Journal: Eur Heart J

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Abstract

The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction.

Ceglarek U, Schellong P, Rosolowski M, Scholz M, ... Pöss J, Thiele H
Background 
Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score.
Methods and results 
A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively).
Conclusions 
A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS.

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: 26 Feb 2021; epub ahead of print
Ceglarek U, Schellong P, Rosolowski M, Scholz M, ... Pöss J, Thiele H
Eur Heart J: 26 Feb 2021; epub ahead of print | PMID: 33647946
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Abstract

Long-term outcomes following endovascular and surgical revascularization for peripheral artery disease: a propensity score-matched analysis.

Parvar SL, Ngo L, Dawson J, Nicholls SJ, ... Psaltis PJ, Ranasinghe I
Aims
Peripheral artery disease (PAD) revascularization can be performed by either endovascular or open surgical approach. Despite increasing use of endovascular revascularization, it is still uncertain which strategy yields better long-term outcomes.
Methods and results
This retrospective cohort study evaluated patients hospitalized with PAD in Australia and New Zealand who underwent either endovascular or surgical revascularization between 2008 and 2015, and compared procedures using a propensity score-matched analysis. Hybrid interventions were excluded. The primary endpoint was mortality or major adverse limb events (MALE), defined as a composite endpoint of acute limb ischaemia, urgent surgical or endovascular reintervention, or major amputation, up to 8 years post-hospitalization using time-to-event analyses 75 189 patients fulfilled eligibility (15 239 surgery and 59 950 endovascular), from whom 14 339 matched pairs (mean ± SD age 71 ± 12 years, 73% male) with good covariate balance were identified. Endovascular revascularization was associated with an increase in combined MALE or mortality [hazard ratio (HR) 1.13, 95% confidence interval (CI): 1.09-1.17, P < 0.001]. There was a similar risk of MALE (HR 1.04, 95% CI: 0.99-1.10, P = 0.15), and all-cause urgent rehospitalizations (HR 1.01, 95% CI: 0.98-1.04, P = 0.57), but higher mortality (HR 1.16, 95% CI: 1.11-1.21, P < 0.001) when endovascular repair was compared to surgery. In subgroup analysis, these findings were consistent for both claudication and chronic limb-threatening ischaemia presentations.
Conclusion
Although the long-term risk of MALE was comparable for both approaches, enduring advantages of surgical revascularization included lower long-term mortality. This is at odds with some prior PAD studies and highlights contention in this space.

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

Eur Heart J: 23 Feb 2021; epub ahead of print
Parvar SL, Ngo L, Dawson J, Nicholls SJ, ... Psaltis PJ, Ranasinghe I
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624819
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Abstract

Tilt testing remains a valuable asset.

Sutton R, Fedorowski A, Olshansky B, Gert van Dijk J, ... Thijs RD, Benditt DG
Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experience supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients.

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

Eur Heart J: 23 Feb 2021; epub ahead of print
Sutton R, Fedorowski A, Olshansky B, Gert van Dijk J, ... Thijs RD, Benditt DG
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624801
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Abstract

All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study.

Butt JH, Fosbøl EL, Gerds TA, Andersson C, ... Køber L, Schou M
Background
On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures.
Methods and results
Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87-0.95; IRR 0.95, 95% CI 0.89-1.02; and IRR 0.87, 95% CI 0.83-0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97-1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88-0.96; out-of-hospital, IRR 1.04, 95% CI1.01-1.08). These trends were consistent irrespective of sex and age.
Conclusions
Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

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

Eur Heart J: 23 Feb 2021; epub ahead of print
Butt JH, Fosbøl EL, Gerds TA, Andersson C, ... Køber L, Schou M
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624011
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Abstract

Outdoor light at night and risk of coronary heart disease among older adults: a prospective cohort study.

Sun S, Cao W, Ge Y, Ran J, ... Tian L, Wellenius GA
Aims
We estimated the association between outdoor light at night at the residence and risk of coronary heart disease (CHD) within a prospective cohort of older adults in Hong Kong.
Methods and results
Over a median of 11 years of follow-up, we identified 3772 incident CHD hospitalizations and 1695 CHD deaths. Annual levels of outdoor light at night at participants\' residential addresses were estimated using time-varying satellite data for a composite of persistent night-time illumination at ∼1 km2 scale. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between outdoor light at night at the residence and risk of CHD. The association between light at night and incident CHD hospitalization and mortality exhibited a monotonic exposure-response function. An interquartile range (IQR) (60.0 nW/cm2/sr) increase in outdoor light at night was associated with an HR of 1.11 (95% CI: 1.03, 1.18) for CHD hospitalizations and 1.10 (95% CI: 1.00, 1.22) for CHD deaths after adjusting for both individual and area-level risk factors. The association did not vary across strata of hypothesized risk factors.
Conclusion
Among older adults, outdoor light at night at the residence was associated with a higher risk of CHD hospitalizations and deaths. We caution against causal interpretation of these novel findings. Future studies with more detailed information on exposure, individual adaptive behaviours, and potential mediators are warranted to further examine the relationship between light at night and CHD risk.

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: 20 Feb 2021; 42:822-830
Sun S, Cao W, Ge Y, Ran J, ... Tian L, Wellenius GA
Eur Heart J: 20 Feb 2021; 42:822-830 | PMID: 33205210
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Abstract

Does night-time aircraft noise trigger mortality? A case-crossover study on 24 886 cardiovascular deaths.

Saucy A, Schäffer B, Tangermann L, Vienneau D, Wunderli JM, Röösli M
Aims
It is unclear whether night-time noise events, including from aeroplanes, could trigger a cardiovascular death. In this study, we investigate the potential acute effects of aircraft noise on mortality and the specific role of different night-time exposure windows by means of a case-crossover study design.
Methods and results
We selected 24 886 cases of death from cardiovascular disease (CVD) from the Swiss National Cohort around Zürich Airport between 2000 and 2015. For night-time deaths, exposure levels 2 h preceding death were significantly associated with mortality for all causes of CVD [OR = 1.44 (1.03-2.04) for the highest exposure group (LAeq > 50 dB vs. <20 dB)]. Most consistent associations were observed for ischaemic heart diseases, myocardial infarction, heart failure, and arrhythmia. Association were more pronounced for females (P = 0.02) and for people living in areas with low road and railway background noise (P = 0.01) and in buildings constructed before 1970 (P = 0.36). We calculated a population attributable fraction of 3% in our study population.
Conclusion
Our findings suggest that night-time aircraft noise can trigger acute cardiovascular mortality. The association was similar to that previously observed for long-term aircraft noise exposure.

