed up for 8±1 years. All-cause and cardiovascular mortality occurred in 2.8% and 1.2% of the population, respectively. Prevalent MEA was an independent predictor of overall (HR=2.3, 95% CI 1.7 to 2.9) and cardiovascular mortality (HR=4.6, 95% CI 3.0 to 7.0) after adjustments for age, race, education and traditional cardiovascular risk factors. Adding MEA to the SCORE resulted in 9% mis-reclassification in the non-event subgroup and 33% correct reclassification in those with a fatal cardiovascular event.
Conclusion
Presence of MEA was an independent predictor of overall and cardiovascular mortality. ECG may have a role in risk prediction of cardiovascular mortality in primary care.

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

Heart: 22 Dec 2020; epub ahead of print
Pinto-Filho MM, Brant LC, Dos Reis RP, Giatti L, ... Barreto SM, Ribeiro ALP
Heart: 22 Dec 2020; epub ahead of print | PMID: 33361354
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Abstract

Cardiovascular or mortality risk of controlled hypertension and importance of physical activity.

Park S, Han K, Lee S, Kim Y, ... Kim YS, Kim DK
Objective
To investigate the risk of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death of patients with controlled hypertension and suggest the benefits of physical activity in their prognosis.
Methods
People aged 40-69 years from the prospective UK Biobank cohort (UKB, n=220 026) and the retrospective Korean National Health Insurance Service cohort (KNHIS, n=3 593 202) were included in this observational cohort study, excluding those with previous cerebrocardiovascular diseases or hypertension without treatment. The study groups were stratified into normotension, controlled hypertension (patients with hypertension with systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and uncontrolled hypertension groups. The outcomes were MACCEs and all-cause mortality, analysed by Cox regression analysis.
Results
We included 161 405/18 844/39 777 and 3 122 890/383 828/86 484 individuals with normotension/controlled hypertension/uncontrolled hypertension state from the UKB and KNHIS cohorts, respectively. The controlled hypertension group showed significantly higher risk of MACCEs (UKB: adjusted HR 1.73 (95% CI 1.55 to 1.92); KNHIS: 1.46 (95% CI 1.43 to 1.49)) and all-cause mortality (UKB: adjusted HR 1.28 (95% CI 1.18 to 1.39); KNHIS: 1.29 (95% CI 1.26 to 1.32)) than individuals with normotension. The controlled hypertension group not involved in any moderate or moderate-to-vigorous physical activity showed high risk of adverse outcomes, which was comparable with or even higher than the risk of patients with uncontrolled hypertension who were engaged in physical activity.
Conclusions
Controlled hypertension is associated with residual risks of adverse outcomes. Clinicians may encourage physical activity for patients with controlled hypertension, not being reassured by their achieved target blood pressure values.

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

Heart: 04 Jan 2021; epub ahead of print
Park S, Han K, Lee S, Kim Y, ... Kim YS, Kim DK
Heart: 04 Jan 2021; epub ahead of print | PMID: 33402363
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Abstract

Adiponectin, Leptin and Cardiovascular Disorders.

Zhao S, Kusminski CM, Scherer PE

The landmark discoveries of leptin and adiponectin firmly established adipose tissue as a sophisticated and highly active endocrine organ, opening a new era of investigating adipose-mediated tissue crosstalk. Both obesity-associated hyperleptinemia and hypoadiponectinemia are important biomarkers to predict cardiovascular outcomes, suggesting a crucial role for adiponectin and leptin in obesity-associated cardiovascular disorders. Normal physiological levels of adiponectin and leptin are indeed essential to maintain proper cardiovascular function. Insufficient adiponectin and leptin signaling results in cardiovascular dysfunction. However, a paradox of high levels of both leptin and adiponectin is emerging in the pathogenesis of cardiovascular disorders. Here, we (1) summarize the recent progress in the field of adiponectin and leptin and its association with cardiovascular disorders, (2) further discuss the underlying mechanisms for this new paradox of leptin and adiponectin action, and (3) explore the possible application of partial leptin reduction, in addition to increasing the adiponectin/leptin ratio as a means to prevent or reverse cardiovascular disorders.



Circ Res: 07 Jan 2021; 128:136-149
Zhao S, Kusminski CM, Scherer PE
Circ Res: 07 Jan 2021; 128:136-149 | PMID: 33411633
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Abstract

Survival and risk of recurrence of takotsubo syndrome.

Lau C, Chiu S, Nayak R, Lin B, Lee MS
Objective
The goal of this study is to evaluate the long-term outcomes of patients with takotsubo syndrome and assess factors associated with death or recurrence.
Methods
This is a retrospective population-based cohort study of consecutive patients who presented to an integrated health system in Southern California with takotsubo syndrome between 2006 and 2016. Medical records were manually reviewed to confirm diagnosis and to identify predisposing factors, medication treatment and long-term outcomes. Factors associated with death or recurrent takotsubo syndrome were tested using Cox regression models.
Results
Between 2006 and 2016, there were 519 patients with a confirmed diagnosis of takotsubo syndrome. Patients were followed for 5.2 years (IQR 3.0-7.2). During the follow-up period, 39 (7.5%) had recurrent takotsubo syndrome and 84 (16.2%) died. In multivariate modelling, factors associated with higher risk of recurrence or death were age (HR 1.56 per 10-year increase, 95% CI 1.29 to 1.87), male sex (HR 2.52, 95% CI 1.38 to 4.60), diabetes (HR 1.6, 95% CI 1.06 to 2.43), pulmonary disease (HR 2.0, 95% CI 1.37 to 2.91) and chronic kidney disease (HR 1.58, 95% CI 1.01 to 2.47). Treatment with beta-blockers were associated with lower risk of recurrence or death (HR 0.46, 95% CI 0.29 to 0.72). No association was observed between treatment with ACE inhibitors or angiotensin-receptor blockers and recurrence or death (HR 0.92, 95% CI 0.59 to 1.42).
Conclusions
Recurrent takotsubo syndrome occurred in a minor subset of patients. Treatment with beta-blocker was associated with higher event-free survival.

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

Heart: 07 Jan 2021; epub ahead of print
Lau C, Chiu S, Nayak R, Lin B, Lee MS
Heart: 07 Jan 2021; epub ahead of print | PMID: 33419884
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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: 07 Jan 2021; epub ahead of print
Møller S, Wissenberg M, Starkopf L, Kragholm K, ... Torp-Pedersen C, Gerds TA
Heart: 07 Jan 2021; epub ahead of print | 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: 07 Jan 2021; epub ahead of print
Leong D, Aghel N, Hillis C, Siegal D, ... Pond G, Seow H
Heart: 07 Jan 2021; epub ahead of print | PMID: 33419879
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Abstract

Sex differences in heart failure hospitalisation risk following acute myocardial infarction.

Yandrapalli S, Malik A, Pemmasani G, Aronow W, ... Frishman W, Panza J
Objective
We evaluated the sex differences in 6-month heart failure (HF) hospitalisation risk in acute myocardial infarction (AMI) survivors.
Methods
For this retrospective cohort analysis, adult survivors of an AMI between January and June 2014 were identified from the US Nationwide Readmissions Database. The primary outcome was a HF hospitalisation within 6 months. Secondary outcomes were fatal HF hospitalisation and the composite of index in-hospital HF or 6-month HF hospitalisation.
Results
Of 237 549 AMI survivors, females (37.9%) were older (70±14 years vs 65±13 years; p<0.001), had a higher prevalence of cardiac comorbidities and a lower revascularisation rate compared with males. The primary outcome occurred in 12 934 patients (5.4%), at a 49% higher rate in females (6.8% vs 4.6% in males, p<0.001), which was attenuated to a 19% higher risk after multivariable adjustment. Findings were consistent across subgroups of age, AMI type and major risk factors. In the propensity-matched time-to-event analysis, female sex was associated with a 13% higher risk for 6-month HF readmission (6.4% vs 5.8% in males; HR 1.13, 95% CI 1.05 to 1.21, p<0.001), and the increased risk was evident early on after the AMI. Fatal HF rate was similar between groups (4.7% vs 4.6%, p=0.936), but females had a higher rate of the composite HF outcome (36.2% vs 27.5%, p<0.001).
Conclusion
In a large all-comers AMI survivors\' cohort, females had a higher HF hospitalisation risk that persisted after adjustment for baseline risk differences. This was consistent across several clinically relevant subgroups and was evident early on after the AMI.

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

Heart: 10 Jan 2021; epub ahead of print
Yandrapalli S, Malik A, Pemmasani G, Aronow W, ... Frishman W, Panza J
Heart: 10 Jan 2021; epub ahead of print | PMID: 33431424
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Impact:
Abstract

Effect of coronary flow on intracoronary alteplase: a prespecified analysis from a randomised trial.

Maznyczka AM, McCartney P, Duklas P, McEntegart M, ... Berry C, T-TIME (Trial of low-dose adjunctive alTeplase during primary PCI) investigators
Objectives
Persistently impaired culprit artery flow (Methods
In T-TIME (trial of low-dose adjunctive alTeplase during primary PCI), patients ≤6 hours from onset of ST-elevation myocardial infarction (STEMI) were randomised to placebo, alteplase 10 mg or alteplase 20 mg, administered by infusion into the culprit artery, pre-stenting. In this prespecified, secondary analysis, coronary flow was assessed angiographically at the point immediately before drug administration. Microvascular obstruction, myocardial haemorrhage and infarct size were assessed by cardiovascular magnetic resonance (CMR) at 2-7 days and 3 months.
Results
TIMI flow was assessed after first treatment (balloon angioplasty/aspiration thrombectomy), immediately pre-drug administration, in 421 participants (mean age 61±10 years, 85% male) and was 3, 2 or 1 in 267, 134 and 19 participants respectively. In patients with TIMI flow ≤2 pre-drug, there was higher incidence of microvascular obstruction with alteplase (alteplase 20 mg (53.1%) and 10 mg (59.5%) combined versus placebo (34.1%); OR=2.47 (95% CI 1.16 to 5.22, p=0.018) interaction p=0.005) and higher incidence of myocardial haemorrhage (alteplase 20 mg (53.1%) and 10 mg (57.9%) combined vs placebo (27.5%); OR=3.26 (95% CI 1.44 to 7.36, p=0.004) interaction p=0.001). These effects were not observed in participants with TIMI 3 flow pre-drug. There were no interactions between TIMI flow pre-drug, alteplase and 3-month CMR findings.
Conclusion
In patients with impaired culprit artery flow (Trial registration number
NCT02257294.

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

Heart: 11 Jan 2021; epub ahead of print
Maznyczka AM, McCartney P, Duklas P, McEntegart M, ... Berry C, T-TIME (Trial of low-dose adjunctive alTeplase during primary PCI) investigators
Heart: 11 Jan 2021; epub ahead of print | PMID: 33436493
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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: 11 Jan 2021; epub ahead of print
Barnes C, Fatovich DM, Macdonald SPJ, Alcock RF, ... Schultz CJ, Hillis GS
Heart: 11 Jan 2021; epub ahead of print | PMID: 33436490
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Impact:
Abstract

Risk of out-of-hospital cardiac arrest in patients with bipolar disorder or schizophrenia.

Barcella CA, Mohr G, Kragholm K, Christensen D, ... Gislason GH, Bach Søndergaard K
Objective
Patients with bipolar disorder and schizophrenia are at high cardiovascular risk; yet, the risk of out-of-hospital cardiac arrest (OHCA) compared with the general population remains scarcely investigated.
Methods
We conducted a nested case-control study using Cox regression to assess the association of bipolar disorder and schizophrenia with the HRs of OHCA of presumed cardiac cause (2001-2015). Reported are the HRs with 95% CIs overall and in subgroups defined by established cardiac disease, cardiovascular risk factors and psychotropic drugs.
Results
We included 35 017 OHCA cases and 175 085 age-matched and sex-matched controls (median age 72 years and 66.9% male). Patients with bipolar disorder or schizophrenia had overall higher rates of OHCA compared with the general population: HR 2.74 (95% CI 2.41 to 3.13) and 4.49 (95% CI 4.00 to 5.10), respectively. The association persisted in patients with both cardiac disease and cardiovascular risk factors at baseline (bipolar disorder HR 2.14 (95% CI 1.72 to 2.66), schizophrenia 2.84 (95% CI 2.20 to 3.67)) and among patients without known risk factors (bipolar disorder HR 2.14 (95% CI 1.09 to 4.21), schizophrenia HR 5.16 (95% CI 3.17 to 8.39)). The results were confirmed in subanalyses only including OHCAs presenting with shockable rhythm or receiving an autopsy. Antipsychotics-but not antidepressants, lithium or antiepileptics (the last two only tested in bipolar disorder)-increased OHCA hazard compared with no use in both disorders.
Conclusions
Patients with bipolar disorder or schizophrenia have a higher rate of OHCA compared with the general population. Cardiac disease, cardiovascular risk factors and antipsychotics represent important underlying mechanisms.

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

Heart: 14 Jan 2021; epub ahead of print
Barcella CA, Mohr G, Kragholm K, Christensen D, ... Gislason GH, Bach Søndergaard K
Heart: 14 Jan 2021; epub ahead of print | PMID: 33452118
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Impact:
Abstract

Omega-3 supplementation and cardiovascular disease: formulation-based systematic review and meta-analysis with trial sequential analysis.