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

Eur Heart J: 20 Feb 2021; 42:835-843
Saucy A, Schäffer B, Tangermann L, Vienneau D, Wunderli JM, Röösli M
Eur Heart J: 20 Feb 2021; 42:835-843 | PMID: 33245107
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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 Feb 2021; 42:861-869
Agerström J, Carlsson M, Bremer A, Herlitz J, Israelsson J, Årestedt K
Eur Heart J: 20 Feb 2021; 42:861-869 | PMID: 33345270
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Abstract

Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation.

Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Aims
The aim of this study was to understand the changing trends in atrial fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role.
Methods and results
We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality, and mortality-to-incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark, and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100 000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women vs. men in 1990 to 74.5% higher in women in 2017).
Conclusion
AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests that there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from AF.

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

Eur Heart J: 20 Feb 2021; 42:847-857
Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Eur Heart J: 20 Feb 2021; 42:847-857 | PMID: 33495788
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Abstract

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

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

Eur Heart J: 17 Feb 2021; epub ahead of print
Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Eur Heart J: 17 Feb 2021; epub ahead of print | PMID: 33596594
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Abstract

Long-term outcomes in young patients with atrioventricular block of unknown aetiology.

Dideriksen JR, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK
Aims
Atrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology.
Methods and results
We identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7-46.2 years]. After a median follow-up of 9.8 years (IQR 5.7-14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9-5.1; P < 0.001]. Patients with persistent AVB at time of diagnosis had a higher risk of the primary endpoint (HR 10.6; 95% CI 5.7-20.0; P < 0.001), and risk was highest early in the follow-up period (HR 6.8; 95% CI 4.6-10.0; P < 0.001, during 0-5 years of follow-up).
Conclusion
Atrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. Patients with persistent AVB were at higher risk. These findings warrant improved follow-up strategies for young patients with AVB of unknown aetiology.

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

Eur Heart J: 17 Feb 2021; epub ahead of print
Dideriksen JR, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK
Eur Heart J: 17 Feb 2021; epub ahead of print | PMID: 33599276
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Abstract

Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study.

Wartolowska KA, Webb AJS
Aims
White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP.
Methods and results 
UK Biobank is a prospective community-based cohort of 40-69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4-12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP.In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: β = 0.064, 95% confidence interval (CI) 0.050-0.078; SBP: β = 0.076, 95% CI 0.062-0.090], but the strongest association was for past DBP (DBP: β = 0.087, 95% CI 0.064-0.109; SBP: β = 0.045, 95% CI 0.022-0.069), particularly under the age of 50 (DBP: β = 0.103, 95% CI 0.055-0.152; SBP: β = 0.012, 95% CI -0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107-1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090-1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH.
Conclusions
WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

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

Eur Heart J: 13 Feb 2021; 42:750-757
Wartolowska KA, Webb AJS
Eur Heart J: 13 Feb 2021; 42:750-757 | PMID: 33238300
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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: 13 Feb 2021; 42:776-785
Anand V, Kane GC, Scott CG, Pislaru SV, ... Pellikka PA, Pislaru C
Eur Heart J: 13 Feb 2021; 42:776-785 | PMID: 33377479
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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: 13 Feb 2021; 42:761-772
Abohashem S, Osborne MT, Dar T, Naddaf N, ... Rajagopalan S, Tawakol A
Eur Heart J: 13 Feb 2021; 42:761-772 | PMID: 33428721
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Abstract

Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo.

Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, ... Mantovani D, Caligiuri G
Aims
The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth.
Methods and results
We produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES.
Conclusion
CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility.

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

Eur Heart J: 12 Feb 2021; epub ahead of print
Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, ... Mantovani D, Caligiuri G
Eur Heart J: 12 Feb 2021; epub ahead of print | PMID: 33580685
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Abstract

Genetic insight into sick sinus syndrome.

Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Holm H, Stefansson K
Aims
The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.
Methods and results
We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).
Conclusion
We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

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

Eur Heart J: 12 Feb 2021; epub ahead of print
Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Holm H, Stefansson K
Eur Heart J: 12 Feb 2021; epub ahead of print | PMID: 33580673
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Impact:
Abstract

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart \'OMics\' in AGEing (HOMAGE) randomized clinical trial.

Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Aims 
To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.
Methods and results 
Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.
Conclusions 
Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

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

Eur Heart J: 10 Feb 2021; 42:684-696
Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:684-696 | PMID: 33215209
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Impact:
Abstract

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Aims
The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).
Methods and results
HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.
Conclusion
The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

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

Eur Heart J: 10 Feb 2021; 42:700-710
Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Eur Heart J: 10 Feb 2021; 42:700-710 | PMID: 33351892
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Impact:
Abstract

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Aims
We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.
Methods and results
The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.
Conclusion
The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

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

Eur Heart J: 10 Feb 2021; 42:671-680
Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:671-680 | PMID: 33459776
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Impact:
Abstract

Cardiac arrest in COVID-19: characteristics and outcomes of in- and out-of-hospital cardiac arrest. A report from the Swedish Registry for Cardiopulmonary Resuscitation.

Sultanian P, Lundgren P, Strömsöe A, Aune S, ... Herlitz J, Rawshani A
Aim
To study the characteristics and outcome among cardiac arrest cases with COVID-19 and differences between the pre-pandemic and the pandemic period in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA).
Method and results
We included all patients reported to the Swedish Registry for Cardiopulmonary Resuscitation from 1 January to 20 July 2020. We defined 16 March 2020 as the start of the pandemic. We assessed overall and 30-day mortality using Cox regression and logistic regression, respectively. We studied 1946 cases of OHCA and 1080 cases of IHCA during the entire period. During the pandemic, 88 (10.0%) of OHCAs and 72 (16.1%) of IHCAs had ongoing COVID-19. With regards to OHCA during the pandemic, the odds ratio for 30-day mortality in COVID-19-positive cases, compared with COVID-19-negative cases, was 3.40 [95% confidence interval (CI) 1.31-11.64]; the corresponding hazard ratio was 1.45 (95% CI 1.13-1.85). Adjusted 30-day survival was 4.7% for patients with COVID-19, 9.8% for patients without COVID-19, and 7.6% in the pre-pandemic period. With regards to IHCA during the pandemic, the odds ratio for COVID-19-positive cases, compared with COVID-19-negative cases, was 2.27 (95% CI 1.27-4.24); the corresponding hazard ratio was 1.48 (95% CI 1.09-2.01). Adjusted 30-day survival was 23.1% in COVID-19-positive cases, 39.5% in patients without COVID-19, and 36.4% in the pre-pandemic period.
Conclusion
During the pandemic phase, COVID-19 was involved in at least 10% of all OHCAs and 16% of IHCAs, and, among COVID-19 cases, 30-day mortality was increased 3.4-fold in OHCA and 2.3-fold in IHCA.