Rizos EC, Markozannes G, Tsapas A, Mantzoros CS, Ntzani EE
Background
Omega-3 supplements are popular for cardiovascular disease (CVD) prevention. We aimed to assess the association between dose-specific omega-3 supplementation and CVD outcomes.
Design
We included double-blind randomised clinical trials with duration ≥1 year assessing omega-3 supplementation and estimated the relative risk (RR) for all-cause mortality, cardiac death, sudden death, myocardial infarction and stroke. Primary analysis was a stratified random-effects meta-analysis by omega-3 dose in 4 a priori defined categories (<1, 1, 2, ≥3 of 1 g capsules/day). Complementary approaches were trial sequential analysis and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid, sample size, statin use, study duration.
Results
Seventeen studies (n=83 617) were included. Omega-3 supplementation as ≤1 capsule/day was not associated with any outcome under study; futility boundaries were crossed for all-cause mortality and cardiac death. For two capsules/day, we observed a statistically significant reduction of cardiac death (n=3, RR 0.55, 95% CI 0.33 to 0.90, I=0%); for ≥3 capsules/day we observed a statistically significant reduction of cardiac death (n=3, RR 0.82, 95% CI 0.68 to 0.99, I=0%), sudden death (n=1, RR 0.70, 95% CI 0.51 to 0.97) and stroke (n=2, RR 0.74, 95% CI 0.57 to 0.95, I=0%).
Conclusion
Omega-3 supplementation at <2 1 g capsules/day showed no association with CVD outcomes; this seems unlikely to change from future research. Compared with the robust scientific evidence available for low doses, the evidence for higher doses (2-4 1 g capsules/day) is weak. The emerging postulated benefit from high-dose supplementation needs replication and further evaluation as to the precise formulation and indication.

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

Heart: 30 Dec 2020; 107:150-158
Rizos EC, Markozannes G, Tsapas A, Mantzoros CS, Ntzani EE
Heart: 30 Dec 2020; 107:150-158 | PMID: 32820013
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Impact:
Abstract

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

Corcoran D, Radjenovic A, Mordi IR, Nazir SA, ... Squire I, Berry C
Aims
The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).
Methods and results
In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.
Conclusion
In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

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

Cardiovasc Res: 31 Dec 2020; 117:320-329
Corcoran D, Radjenovic A, Mordi IR, Nazir SA, ... Squire I, Berry C
Cardiovasc Res: 31 Dec 2020; 117:320-329 | PMID: 32065620
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Impact:
Abstract

Place and causes of acute cardiovascular mortality during the COVID-19 pandemic.

Wu J, Mamas MA, Mohamed MO, Kwok CS, ... Deanfield JE, Gale CP
Objective
To describe the place and causes of acute cardiovascular death during the COVID-19 pandemic.
Methods
Retrospective cohort of adult (age ≥18 years) acute cardiovascular deaths (n=5 87 225) in England and Wales, from 1 January 2014 to 30 June 2020. The exposure was the COVID-19 pandemic (from onset of the first COVID-19 death in England, 2 March 2020). The main outcome was acute cardiovascular events directly contributing to death.
Results
After 2 March 2020, there were 28 969 acute cardiovascular deaths of which 5.1% related to COVID-19, and an excess acute cardiovascular mortality of 2085 (+8%). Deaths in the community accounted for nearly half of all deaths during this period. Death at home had the greatest excess acute cardiovascular deaths (2279, +35%), followed by deaths at care homes and hospices (1095, +32%) and in hospital (50, +0%). The most frequent cause of acute cardiovascular death during this period was stroke (10 318, 35.6%), followed by acute coronary syndrome (ACS) (7 098, 24.5%), heart failure (6 770, 23.4%), pulmonary embolism (2 689, 9.3%) and cardiac arrest (1 328, 4.6%). The greatest cause of excess cardiovascular death in care homes and hospices was stroke (715, +39%), compared with ACS (768, +41%) at home and cardiogenic shock (55, +15%) in hospital.

Conclusions:
and relevance
The COVID-19 pandemic has resulted in an inflation in acute cardiovascular deaths, nearly half of which occurred in the community and most did not relate to COVID-19 infection suggesting there were delays to seeking help or likely the result of undiagnosed COVID-19.

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

Heart: 30 Dec 2020; 107:113-119
Wu J, Mamas MA, Mohamed MO, Kwok CS, ... Deanfield JE, Gale CP
Heart: 30 Dec 2020; 107:113-119 | PMID: 32988988
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Impact:
Abstract

Office, central and ambulatory blood pressure for predicting incident atrial fibrillation in older adults.

Matsumoto K, Jin Z, Homma S, Elkind MSV, ... Sacco RL, Di Tullio MR
Objectives
Recently, more sophisticated blood pressure (BP) measurements, such as central and ambulatory BP (ABP), have proven to be stronger predictors of future cardiovascular disease than conventional office BP. Their predictive value for atrial fibrillation development is not established. We investigated the prognostic impact for incident atrial fibrillation of office, central and ambulatory BP measurements in a predominantly older population-based cohort.
Methods
Of 1004 participants in the Cardiovascular Abnormalities and Brain Lesions (CABL) study, 769 in sinus rhythm with no history of atrial fibrillation or stroke (mean age 70.5 years) underwent ABP and arterial wave reflection analysis for central BP determination. Fine and Gray\'s proportional subdistribution hazards models were used to assess the association of BP parameters with incident atrial fibrillation.
Results
During 9.5 years, atrial fibrillation occurred in 83 participants. No office BP variable showed a significant association with incident atrial fibrillation. Central SBP and central pulse pressure were marginally associated with incident atrial fibrillation in multivariate analysis. Among ABP variables, 24-h SBP [adjusted hazard ratio per 10 mmHg, 1.24; 95% confidence interval (CI) 1.07--1.44; P = 0.004], daytime SBP (adjusted hazard ratio per 10 mmHg, 1.21; 95% CI 1.04--1.40; P = 0.011) and night-time SBP (adjusted hazard ratio per 10 mmHg, 1.22; 95% CI 1.07--1.39; P = 0.002) were significantly associated with incident atrial fibillation.
Conclusion
In a predominantly older, stroke-free community-based cohort, ABP was a better independent predictor of incident atrial fibrillation than central BP, whereas office BP was inadequate for this purpose.



J Hypertens: 30 Dec 2020; 39:46-52
Matsumoto K, Jin Z, Homma S, Elkind MSV, ... Sacco RL, Di Tullio MR
J Hypertens: 30 Dec 2020; 39:46-52 | PMID: 33031165
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Impact:
Abstract

Changes in 24-h ambulatory blood pressure following restoration of sinus rhythm in patients with atrial fibrillation.