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

Eur Heart J: 04 Feb 2021; epub ahead of print
Sultanian P, Lundgren P, Strömsöe A, Aune S, ... Herlitz J, Rawshani A
Eur Heart J: 04 Feb 2021; epub ahead of print | PMID: 33543259
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Impact:
Abstract

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Hartiala JA, Han Y, Jia Q, Hilser JR, ... Hazen SL, Allayee H
Aims
While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.
Methods and results
We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.
Conclusions
A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

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: 02 Feb 2021; epub ahead of print
Hartiala JA, Han Y, Jia Q, Hilser JR, ... Hazen SL, Allayee H
Eur Heart J: 02 Feb 2021; epub ahead of print | PMID: 33532862
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Impact:
Abstract

Joint exposure to various ambient air pollutants and incident heart failure: a prospective analysis in UK Biobank.

Wang M, Zhou T, Song Y, Li X, ... Heianza Y, Qi L
Aims 
Little is known about the relation between the long-term joint exposure to various ambient air pollutants and the incidence of heart failure (HF). We aimed to assess the joint association of various air pollutants with HF risk and examine the modification effect of the genetic susceptibility.
Methods and results 
This study included 432 530 participants free of HF, atrial fibrillation, or coronary heart disease in the UK Biobank study. All participants were enrolled from 2006 to 2010 and followed up to 2018. The information on particulate matter (PM) with diameters ≤2.5 µm (PM2.5), ≤10 µm (PM10), and between 2.5 and 10 µm (PM2.5-10) as well as nitrogen oxides (NO2 and NOx) was collected. We newly proposed an air pollution score to assess the joint exposure to the five air pollutants through summing each pollutant concentration weighted by the regression coefficients with HF from single-pollutant models. We also calculated the weighted genetic risk score of HF. During a median of 10.1 years (4 346 642 person-years) of follow-up, we documented 4201 incident HF. The hazard ratios (HRs) [95% confidence interval (CI)] of HF for a 10 µg/m3 increase in PM2.5, PM10, PM2.5-10, NO2, and NOx were 1.85 (1.34-2.55), 1.61 (1.30-2.00), 1.13 (0.80-1.59), 1.10 (1.04-1.15), and 1.04 (1.02-1.06), respectively. We found that the air pollution score was associated with an increased risk of incident HF in a dose-response fashion. The HRs (95% CI) of HF were 1.16 (1.05-1.28), 1.19 (1.08-1.32), 1.21 (1.09-1.35), and 1.31 (1.17-1.48) in higher quintile groups compared with the lowest quintile of the air pollution score (P trend <0.001). In addition, we observed that the elevated risk of HF associated with a higher air pollution score was strengthened by the genetic susceptibility to HF.
Conclusion 
Our results indicate that the long-term joint exposure to various air pollutants including PM2.5, PM10, PM2.5-10, NO2, and NOx is associated with an elevated risk of incident HF in an additive manner. Our findings highlight the importance to comprehensively assess various air pollutants in relation to the HF risk.

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: 01 Feb 2021; epub ahead of print
Wang M, Zhou T, Song Y, Li X, ... Heianza Y, Qi L
Eur Heart J: 01 Feb 2021; epub ahead of print | PMID: 33527989
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Impact:
Abstract

Chronic obstructive pulmonary disease and atrial fibrillation: an interdisciplinary perspective.

Simons SO, Elliott A, Sastry M, Hendriks JM, ... Crijns HJGM, Linz D
Chronic obstructive pulmonary disease (COPD) is highly prevalent among patients with atrial fibrillation (AF), shares common risk factors, and adds to the overall morbidity and mortality in this population. Additionally, it may promote AF and impair treatment efficacy. The prevalence of COPD in AF patients is high and is estimated to be ∼25%. Diagnosis and treatment of COPD in AF patients requires a close interdisciplinary collaboration between the electrophysiologist/cardiologist and pulmonologist. Differential diagnosis may be challenging, especially in elderly and smoking patients complaining of unspecific symptoms such as dyspnoea and fatigue. Routine evaluation of lung function and determination of natriuretic peptides and echocardiography may be reasonable to detect COPD and heart failure as contributing causes of dyspnoea. Acute exacerbation of COPD transiently increases AF risk due to hypoxia-mediated mechanisms, inflammation, increased use of beta-2 agonists, and autonomic changes. Observational data suggest that COPD promotes AF progression, increases AF recurrence after cardioversion, and reduces the efficacy of catheter-based antiarrhythmic therapy. However, it remains unclear whether treatment of COPD improves AF outcomes and which metric should be used to determine COPD severity and guide treatment in AF patients. Data from non-randomized studies suggest that COPD is associated with increased AF recurrence after electrical cardioversion and catheter ablation. Future prospective cohort studies in AF patients are needed to confirm the relationship between COPD and AF, the benefits of treatment of either COPD or AF in this population, and to clarify the need and cost-effectiveness of routine COPD screening.

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

Eur Heart J: 31 Jan 2021; 42:532-540
Simons SO, Elliott A, Sastry M, Hendriks JM, ... Crijns HJGM, Linz D
Eur Heart J: 31 Jan 2021; 42:532-540 | PMID: 33206945
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Impact:
Abstract

Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole.

Brignole M, Russo V, Arabia F, Oliveira M, ... Tomaino M, BioSync CLS trial Investigators
Aim
The benefit of cardiac pacing in patients with severe recurrent reflex syncope and asystole induced by tilt testing has not been established. The usefulness of tilt-table test to select candidates for cardiac pacing is controversial.
Methods and results
We randomly assigned patients aged 40 years or older who had at least two episodes of unpredictable severe reflex syncope during the last year and a tilt-induced syncope with an asystolic pause longer than 3 s, to receive either an active (pacing ON; 63 patients) or an inactive (pacing OFF; 64 patients) dual-chamber pacemaker with closed loop stimulation (CLS). The primary endpoint was the time to first recurrence of syncope. Patients and independent outcome assessors were blinded to the assigned treatment. After a median follow-up of 11.2 months, syncope occurred in significantly fewer patients in the pacing group than in the control group [10 (16%) vs. 34 (53%); hazard ratio, 0.23; P = 0.00005]. The estimated syncope recurrence rate at 1 year was 19% (pacing) and 53% (control) and at 2 years, 22% (pacing) and 68% (control). A combined endpoint of syncope or presyncope occurred in significantly fewer patients in the pacing group [23 (37%) vs. 40 (63%); hazard ratio, 0.44; P = 0.002]. Minor device-related adverse events were reported in five patients (4%).
Conclusion
In patients aged 40 years or older, affected by severe recurrent reflex syncope and tilt-induced asystole, dual-chamber pacemaker with CLS is highly effective in reducing the recurrences of syncope. Our findings support the inclusion of tilt testing as a useful method to select candidates for cardiac pacing.
Study registration
ClinicalTrials.gov identifier NCT02324920, Eudamed number CIV-05-013546.

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

Eur Heart J: 31 Jan 2021; 42:508-516
Brignole M, Russo V, Arabia F, Oliveira M, ... Tomaino M, BioSync CLS trial Investigators
Eur Heart J: 31 Jan 2021; 42:508-516 | PMID: 33279955
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Impact:
Abstract

The year in cardiovascular medicine 2020: arrhythmias.

Crijns HJGM, Prinzen F, Lambiase PD, Sanders P, Brugada J
of the progress in arrhythmias in 2020. RACE4 and ALL-IN indicated that integrated nurse-led care improves outcomes in AF patients.3,4 The same was reported for early rhythm control therapy15 and cryoablation as initial AF treatment.25,26 Subcutaneous ICD was non-inferior to classical transvenous ICD therapy in PRAETORIAN.54 One mechanistic study showed that autoantibodies against misexpressed actin, keratin, and connexin-43 proteins create a blood-borne biomarker profile enhancing diagnosis of Brugada syndrome.50 Another mechanistic study indicated that transseptal LV pacing yields similar improvement in contractility as His bundle pacing whilst being more easy to execute.44 In PRE-DETERMINE a simple-to-use ECG risk score improved risk prediction in patients with ischemic heart disease possibly enhancing appropriate ICD therapy in high risk patients.58.

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: 31 Jan 2021; 42:499-507
Crijns HJGM, Prinzen F, Lambiase PD, Sanders P, Brugada J
Eur Heart J: 31 Jan 2021; 42:499-507 | PMID: 33388752
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Impact:
Abstract

Silent brain infarcts and early cognitive outcomes after transcatheter aortic valve implantation: a systematic review and meta-analysis.

Woldendorp K, Indja B, Bannon PG, Fanning JP, Plunkett BT, Grieve SM
Background
Silent brain infarcts (SBIs) are frequently identified after transcatheter aortic valve implantation (TAVI), when patients are screened with diffusion-weighted magnetic resonance imaging (DW-MRI). Outside the cardiac literature, SBIs have been correlated with progressive cognitive dysfunction; however, their prognostic utility after TAVI remains uncertain. This study\'s main goals were to explore (i) the incidence of and potential risk factors for SBI after TAVI; and (ii) the effect of SBI on early post-procedural cognitive dysfunction (PCD).
Methods and results
A systematic literature review was performed to identify all publications reporting SBI incidence, as detected by DW-MRI after TAVI. Silent brain infarct incidence, baseline characteristics, and the incidence of early PCD were evaluated via meta-analysis and meta-regression models. We identified 39 relevant studies encapsulating 2408 patients. Out of 2171 patients who underwent post-procedural DW-MRI, 1601 were found to have at least one new SBI (pooled effect size 0.76, 95% CI: 0.72-0.81). The incidence of reported stroke with focal neurological deficits was 3%. Meta-regression noted that diabetes, chronic renal disease, 3-Tesla MRI, and pre-dilation were associated with increased SBI risk. The prevalence of early PCD increased during follow-up, from 16% at 10.0 ± 6.3 days to 26% at 6.1 ± 1.7 months and meta-regression suggested an association between the mean number of new SBI and incidence of PCD. The use of cerebral embolic protection devices (CEPDs) appeared to decrease the volume of SBI, but not their overall incidence.
Conclusions
Silent brain infarcts are common after TAVI; and diabetes, kidney disease, and pre-dilation increase overall SBI risk. While higher numbers of new SBIs appear to adversely affect early neurocognitive outcomes, long-term follow-up studies remain necessary as TAVI expands to low-risk patient populations. The use of CEPD did not result in a significant decrease in the occurrence of SBI.

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: 31 Jan 2021; epub ahead of print
Woldendorp K, Indja B, Bannon PG, Fanning JP, Plunkett BT, Grieve SM
Eur Heart J: 31 Jan 2021; epub ahead of print | PMID: 33517376
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Impact:
Abstract

Death of a child and the risk of atrial fibrillation: a nationwide cohort study in Sweden.

Wei D, Olofsson T, Chen H, Janszky I, ... Li J, László KD
Aims
The role of psychological stress in the aetiology of atrial fibrillation (AF) is unclear. The death of a child is one of the most severe sources of stress. We aimed to investigate whether the death of a child is associated with an increased risk of AF.
Methods and results
We studied parents with children born during 1973-2014 included the Swedish Medical Birth Register (n = 3 924 237). Information on death of a child, AF and socioeconomic, lifestyle and health-related covariates was obtained through linkage to nationwide population and health registers. We examined the link between death of a child and AF risk using Poisson regression. Parents who lost a child had a 15% higher risk of AF than unexposed parents [incidence rate ratio (IRR) and 95% confidence intervals (CI): 1.15 (1.10-1.20)]. An increased risk of AF was observed not only if the child died due to cardiovascular causes [IRR (95% CI): 1.35 (1.17-1.56)], but also in case of deaths due to other natural [IRR (95% CI): 1.15 (1.09-1.21)] or unnatural [IRR (95% CI): 1.10 (1.02-1.19)] causes. The risk of AF was highest in the 1st week after the loss [IRR (95% CI): 2.87 (1.44-5.75)] and remained 10-40% elevated on the long term.
Conclusions
Death of a child was associated with a modestly increased risk of AF. Our finding that an increased risk was observed also after loss of a child due to unnatural deaths suggests that stress-related mechanisms may also be implicated in the development of AF.