Olbers J, Östergren J, Rosenqvist M, Skuladottir H, ... Ljungman P, Witt N
Objective
The interplay between atrial fibrillation and blood pressure (BP) is insufficiently studied. In symptomatic patients with persistent atrial fibrillation, electrical cardioversion (ECV) is often used to restore sinus rhythm. In this prospective study, we investigated how restoration of sinus rhythm affected 24-h ambulatory BP.
Methods
Ninety-eight patients with persistent atrial fibrillation were examined with 24-h ambulatory BP monitoring before and approximately a week after ECV.
Results
Sixty-two patients remained in sinus rhythm at the time of the second ambulatory BP monitoring (AF-SR group), whereas 36 patients had relapsed into atrial fibrillation (AF-AF group). In the AF-SR group, there was a significant increase in mean systolic 24-h BP (5.6 mmHg), a significant decrease in mean diastolic 24-h BP (-4.7 mmHg) and accordingly, a significant 25% (10.4 mmHg) increase in mean 24-h pulse pressure.
Conclusion
These findings may reflect the haemodynamic conditions that are prevalent in atrial fibrillation, ambulatory BP measurement bias in atrial fibrillation or a combination of both factors. From a clinical standpoint, our results suggest that an increased attention to BP is needed when sinus rhythm is restored, as underlying hypertension may be masked by BP changes during atrial fibrillation. From a general standpoint, it may be speculated that BP, as indicated by the relatively large difference in pulse pressure, may be inherently different in atrial fibrillation and may therefore not be interpretable in the equivalent manner as BP in sinus rhythm.

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

J Hypertens: 31 Jan 2021; 39:243-249
Olbers J, Östergren J, Rosenqvist M, Skuladottir H, ... Ljungman P, Witt N
J Hypertens: 31 Jan 2021; 39:243-249 | PMID: 32833921
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Impact:
Abstract

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

Tsivgoulis G, Katsanos AH, Mandava P, Köhrmann M, ... Alexandrov AV,
Objective
To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA).
Methods
We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER.
Results
The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53).
Conclusion
BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

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

J Hypertens: 31 Jan 2021; 39:266-272
Tsivgoulis G, Katsanos AH, Mandava P, Köhrmann M, ... Alexandrov AV,
J Hypertens: 31 Jan 2021; 39:266-272 | PMID: 32956103
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Impact:
Abstract

Exercise training reduces arterial stiffness in adults with hypertension: a systematic review and meta-analysis.

Lopes S, Afreixo V, Teixeira M, Garcia C, ... Mesquita-Bastos J, Ribeiro F
Objective
Arterial stiffness, namely pulse wave velocity (PWV), is an emerging biomarker in the assessment of vascular health. This meta-analysis aims to determine the effects of exercise training on PWV in patients with hypertension, and to identify the possible moderator variables (e.g. type of exercise) of the effect of exercise on PWV.
Methods
MEDLINE, EMBASE, Cochrane and Web of Science were searched up until July 2019 for randomized controlled trials assessing the effect of exercise interventions lasting 4 or more weeks on PWV in adults with hypertension. Random-effects modelling was used to compare changes from pre to postintervention in PWV between exercise and control groups. Data were reported as weighted mean difference (WMD) and 95% confidence interval (95% CI). Protocol registration: PROSPERO registration number CRD42019138658.
Results
We included 14 trials (15 interventions), involving five aerobic, two dynamic resistance, six combined and two isometric resistance groups, totalling 642 participants with hypertension. PWV was significantly reduced by exercise training [(WMD (95% CI) = -0.76 m/s (-1.05 to -0.47)]. Analysis of moderator variables showed that aerobic exercise [WMD (95% CI) = -0.70 m/s (-1.20 to -0.19)], combined exercise [WMD (95% CI) = -0.74 m/s (-1.41 to -0.08)] and isometric resistance exercise [WMD (95% CI) = -0.98 m/s (-1.24 to -0.73)] reduced PWV. There was no significant reduction in PWV in participants undertaking dynamic resistance training [WMD (95% CI) = -0.58 (-1.58 to 0.42)].
Conclusion
This meta-analysis supports that exercise interventions based on aerobic, combined or isometric exercise are suitable to improve PWV in adults with hypertension.

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

J Hypertens: 31 Jan 2021; 39:214-222
Lopes S, Afreixo V, Teixeira M, Garcia C, ... Mesquita-Bastos J, Ribeiro F
J Hypertens: 31 Jan 2021; 39:214-222 | PMID: 32833924
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Impact:
Abstract

Prediabetes and risk for myocardial infarction by hypertension status in a Chinese population: a prospective cohort study.

Liu X, Song Q, Wu S, Zhou W, Wang X
Background
Whether prediabetes alone or combined with hypertension is a more important risk factor for cardiovascular disease is controversial. In this study, we aimed to examine this association to fill the research gap.
Methods and results
A total of 85 570 participants (mean age: 58.0 years) without diabetes and no previous myocardial infarction (MI) were recruited for this study. Participants were divided into four groups according to prediabetes status and were further stratified according to hypertension status. Hazard ratios with 95% confidence intervals (CIs) were calculated using Cox regression models. After a mean follow-up period of 11.0 years, 1122 (rate 1.19/1000 person-years) individuals developed MI. Compared with participants without either condition, the multivariable-adjusted hazard ratios for MI events among participants with prediabetes alone, hypertension alone, and both prediabetes and hypertension were 1.06 (95% CI: 0.84-1.36), 1.73 (95% CI 1.49-2.00), and 1.89 (95% CI 1.57-2.27), respectively. Among participants with and without hypertension, there was no association between prediabetes and an increased risk for MI (hazard ratio: 1.11 95% CI 0.94-1.32 and hazard ratio: 1.02 95% CI 0.80-1.30, respectively).
Conclusion
The current study indicated that among the Chinese general population, the increased risk of MI associated with prediabetes is largely driven by concomitant hypertension rather than prediabetes per se.



J Hypertens: 30 Dec 2020; 39:77-83
Liu X, Song Q, Wu S, Zhou W, Wang X
J Hypertens: 30 Dec 2020; 39:77-83 | PMID: 32868639
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Impact:
Abstract

Left ventricular mass reduction and hypertrophy regression following renal artery revascularization: a meta-analysis.

Cuspidi C, Tadic M, Sala C, Quarti-Trevano F, ... Mancia G, Grassi G
Aim
Few echocardiographic studies have focused on regression of left ventricular hypertrophy (LVH) in patients with renal artery stenosis after revascularization, with inconsistent results. We performed a systematic meta-analysis of these studies in order to offer a comprehensive information on this topic.
Methods
The PubMed, OVID-MEDLINE, and Cochrane library databases were analyzed to search English-language articles published from 1 January 1990 up to 31 March 2020. Studies were identified by crossing the following terms: \'renal artery stenosis\', \'renovascular hypertension\', \'fibromuscular dysplasia\', \'renal artery stenting\', \'renal artery surgery\' with \'cardiac damage\', \'hypertensive heart disease\' \'left ventricular mass\', \'left ventricular hypertrophy\', \'echocardiography\'.
Results
A total of 726 hypertensive patients with renal artery stenosis (mean age 61 years, 64% men, 98% treated, 10% with fibromuscular dysplasia) were included in 13 studies. Baseline and postintervention pooled mean LVM values were 220 ± 15 and 203 ± 19 g, respectively (SMD -0.24 ± 0.06, CI -0.37 to -0.21, P<0.0001); corresponding values for LV mass index were 129.0 ± 6 and 115 ± 7 g/m, respectively (SMD -0.28 ± 0.04, CI -0.36 to 0.21, P < 0.0001). Renal revascularization was associated with a 40% lower risk of LVH. This trend was accompanied by a reduction in the number of antihypertensive drugs (SMD -0.27 ± 0.04, CI -0.37 to 0.17, P < 0.0001).
Conclusion
The present meta-analysis suggests that renal artery revascularization added to antihypertensive therapy promotes a favourable effect on LV structure, as reflected by a significant decrease in absolute and indexed LV mass index as well by a lower risk of LVH. Limitations include: high prevalence of modest renal artery stenosis (≥50%); small sample of fibromuscular dysplasia; lack of randomized design of most studies.