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

Eur Heart J: 29 Jan 2021; epub ahead of print
Wei D, Olofsson T, Chen H, Janszky I, ... Li J, László KD
Eur Heart J: 29 Jan 2021; epub ahead of print | PMID: 33515041
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Impact:
Abstract

Patient-tailored antithrombotic therapy following percutaneous coronary intervention.

van der Sangen NMR, Rozemeijer R, Chan Pin Yin DRPP, Valgimigli M, ... Voskuil M, Kikkert WJ
Dual antiplatelet therapy has long been the standard of care in preventing coronary and cerebrovascular thrombotic events in patients with chronic coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, but choosing the optimal treatment duration and composition has become a major challenge. Numerous studies have shown that certain patients benefit from either shortened or extended treatment duration. Furthermore, trials evaluating novel antithrombotic strategies, such as P2Y12 inhibitor monotherapy, low-dose factor Xa inhibitors on top of antiplatelet therapy, and platelet function- or genotype-guided (de-)escalation of treatment, have shown promising results. Current guidelines recommend risk stratification for tailoring treatment duration and composition. Although several risk stratification methods evaluating ischaemic and bleeding risk are available to clinicians, such as the use of risk scores, platelet function testing , and genotyping, risk stratification has not been broadly adopted in clinical practice. Multiple risk scores have been developed to determine the optimal treatment duration, but external validation studies have yielded conflicting results in terms of calibration and discrimination and there is limited evidence that their adoption improves clinical outcomes. Likewise, platelet function testing and genotyping can provide useful prognostic insights, but trials evaluating treatment strategies guided by these stratification methods have produced mixed results. This review critically appraises the currently available antithrombotic strategies and provides a viewpoint on the use of different risk stratification methods alongside clinical judgement in current clinical practice.

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

Eur Heart J: 28 Jan 2021; epub ahead of print
van der Sangen NMR, Rozemeijer R, Chan Pin Yin DRPP, Valgimigli M, ... Voskuil M, Kikkert WJ
Eur Heart J: 28 Jan 2021; epub ahead of print | PMID: 33515031
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Impact:
Abstract

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Pristipino C, Germonpré P, Toni D, Sievert H, ... Byrne R, Kunadian V
Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.

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: 27 Jan 2021; epub ahead of print
Pristipino C, Germonpré P, Toni D, Sievert H, ... Byrne R, Kunadian V
Eur Heart J: 27 Jan 2021; epub ahead of print | PMID: 33507260
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Impact:
Abstract

Taking a stand against air pollution - the impact on cardiovascular disease.

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

The article has been co-published with permission in the European Heart Journal, the Journal of the American College of Cardiology, Circulation, and Global Heart. © The Author(s) 2021.

Eur Heart J: 27 Jan 2021; epub ahead of print
Brauer M, Casadei B, Harrington RA, Kovacs R, Sliwa K
Eur Heart J: 27 Jan 2021; epub ahead of print | PMID: 33507239
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Impact:
Abstract

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

Frey A, Homola GA, Henneges C, Mühlbauer L, ... Störk S, Stoll G
Aims
We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years.
Methods and results
A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with \'intensity of attention\' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29).
Conclusion
In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

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

Eur Heart J: 25 Jan 2021; epub ahead of print
Frey A, Homola GA, Henneges C, Mühlbauer L, ... Störk S, Stoll G
Eur Heart J: 25 Jan 2021; epub ahead of print | PMID: 33496311
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Impact:
Abstract

Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: a consensus document from European cardiologists, gynaecologists, and endocrinologists.

Maas AHEM, Rosano G, Cifkova R, Chieffo A, ... van Trotsenburg M, Collins P
Women undergo important changes in sex hormones throughout their lifetime that can impact cardiovascular disease risk. Whereas the traditional cardiovascular risk factors dominate in older age, there are several female-specific risk factors and inflammatory risk variables that influence a woman\'s risk at younger and middle age. Hypertensive pregnancy disorders and gestational diabetes are associated with a higher risk in younger women. Menopause transition has an additional adverse effect to ageing that may demand specific attention to ensure optimal cardiovascular risk profile and quality of life. In this position paper, we provide an update of gynaecological and obstetric conditions that interact with cardiovascular risk in women. Practice points for clinical use are given according to the latest standards from various related disciplines (Figure 1).

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

Eur Heart J: 24 Jan 2021; epub ahead of print
Maas AHEM, Rosano G, Cifkova R, Chieffo A, ... van Trotsenburg M, Collins P
Eur Heart J: 24 Jan 2021; epub ahead of print | PMID: 33495787
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Impact:
Abstract

Cardiac procedural myocardial injury, infarction, and mortality in patients undergoing elective percutaneous coronary intervention: a pooled analysis of patient-level data.

Silvain J, Zeitouni M, Paradies V, Zheng HL, ... Bulluck H, Hausenloy DJ
Aims
The prognostic importance of cardiac procedural myocardial injury and myocardial infarction (MI) in chronic coronary syndrome (CCS) patients undergoing elective percutaneous coronary intervention (PCI) is still debated.
Methods and results
We analysed individual data of 9081 patients undergoing elective PCI with normal pre-PCI baseline cardiac troponin (cTn) levels. Multivariate models evaluated the association between post-PCI elevations in cTn and 1-year mortality, while an interval analysis evaluated the impact of the size of the myocardial injury on mortality. Our analysis was performed in the overall population and also according to the type of cTn used [52.0% had high-sensitivity cTn (hs-cTn)]. Procedural myocardial injury, as defined by the Fourth Universal Definition of MI (UDMI) [post-PCI cTn elevation ≥1 × 99th percentile upper reference limit (URL)], occurred in 52.8% of patients and was not associated with 1-year mortality [adj odds ratio (OR), 1.35, 95% confidence interval (CI) (0.84-1.77), P = 0.21]. The association between post-PCI cTn elevation and 1-year mortality was significant starting ≥3 × 99th percentile URL. Major myocardial injury defined by post-PCI ≥5 × 99th percentile URL occurred in 18.2% of patients and was associated with a two-fold increase in the adjusted odds of 1-year mortality [2.29, 95% CI (1.32-3.97), P = 0.004]. In the subset of patients for whom periprocedural evidence of ischaemia was collected (n = 2316), Type 4a MI defined by the Fourth UDMI occurred in 12.7% of patients and was strongly associated with 1-year mortality [adj OR 3.21, 95% CI (1.42-7.27), P = 0.005]. We also present our results according to the type of troponin used (hs-cTn or conventional troponin).
Conclusion
Our analysis has demonstrated that in CCS patients with normal baseline cTn levels, the post-PCI cTn elevation of ≥5 × 99th percentile URL used to define Type 4a MI is associated with 1-year mortality and could be used to detect \'major\' procedural myocardial injury in the absence of procedural complications or evidence of new myocardial ischaemia.

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: 20 Jan 2021; 42:323-334
Silvain J, Zeitouni M, Paradies V, Zheng HL, ... Bulluck H, Hausenloy DJ
Eur Heart J: 20 Jan 2021; 42:323-334 | PMID: 33257958
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Impact:
Abstract

Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials.

Giacoppo D, Matsuda Y, Fovino LN, D\'Amico G, ... Mehran R, Tarantini G
Aims
After percutaneous coronary intervention (PCI) with second-generation drug-eluting stent (DES), whether short dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with a P2Y12 receptor inhibitor confers benefits compared with prolonged DAPT is unclear.
Methods and results
Multiple electronic databases, including PubMed, Scopus, Web of Sciences, Ovid, and ScienceDirect, were searched to identify randomized clinical trials comparing ≤3 months of DAPT followed by P2Y12 inhibitor SAPT vs. 12 months of DAPT after PCI with second-generation DES implantation. The primary and co-primary outcomes of interest were major bleeding and stent thrombosis 1 year after randomization. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fixed-effect and random-effects models. Multiple sensitivity analyses including random-effects models 95% CI adjustment were applied. A sensitivity analysis comparing trials using P2Y12 inhibitor SAPT with those using aspirin SAPT was performed. A total of five randomized clinical trials (32 145 patients) were available. Major bleeding was significantly lower in the patients assigned to short DAPT followed by P2Y12 inhibitor SAPT compared with those assigned to 12-month DAPT (random-effects model: HR 0.63, 95% 0.45-0.86). No significant differences between groups were observed in terms of stent thrombosis (random-effects model: HR 1.19, 95% CI 0.86-1.65) and the secondary endpoints of all-cause death (random-effects model: HR 0.85, 95% CI 0.70-1.03), myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23), and stroke (random-effects model: HR 1.08, 95% CI 0.68-1.74). Sensitivity analyses showed overall consistent results. By comparing trials testing ≤3 months of DAPT followed by P2Y12 inhibitor SAPT vs. 12 months of DAPT with trials testing ≤3 months of DAPT followed by aspirin SAPT vs. 12-month of DAPT, there was no treatment-by-subgroup interaction for each endpoint. By combining all these trials, regardless of the type of SAPT, short DAPT was associated with lower major bleeding (random-effects model: HR 0.63, 95% CI 0.48-0.83) and no differences in stent thrombosis, all-cause death, myocardial infarction, and stroke were observed between regimens.
Conclusion
After second-generation DES implantation, 1-3 months of DAPT followed by P2Y12 inhibitor SAPT is associated with lower major bleeding and similar stent thrombosis, all-cause death, myocardial infarction, and stroke compared with prolonged DAPT. Whether P2Y12 inhibitor SAPT is preferable to aspirin SAPT needs further investigation.

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: 20 Jan 2021; 42:308-319
Giacoppo D, Matsuda Y, Fovino LN, D'Amico G, ... Mehran R, Tarantini G
Eur Heart J: 20 Jan 2021; 42:308-319 | PMID: 33284979
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Impact:
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: 20 Jan 2021; 42:339-351
Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R
Eur Heart J: 20 Jan 2021; 42:339-351 | PMID: 33367641
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Impact:
Abstract

Interdisciplinary management of acute ischaemic stroke: Current evidence training requirements for endovascular stroke treatment: Position Paper from the ESC Council on Stroke and the European Association for Percutaneous Cardiovascular Interventions with the support of the European Board of Neurointervention.

Nardai S, Lanzer P, Abelson M, Baumbach A, ... Flodmark O, Widimsky P
This ESC Council on Stroke/EAPCI/EBNI position paper summarizes recommendations for training of cardiologists in endovascular treatment of acute ischaemic stroke. Interventional cardiologists adequately trained to perform endovascular stroke interventions could complement stroke teams to provide the 24/7 on call duty and thus to increase timely access of stroke patients to endovascular treatment. The training requirements for interventional cardiologists to perform endovascular therapy are described in details and should be based on two main principles: (i) patient safety cannot be compromised, (ii) proper training of interventional cardiologists should be under supervision of and guaranteed by a qualified neurointerventionist and within the setting of a stroke team. Interdisciplinary cooperation based on common standards and professional consensus is the key to the quality improvement in stroke treatment.

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: 20 Jan 2021; 42:298-307
Nardai S, Lanzer P, Abelson M, Baumbach A, ... Flodmark O, Widimsky P
Eur Heart J: 20 Jan 2021; 42:298-307 | PMID: 33521827
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Impact:
Abstract

Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations.

Assmus B, Cremer S, Kirschbaum K, Culmann D, ... Dimmeler S, Zeiher AM
Aims
Somatic mutations of the epigenetic regulators DNMT3A and TET2 causing clonal expansion of haematopoietic cells (clonal haematopoiesis; CH) were shown to be associated with poor prognosis in chronic ischaemic heart failure (CHF). The aim of our analysis was to define a threshold of variant allele frequency (VAF) for the prognostic significance of CH in CHF.
Methods and results
We analysed bone marrow and peripheral blood-derived cells from 419 patients with CHF by error-corrected amplicon sequencing. Cut-off VAFs were optimized by maximizing sensitivity plus specificity from a time-dependent receiver operating characteristic (ROC) curve analysis from censored data. 56.2% of patients were carriers of a DNMT3A- (N = 173) or a TET2- (N = 113) mutation with a VAF >0.5%, with 59 patients harbouring mutations in both genes. Survival ROC analyses revealed an optimized cut-off value of 0.73% for TET2- and 1.15% for DNMT3A-CH-driver mutations. Five-year-mortality was 18% in patients without any detected DNMT3A- or TET2 mutation (VAF < 0.5%), 29% with only one DNMT3A- or TET2-CH-driver mutations above the respective cut-off level and 42% in patients harbouring both DNMT3A- and TET2-CH-driver mutations above the respective cut-off levels. In carriers of a DNMT3A mutation with VAF ≥ 1.15%, 5-year mortality was 31%, compared with 18% mortality in those with VAF < 1.15% (P = 0.048). Likewise, in patients with TET2 mutations, 5-year mortality was 32% with VAF ≥ 0.73%, compared with 19% mortality with VAF < 0.73% (P = 0.029).
Conclusion
The present study defines novel threshold levels for clone size caused by acquired somatic mutations in the CH-driver genes DNMT3A and TET2 that are associated with worse outcome in patients with CHF.