J Hypertens: 30 Dec 2020; 39:4-11
Cuspidi C, Tadic M, Sala C, Quarti-Trevano F, ... Mancia G, Grassi G
J Hypertens: 30 Dec 2020; 39:4-11 | PMID: 32833917
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Impact:
Abstract

The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update.

Xu C

: Although considerable success has been shown for antihypertensive medications, the resistant hypertension and hypertension-related organ damages are still the important clinical issues and pose as high health and economic pressure. Therefore, novel therapeutic techniques and antihypertensive drugs are needed to advance more effective therapy of hypertension and hypertension-related disease to ameliorate mortality and healthcare costs worldwide. In this review, we highlight the latest progress in supporting the therapeutic potential of Elabela (ELA), a recently discovered early endogenous ligand for G-protein-coupled receptor apelin peptide jejunum, apelin receptor. Systemic administration of ELA exerts vasodilatory, antihypertensive, cardioprotective, and renoprotective effects, whereas central application of ELA increases blood pressure and causes cardiovascular remodeling primarily secondary to the hypertension. In addition, ELA drives extravillous trophoblast differentiation and prevents the pathogenesis of preeclampsia (a gestational hypertensive syndrome) by promoting placental angiogenesis. These findings strongly suggest peripheral ELA\'s therapeutic potential in preventing and treating hypertension and hypertension-related diseases including cardiovascular disease, kidney disease, and preeclampsia. Since therapeutic use of ELA is mainly limited by its short half-life and parenteral administration, it may be a clinical application candidate for the therapy of hypertension and its complications when fused with a large inert chemicals (e.g. polyethylene glycol, termed polyethylene glycol-ELA-21) or other proteins (e.g. the Fc fragment of IgG and albumin, termed Fc-ELA-21 or albumin-ELA-21), and new delivery methods are encouraged to develop to improve the efficacy of ELA fragments on apelin peptide jejunum or alternative unknown receptors.



J Hypertens: 30 Dec 2020; 39:12-22
Xu C
J Hypertens: 30 Dec 2020; 39:12-22 | PMID: 32740407
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Impact:
Abstract

Combined effect of high depressive symptom burden and hypertension on new-onset stroke: evidence from a nationwide prospective cohort study.

Liu S, Qiao Y, Zhang Y, Wu Y, Ke C, Shen Y
Objective
The aim of this study was to investigate whether the combination of high depressive symptom burden and hypertension increased the risk of stroke among the middle-aged and elderly Chinese using a nationwide prospective study.
Methods
Data from the China Health and Retirement Longitudinal Study (CHARLS) during 2011-2015 were used. A total of 12 604 Chinese participants aged 45 years and older were included for final analysis. Multivariate Cox proportional hazards regression model was used to explore the associations between high depressive symptom burden, hypertension and new-onset stroke.
Results
There were 244 stroke events occurred during a 4-year follow-up. Compared with those without high depressive symptom burden and hypertension, the adjusted hazard ratios (95% confidence intervals) were 1.96 (1.13-3.42) for individuals with high depressive symptom burden alone, 2.84 (1.77-4.57) for individuals with hypertension alone and 4.38 (2.66-7.20) for individuals with comorbid high depressive symptom burden and hypertension, respectively. In the subgroup analyses, people with the coexistence of high depressive symptom burden and hypertension had the highest risk of new-onset stroke in all subgroups.
Conclusion
Our results suggest a combined effect of high depressive symptom burden and hypertension on stroke risk among the middle-aged and elderly Chinese.



J Hypertens: 30 Dec 2020; 39:70-76
Liu S, Qiao Y, Zhang Y, Wu Y, Ke C, Shen Y
J Hypertens: 30 Dec 2020; 39:70-76 | PMID: 32740408
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Impact:
Abstract

Low medication adherence is associated with decline in health-related quality of life: results of a longitudinal analysis among older women and men with hypertension.

Peacock E, Joyce C, Craig LS, Lenane Z, ... Muntner P, Krousel-Wood M
Objective
The aim of this study was to determine the association of low antihypertensive medication adherence with decline in health-related quality of life (HRQOL) over 1 year.
Methods
We used data from older men and women with hypertension (n = 1525) enrolled in the Cohort Study of Medication Adherence among Older Adults. Adherence was measured using the validated self-report four-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4) (low adherence = score ≥1) and prescription refill-based proportion of days covered (PDC) (low adherence = PDC < 0.80). We defined decline in HRQOL as a decrease in Mental Component Summary (MCS) or Physical Component Summary (PCS) score (from the RAND 36-Item Health Survey 1.0 administered at two time points - at the time of adherence assessment and 1 year later) equivalent to the minimal important difference (MID) for each respective summary score, calculated as the average of MID estimates derived from distribution and anchor-based approaches.
Results
The prevalence of low adherence was 38.6% using the K-Wood-MAS-4 and 23.9% using PDC. On the basis of mean MID estimates of 4.40 for MCS and 5.16 for PCS, 21.8 and 25.2% of participants experienced a decline in MCS and PCS, respectively, over 1 year. Low adherence was associated with a decline in MCS for K-Wood-MAS-4 [prevalence ratio = 1.32, 95% confidence interval (95% CI) 1.08-1.62, P = 0.008], but not PDC (prevalence ratio  = 1.17, 95% CI 0.94-1.47, P = 0.168). Low adherence was not associated with decline in PCS (K-Wood-MAS-4: prevalence ratio  = 0.95, 95% CI 0.79-1.16; PDC: prevalence ratio  = 1.10, 95% CI 0.90-1.35).
Conclusion
Low self-report medication adherence is associated with decline in mental HRQOL over 1 year in older adults with hypertension.



J Hypertens: 30 Dec 2020; 39:153-161
Peacock E, Joyce C, Craig LS, Lenane Z, ... Muntner P, Krousel-Wood M
J Hypertens: 30 Dec 2020; 39:153-161 | PMID: 32675745
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Impact:
Abstract

Additive association of knowledge and awareness on control of hypertension: a cross-sectional survey in rural India.

Ragavan RS, Joshi R, Evans RG, Riddell MA, ... Busingye D, Thrift AG
Objective
To determine whether there is an interaction between knowledge about hypertension and awareness of hypertension on the treatment and control of hypertension in three regions of South India at different stages of epidemiological transition (see Video, Supplemental Digital Content 1, http://links.lww.com/HJH/B426).
Methods
Using a cross-sectional design, we randomly selected villages within each of rural Trivandrum, West Godavari, and Chittoor. Sampling was stratified by age group and sex. We measured blood pressure and administered a questionnaire to determine knowledge and awareness of hypertension. Logistic regression was used to assess associations of awareness and knowledge about hypertension with its treatment and control in participants with hypertension, while examining for statistical interaction.
Results
Among a total of 11 657 participants (50% male; median age 45 years), 3455 had hypertension. In analyses adjusted for age and sex, both knowledge score [adjusted odds ratio (aOR) 1.14 [95% confidence interval (CI) 1.12--1.17)] and awareness [aOR 104 (95% CI 82--134)] were associated with treatment for hypertension. Similarly, both knowledge score [aOR 1.10; 95% CI (1.08--1.12)] and awareness [aOR 13.4; 95% CI (10.7--16.7)], were positively associated with control of blood pressure in those with hypertension, independent of age and sex. There was an interaction between knowledge and awareness on both treatment and control of hypertension (P of attributable proportion <0.001 for each).
Conclusion
Health education to improve knowledge about hypertension and screening programs to improve awareness of hypertension may act in an additive fashion to improve management of hypertension in rural Indian populations.



J Hypertens: 30 Dec 2020; 39:107-116
Ragavan RS, Joshi R, Evans RG, Riddell MA, ... Busingye D, Thrift AG
J Hypertens: 30 Dec 2020; 39:107-116 | PMID: 32833918
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Impact:
Abstract

Low blood pressure and adverse outcomes in acute stroke: HeadPoST study explanations.

Ouyang M, Muñoz-Venturelli P, Billot L, Wang X, ... Robinson T, Anderson CS
Objective
As uncertainties exist over underlying causes, we aimed to define the characteristics and prognostic significance of low blood pressure (BP) early after the onset of acute stroke.
Methods
Post hoc analyzes of the international Head Positioning in acute Stroke Trial (HeadPoST), a pragmatic cluster-crossover randomized trial of lying flat versus sitting up in stroke patients from nine countries during 2015-2016. Associations of baseline BP and death or dependency [modified Rankin scale (mRS) scores 3-6] and serious adverse events (SAEs) at 90 days were assessed in generalized linear mixed models with adjustment for multiple confounders. SBP and DBP was analysed as continuous measures fitted with a cubic spline, and as categorical measures with low (<10th percentile) and high (≥140 and ≥90 mmHg, respectively) levels compared with a normal range (≥10th percentile; 120-139 and 70-89 mmHg, respectively).
Results
Among 11 083 patients (mean age 68 years, 39.9% women) with baseline BP values, 7.2 and 11.7% had low SBP (<120 mmHg) and DBP (<70 mmHg), respectively. Patients with low SBP were more likely to have preexisting cardiac and ischemic stroke and functional impairment, and to present earlier with more severe neurological impairment than other patients. Nonlinear \'J-shaped\' relationships of BP and poor outcome were apparent: compared with normal SBP, those with low SBP had worse functional outcome (adjusted odds ratio 1.27, 95% confidence interval 1.02-1.58) and more SAEs, particularly cardiac events, with adjustment for potential confounders to minimize reverse causation. The findings were consistent for DBP and were stronger for ischemic rather than hemorrhagic stroke.
Conclusion
The prognostic significance of low BP on poor outcomes in acute stroke was not explained by reverse causality from preexisting cardiovascular disease, and propensity towards greater neurological deficits and cardiac events. These findings provide support for the hypothesis that low BP exacerbates cardiac and cerebral ischemia in acute ischemic stroke.

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

J Hypertens: 31 Jan 2021; 39:273-279
Ouyang M, Muñoz-Venturelli P, Billot L, Wang X, ... Robinson T, Anderson CS
J Hypertens: 31 Jan 2021; 39:273-279 | PMID: 32897905
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Impact:
Abstract

The effect of plant-based dietary patterns on blood pressure: a systematic review and meta-analysis of controlled intervention trials.

Gibbs J, Gaskin E, Ji C, Miller MA, Cappuccio FP
Objectives
The consumption of strict vegetarian diets with no animal products is associated with low blood pressure (BP). It is not clear whether less strict plant-based diets (PBDs) containing some animal products exert a similar effect. The main objective of this meta-analysis was to assess whether PBDs reduce BP in controlled clinical trials.
Methods
We searched Cumulative Index to Nursing and Allied Health Literature, Medline, Embase, and Web of Science to identify controlled clinical trials investigating the effect of PBDs on BP. Standardized mean differences in BP and 95% confidence intervals were pooled using a random effects model. Risk of bias, sensitivity, heterogeneity, and publication bias were assessed.
Results
Of the 790 studies identified, 41 clinical trials met the inclusion criteria (8416 participants of mean age 49.2 years). In the pooled analysis, PBDs were associated with lower SBP [Dietary Approach to Stop Hypertension -5.53 mmHg (95% confidence intervals -7.95,-3.12), Mediterranean -0.95 mmHg (-1.70,-0.20), Vegan -1.30 mmHg (-3.90,1.29), Lacto-ovo vegetarian -5.47 mmHg (-7.60,-3.34), Nordic -4.47 mmHg (-7.14,-1.81), high-fiber -0.65 mmHg (-1.83,0.53), high-fruit and vegetable -0.57 mmHg (-7.45,6.32)]. Similar effects were seen on DBP. There was no evidence of publication bias and some heterogeneity was detected. The certainty of the results is high for the lacto-ovo vegetarian and Dietary Approach to Stop Hypertension diets, moderate for the Nordic and Mediterranean diets, low for the vegan diet, and very low for the high-fruit and vegetable and high-fiber diets.
Conclusion
PBDs with limited animal products lower both SBP and DBP, across sex and BMI.