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

Eur Heart J: 19 Jan 2021; 42:257-265
Assmus B, Cremer S, Kirschbaum K, Culmann D, ... Dimmeler S, Zeiher AM
Eur Heart J: 19 Jan 2021; 42:257-265 | PMID: 33241418
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Impact:
Abstract

Management of refractory angina: an update.

Davies A, Fox K, Galassi AR, Banai S, Ylä-Herttuala S, Lüscher TF
Despite the use of anti-anginal drugs and/or percutaneous coronary interventions (PCI) or coronary artery bypass grafting, the proportion of patients with coronary artery disease who have daily or weekly angina ranges from 2% to 24%. Refractory angina refers to long-lasting symptoms (for >3 months) due to established reversible ischaemia, which cannot be controlled by escalating medical therapy with the use of 2nd- and 3rd-line pharmacological agents, bypass grafting, or stenting. While there is uncertain prognostic benefit, the treatment of refractory angina is important to improve the quality of life of the patients affected. This review focuses on conventional pharmacological approaches to treating refractory angina, including guideline directed drug combination and dosages. The symptomatic and prognostic impact of advanced and novel revascularization strategies such as chronic total occlusion PCI, transmyocardial laser revascularization, coronary sinus occlusion, radiation therapy for recurrent restenosis, and spinal cord stimulation are also covered and recommendations of the 2019 ESC Guidelines on the Diagnosis and Management of Chronic Coronary Syndromes discussed. Finally, the potential clinical use of current angiogenetic and stem cell therapies in reducing ischaemia and/or pain is evaluated.

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

Eur Heart J: 19 Jan 2021; 42:269-283
Davies A, Fox K, Galassi AR, Banai S, Ylä-Herttuala S, Lüscher TF
Eur Heart J: 19 Jan 2021; 42:269-283 | PMID: 33367764
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Impact:
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: 19 Jan 2021; 42:243-252
Schubert J, Lindahl B, Melhus H, Renlund H, ... Jernberg T, Hagström E
Eur Heart J: 19 Jan 2021; 42:243-252 | PMID: 33367526
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Impact:
Abstract

Coronary flow velocity reserve predicts adverse prognosis in women with angina and no obstructive coronary artery disease: results from the iPOWER study.

Schroder J, Michelsen MM, Mygind ND, Suhrs HE, ... Kastrup J, Prescott E
Aims 
Many patients with angina, especially women, do not have obstructive coronary artery disease (CAD) yet have impaired prognosis. We investigated whether routine assessment of coronary microvascular dysfunction (CMD) is feasible and predicts adverse outcome in women with angina and no obstructive CAD.
Methods and results 
After screening 7253, we included 1853 women with angina and no obstructive CAD on angiogram who were free of previous CAD, heart failure, or valvular heart disease in the prospective iPOWER (Improving Diagnosis and Treatment of Women with Angina Pectoris and Microvascular Disease) study. CMD was assessed by Doppler echocardiography in the left anterior descending artery as coronary flow velocity reserve (CFVR). Patients were followed for a composite outcome of cardiovascular death, myocardial infarction (MI), heart failure, stroke, and coronary revascularization. CFVR was obtained in 1681 patients (91%) and the median CFVR was 2.33 (quartiles 1-3: 2.00-2.74). During a median follow-up of 4.5 years, 96 events occurred. In univariate Cox regression, CFVR was associated with the composite outcome {hazard ratio (HR) 1.07 [95% confidence interval (CI) 1.03-1.11] per 0.1 unit decrease in CFVR; P < 0.001}, primarily driven by an increased risk of MI and heart failure. Results remained significant in multivariate analysis [HR 1.05 (95% CI 1.01-1.09) per 0.1 unit decrease in CFVR; P = 0.01]. In exploratory analyses, CFVR was also associated with the risk of repeated hospital admission for angina and all-cause mortality.
Conclusion 
Assessment of CFVR by echocardiography is feasible and predictive of adverse outcome in women with angina and no obstructive CAD. Results support a more aggressive preventive management of these patients and underline the need for trials targeting CMD.

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

Eur Heart J: 19 Jan 2021; 42:228-239
Schroder J, Michelsen MM, Mygind ND, Suhrs HE, ... Kastrup J, Prescott E
Eur Heart J: 19 Jan 2021; 42:228-239 | PMID: 33477168
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Impact:
Abstract

How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol.

Karagiannis AD, Mehta A, Dhindsa DS, Virani SS, ... Stone NJ, Sperling LS
Low-density lipoprotein cholesterol (LDL-C) is a proven causative factor for developing atherosclerotic cardiovascular disease. Individuals with genetic conditions associated with lifelong very low LDL-C levels can be healthy. We now possess the pharmacological armamentarium (statins, ezetimibe, PCSK9 inhibitors) to reduce LDL-C to an unprecedented extent. Increasing numbers of patients are expected to achieve very low (<30 mg/dL) LDL-C. Cardiovascular event reduction increases log linearly in association with lowering LDL-C, without reaching any clear plateau even when very low LDL-C levels are achieved. It is still controversial whether lower LDL-C levels are associated with significant clinical adverse effects (e.g. new-onset diabetes mellitus or possibly haemorrhagic stroke) and long-term data are needed to address safety concerns. This review presents the familial conditions characterized by very low LDL-C, analyses trials with lipid-lowering agents where patients attained very low LDL-C, and summarizes the benefits and potential adverse effects associated with achieving very low LDL-C. Given the potential for cardiovascular benefit and short-term safe profile of very low LDL-C, it may be advantageous to attain such low levels in specific high-risk populations. Further studies are needed to compare the net clinical benefit of non-LDL-C-lowering interventions with very low LDL-C approaches, in addition to comparing the efficacy and safety of very low LDL-C levels vs. current recommended targets.