J Hypertens: 30 Dec 2020; 39:23-37
Gibbs J, Gaskin E, Ji C, Miller MA, Cappuccio FP
J Hypertens: 30 Dec 2020; 39:23-37 | PMID: 33275398
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Abstract

Hypertension awareness, treatment and control among ethnic minority populations in Europe: a systematic review and meta-analysis.

van der Linden EL, Couwenhoven BN, Beune EJAJ, Daams JG, van den Born BH, Agyemang C
Objective
Ethnic minority populations (EMPs) are disproportionally affected by hypertension-mediated complications compared with European host populations (EHPs), which might be due to disparities in hypertension awareness, treatment and control. We conducted a systematic review and meta-analysis to compare awareness, treatment and control rates among EMPs with EHPs.
Methods
MEDLINE, EMBASE and Web of Science were searched from inception to 29 January 2020. Critical appraisal was performed according to methods of Hoy et al. Pooled odds ratios with corresponding 95% confidence intervals were calculated for these rates, stratified by ethnic group, using either random or fixed effect meta-analysis based on I2-statistics. Study was registered in PROSPRO (CRD42020107897).
Results
A total of 3532 records were screened of which 16 were included in the analysis with data on 26 800 EMP and 57 000 EHP individuals. Compared with EHPs, African origin populations were more likely to be aware (odds ratio 1.26, 95% confidence interval 1.02-1.56) and treated (1.49, 1.18-1.88) for hypertension, but were less likely to have their blood pressure controlled (0.56, 0.40-0.78), whereas South Asian populations were more likely to be aware (1.15, 1.02-1.30), but had similar treatment and control rates. In Moroccan populations, hypertension awareness (0.79, 0.62-1.00) and treatment levels (0.77, 0.60-0.97) were lower compared with EHPs, while in Turkish populations awareness was lower (0.81, 0.65-1.00).
Conclusion
Levels of hypertension awareness, treatment and control differ between EMPs and EHPs. Effort should be made to improve these suboptimal rates in EMPs, aiming to reduce ethnic inequalities in hypertension-mediated complications.

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

J Hypertens: 31 Jan 2021; 39:202-213
van der Linden EL, Couwenhoven BN, Beune EJAJ, Daams JG, van den Born BH, Agyemang C
J Hypertens: 31 Jan 2021; 39:202-213 | PMID: 32925300
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Abstract

Local transversal aortic strain is impaired in ascending aorta dilatation.

Cesareo M, Sabia L, Leone D, Avenatti E, ... Vallelonga F, Milan A
Background
Ascending aorta dilatation is found in 13% of hypertensive patients. Little is known about elastic properties of ascending aorta in such patients. Echo-based transverse aortic strain analysis can describe mechanical properties of ascending aorta but has never been applied to patients with ascending aorta dilatation.
Aim
To assess mechanical properties of ascending aorta by transverse aortic strain analysis (as β2-stiffness index) in hypertensive patients with ascending aorta dilatation and association between mechanical properties of ascending aorta and cardiovascular damage.
Methods
A total of 100 hypertensive outpatients underwent transthoracic echocardiography and assessment of pulse wave velocity (PWV). Strain analysis of ascending aorta was performed with echocardiographic speckle-tracking software. Patients were divided in three groups based on ascending aorta diameter: less than 40, 40-45, and at least 45 mm.
Results
Beta-SI increased exponentially with ascending aorta dimensions (P < 0.001). Patients with ascending aorta dilatation had Beta-SI significantly higher than those with normal ascending aorta diameter. A greater proportion of patient with impaired (i.e., elevated) Beta-SI was present in groups with larger ascending aorta (18.2 vs. 48.4 vs. 80%, respectively, P < 0.05). On multivariate logistic regression only impaired Beta-SI predicted ascending aorta dilatation (P < 0.001). Beta-SI was related to cardiovascular damage in terms of left ventricular (LV) mass (LV mass indexed to BSA, P = 0.030) and PWV (P = 0.028). Patients with high Beta-SI had greater LV mass indexed to BSA (117 ± 47 vs. 94 ± 24 g/m2; P = 0.010) and PWV (10.20 ± 2.99 vs. 8.63 ± 1.88 m/s; P = 0.013).
Conclusion
Ascending aorta dilatation is associated with increased local aortic stiffness in hypertensive patients. Strain analysis adds functional information to the mere morphological evaluation of aortic diameter and could be a useful tool to better define cardiovascular risk in this population.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 03 Jan 2021; epub ahead of print
Cesareo M, Sabia L, Leone D, Avenatti E, ... Vallelonga F, Milan A
J Hypertens: 03 Jan 2021; epub ahead of print | PMID: 33399306
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Abstract

Elevated heart rate and cardiovascular risk in hypertension.

Mancia G, Masi S, Palatini P, Tsioufis C, Grassi G

Epidemiological studies have shown that chronically elevated resting heart rate (HR) is significantly associated with organ damage, morbidity and mortality in a wide range of patients including hypertensive patients. Evidence is also available that an increased HR reflects sympathetic nervous system overdrive which is also known to adversely affect organ structure and function and to increase the risk of unfavourable outcomes in several diseases. The causal relationship between elevated HR, organ damage, and cardiovascular outcomes can thus be explained by its relationship with sympathetic cardiovascular influences although evidence of sympathetically-independent adverse effect of HR increases per se makes it more complex. Interventions that target HR by modulating the sympathetic nervous system have therefore a strong pathophysiological and clinical rationale. As most clinical guidelines now recommend the use of combination therapies in patients with hypertension, it might be desirable to consider as combination components drugs which lower HR, if HR is elevated such as, according to guideliines, when it is above 80 b/min.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 03 Jan 2021; epub ahead of print
Mancia G, Masi S, Palatini P, Tsioufis C, Grassi G
J Hypertens: 03 Jan 2021; epub ahead of print | PMID: 33399305
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Abstract

Beat-to-beat blood pressure variability: an early predictor of disease and cardiovascular risk.

Bakkar NZ, El-Yazbi AF, Zouein FA, Fares SA

Blood pressure (BP) varies on the long, short and very-short term. Owing to the hidden physiological and pathological information present in BP time-series, increasing interest has been given to the study of continuous, beat-to-beat BP variability (BPV) using invasive and noninvasive methods. Different linear and nonlinear parameters of variability are employed in the characterization of BP signals in health and disease. Although linear parameters of beat-to-beat BPV are mainly measures of dispersion, such as standard deviation (SD), nonlinear parameters of BPV quantify the degree of complexity/irregularity- using measures of entropy or self-similarity/correlation. In this review, we summarize the value of linear and nonlinear parameters in reflecting different information about the pathophysiology of changes in beat-to-beat BPV independent of or superior to mean BP. We then provide a comparison of the relative power of linear and nonlinear parameters of beat-to-beat BPV in detecting early and subtle differences in various states. The practical advantage and utility of beat-to-beat BPV monitoring support its incorporation into routine clinical practices.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 03 Jan 2021; epub ahead of print
Bakkar NZ, El-Yazbi AF, Zouein FA, Fares SA
J Hypertens: 03 Jan 2021; epub ahead of print | PMID: 33399302
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Abstract

Current prevalence of self-monitoring of blood pressure during pregnancy: the BUMP Survey.

Tucker KL, Hodgkinson J, Wilson HM, Crawford C, ... Chappell LC, McManus RJ
Objective
To understand the current prevalence of, and attitudes to, self-monitoring of blood pressure (BP) during pregnancy.
Methods
Five thousand, five hundred and fifty-five pregnant women from antenatal clinics in 16 hospitals in England were invited to complete a survey.
Main outcome measures
The primary outcome was the proportion of women currently BP self-monitoring. Secondary outcomes included self-monitoring schedules and women\'s interactions with clinicians regarding self-monitoring. Population characteristics including risk factors for preeclampsia, ethnicity and deprivation level were considered.
Results
Completed surveys were received and analysed from 5181 pregnant women (93% response rate). Comparison to hospital demographic data suggests that respondents were representative of the UK population. Nine hundred and eighty-three of 5181 (19%) women were currently self-monitoring their BP, constituting 189 of 389 (49%) hypertensive women and 794 of 4792 (17%) normotensive women. However, only 482 of 983 (49%) reported ever sharing this information with antenatal care teams. Of those who self-monitored, 68% (668/983) were able to provide a previous BP reading, compared with 1% (67/5181) of those who did not self-monitor.
Conclusion
Many women are now choosing to self-monitor their BP during pregnancy and clinicians should enquire about this proactively and consider providing better information on BP monitoring. Those who self-monitor appear to have better knowledge about their blood pressure. If these findings were replicated nationwide, around 125 000 pregnant women would be currently self-monitoring BP in the UK, yet only half of these women may communicate their readings to their antenatal care teams, suggesting a missed opportunity for enhanced care. Current trials will make the place of self-monitoring in pregnancy clearer.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 03 Jan 2021; epub ahead of print
Tucker KL, Hodgkinson J, Wilson HM, Crawford C, ... Chappell LC, McManus RJ
J Hypertens: 03 Jan 2021; epub ahead of print | PMID: 33399304
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Abstract

A 65-Year-Old Woman With Dyspnea After Atrial Fibrillation Ablation.

Gul F, Casey D, Mainigi S, Eiger G, Niroula A
Case presentation
A 65-year-old woman with a history of chronic persistent atrial fibrillation, tobacco use, and COPD was admitted to the hospital 2 months after catheter ablation for persistent atrial fibrillation and dyspnea. Her dyspnea was present at rest and worsened by exertion with limitation to ambulating less than two blocks. She also endorsed a 1-month history of cough with minimally productive whitish sputum with frequent nocturnal exacerbations and orthopnea. She denied any fevers, chest pain, or hemoptysis.

Published by Elsevier Inc.

Chest: 30 Dec 2020; 159:e29-e33
Gul F, Casey D, Mainigi S, Eiger G, Niroula A
Chest: 30 Dec 2020; 159:e29-e33 | PMID: 33422237
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Abstract

Ambulatory blood pressure adaptations to high-intensity interval training: a randomized controlled study.

Edwards JJ, Taylor KA, Cottam C, Jalaludeen N, ... Sharma R, O\'Driscoll JM
Objective
Hypertension remains the leading cause of cardiovascular disease and premature mortality globally. Although high-intensity interval training (HIIT) is an effective nonpharmacological intervention for the reduction of clinic blood pressure (BP), very little research exists regarding its effects on ambulatory BP. The aim of this study was to measure alterations in ambulatory and clinic BP following HIIT in physically inactive adults.
Methods
Forty-one participants (22.8 ± 2.7 years) were randomly assigned to a 4-week HIIT intervention or control group. The HIIT protocol was performed on a cycle ergometer set against a resistance of 7.5% bodyweight and consisted of 3 × 30-s maximal sprints separated with 2-min active recovery. Clinic and ambulatory BP was recorded pre and post the control period and HIIT intervention.
Results
Following the HIIT intervention, 24-h ambulatory BP significantly decreased by 5.1 mmHg in sBP and 2.3 mmHg in dBP (P = 0.011 and 0.012, respectively), compared with the control group. In addition, clinic sBP significantly decreased by 6.6 mmHg compared with the control group (P = 0.021), with no significant changes in dBP and mean BP (mBP). Finally, 24-h ambulatory diastolic, daytime sBP, mBP and dBP, and night-time sBP and mBP variability significantly decreased post-HIIT compared with the control group.
Conclusion
HIIT remains an effective intervention for the management of BP. Our findings support enduring BP reduction and improved BP variability, which are important independent risk factors for cardiovascular disease.

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

J Hypertens: 31 Jan 2021; 39:341-348
Edwards JJ, Taylor KA, Cottam C, Jalaludeen N, ... Sharma R, O'Driscoll JM
J Hypertens: 31 Jan 2021; 39:341-348 | PMID: 33031171
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Abstract

Comparative effects of intensive-blood pressure versus standard-blood pressure-lowering treatment in patients with severe ischemic stroke in the ENCHANTED trial.

Minhas JS, Wang X, Lindley RI, Delcourt C, ... Robinson TG,
Objective
Limited data exist on the optimum level of SBP in thrombolyzed patients with acute ischemic stroke (AIS). We aimed to determine the effects of intensive blood pressure (BP) lowering, specifically in patients with severe AIS who participated in the international, Enhanced Control of Hypertension and Thrombolysis Stroke Study.
Methods
Prespecificed subgroup analyzes of the BP arm of Enhanced Control of Hypertension and Thrombolysis Stroke Study, a multicenter, partial-factorial, open, blinded outcome assessed trial, in which 2227 thrombolysis-eligible and treated AIS patients with elevated SBP (>150 mmHg) were randomized to intensive (target 130-140 mmHg) or guideline-recommended (<180 mmHg) BP management. Severe stroke was defined by computed tomography or magnetic resonance angiogram confirmation of large-vessel occlusion, receipt of endovascular therapy, final diagnosis of large artery atheromatous disease, or high (>10) baseline neurological scores on the National Institutes of Health Stroke Scale. The primary efficacy outcome was death or any disability (modified Rankin scale scores 2-6). The key safety outcome was intracranial hemorrhage (ICH). Treatment effects estimated in logistic regression models are reported as odds ratios (ORs) with 95% confidence intervals (CIs).
Results
There were 1311 patients [mean age 67 years; 37% female; median baseline National Institutes of Health Stroke Scale of 11 (range 6.0-15.0)] with severe AIS. Overall, there was no significant difference in the primary outcome of death or disability. However, intensive BP lowering significantly increased mortality (OR 1.52, 95% CI 1.09-2.13; P = 0.014) compared with guideline BP lowering, despite significantly lowering clinician-reported ICH (OR 0.63, 95% CI 0.43-0.92; P = 0.016).
Conclusion
Intensive BP lowering is associated with increased mortality in patients with severe AIS despite lowering the risk of ICH. Further randomized trials are required to provide reliable evidence over the optimum SBP target in the most serious type of AIS.
Trial registration
ClinicalTrials.gov Identifier: NCT01422616.

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

J Hypertens: 31 Jan 2021; 39:280-285
Minhas JS, Wang X, Lindley RI, Delcourt C, ... Robinson TG,
J Hypertens: 31 Jan 2021; 39:280-285 | PMID: 33031175
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