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

Eur Heart J: 18 Jan 2021; epub ahead of print
Karagiannis AD, Mehta A, Dhindsa DS, Virani SS, ... Stone NJ, Sperling LS
Eur Heart J: 18 Jan 2021; epub ahead of print | PMID: 33463677
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Impact:
Abstract

Stress-associated neurobiological activity is linked with acute plaque instability via enhanced macrophage activity: a prospective serial 18F-FDG-PET/CT imaging assessment.

Kang DO, Eo JS, Park EJ, Nam HS, ... Yoo H, Kim JW
Aims
Emotional stress is associated with future cardiovascular events. However, the mechanistic linkage of brain emotional neural activity with acute plaque instability is not fully elucidated. We aimed to prospectively estimate the relationship between brain amygdalar activity (AmygA), arterial inflammation (AI), and macrophage haematopoiesis (HEMA) in acute myocardial infarction (AMI) as compared with controls.
Methods and results
18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging was performed within 45 days of the index episode in 62 patients (45 with AMI, mean 60.0 years, 84.4% male; 17 controls, mean 59.6 years, 76.4% male). In 10 patients of the AMI group, serial 18F-FDG-PET/CT imaging was performed after 6 months to estimate the temporal changes. The signals were compared using a customized 3D-rendered PET reconstruction. AmygA [target-to-background ratio (TBR), mean ± standard deviation: 0.65 ± 0.05 vs. 0.60 ± 0.05; P = 0.004], carotid AI (TBR: 2.04 ± 0.39 vs. 1.81 ± 0.25; P = 0.026), and HEMA (TBR: 2.60 ± 0.38 vs. 2.22 ± 0.28; P < 0.001) were significantly higher in AMI patients compared with controls. AmygA correlated significantly with those of the carotid artery (r = 0.350; P = 0.005), aorta (r = 0.471; P < 0.001), and bone marrow (r = 0.356; P = 0.005). Psychological stress scales (PHQ-9 and PSS-10) and AmygA assessed by PET/CT imaging correlated well (P < 0.001). Six-month after AMI, AmygA, carotid AI, and HEMA decreased to a level comparable with the controls.
Conclusion
AmygA, AI, and HEMA were concordantly enhanced in patients with AMI, showing concurrent dynamic changes over time. These results raise the possibility that stress-associated neurobiological activity is linked with acute plaque instability via augmented macrophage activity and could be a potential therapeutic target for plaque inflammation in AMI.

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: 17 Jan 2021; epub ahead of print
Kang DO, Eo JS, Park EJ, Nam HS, ... Yoo H, Kim JW
Eur Heart J: 17 Jan 2021; epub ahead of print | PMID: 33462618
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Impact:
Abstract

The cardiovascular-dialysis nexus: the transition to dialysis is a treacherous time for the heart.

Chan K, Moe SM, Saran R, Libby P
Chronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.

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: 16 Jan 2021; epub ahead of print
Chan K, Moe SM, Saran R, Libby P
Eur Heart J: 16 Jan 2021; epub ahead of print | PMID: 33458768
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Impact:
Abstract

C-reactive protein and clinical outcomes in patients with COVID-19.

Smilowitz NR, Kunichoff D, Garshick M, Shah B, ... Hochman JS, Berger JS
Background
A systemic inflammatory response is observed in coronavirus disease 2019 (COVID-19). Elevated serum levels of C-reactive protein (CRP), a marker of systemic inflammation, are associated with severe disease in bacterial or viral infections. We aimed to explore associations between CRP concentration at initial hospital presentation and clinical outcomes in patients with COVID-19.
Methods and results
Consecutive adults aged ≥18 years with COVID-19 admitted to a large New York healthcare system between 1 March and 8 April 2020 were identified. Patients with measurement of CRP were included. Venous thrombo-embolism (VTE), acute kidney injury (AKI), critical illness, and in-hospital mortality were determined for all patients. Among 2782 patients hospitalized with COVID-19, 2601 (93.5%) had a CRP measurement [median 108 mg/L, interquartile range (IQR) 53-169]. CRP concentrations above the median value were associated with VTE [8.3% vs. 3.4%; adjusted odds ratio (aOR) 2.33, 95% confidence interval (CI) 1.61-3.36], AKI (43.0% vs. 28.4%; aOR 2.11, 95% CI 1.76-2.52), critical illness (47.6% vs. 25.9%; aOR 2.83, 95% CI 2.37-3.37), and mortality (32.2% vs. 17.8%; aOR 2.59, 95% CI 2.11-3.18), compared with CRP below the median. A dose response was observed between CRP concentration and adverse outcomes. While the associations between CRP and adverse outcomes were consistent among patients with low and high D-dimer levels, patients with high D-dimer and high CRP have the greatest risk of adverse outcomes.
Conclusions
Systemic inflammation, as measured by CRP, is strongly associated with VTE, AKI, critical illness, and mortality in COVID-19. CRP-based approaches to risk stratification and treatment should be tested.

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: 14 Jan 2021; epub ahead of print
Smilowitz NR, Kunichoff D, Garshick M, Shah B, ... Hochman JS, Berger JS
Eur Heart J: 14 Jan 2021; epub ahead of print | PMID: 33448289
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Impact:
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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Impact:
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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Impact:
Abstract

Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.

Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M

Listen to the audio abstract of this contribution at https://doi.org/10.1093/eurheartj/ehaa1058.
Aims
We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF).
Methods and results
Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%).
Conclusions
In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

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
Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M
Eur Heart J: 10 Jan 2021; epub ahead of print | PMID: 33428707
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Impact:
Abstract

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM
Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of \'reduced RVOT conduction reserve\'.

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: 08 Jan 2021; epub ahead of print
Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM
Eur Heart J: 08 Jan 2021; epub ahead of print | PMID: 33421051
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Impact:
Abstract

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Aims
In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction.
Methods and results
Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains.
Conclusion
Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

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

Eur Heart J: 08 Jan 2021; epub ahead of print
Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Eur Heart J: 08 Jan 2021; epub ahead of print | PMID: 33420498
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Impact:
Abstract

Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

Younis A, Goldberger JJ, Kutyifa V, Zareba W, ... Stein K, Goldenberg I
Aims
The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks.
Methods and results
The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability.
Conclusions
We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality.

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: 07 Jan 2021; epub ahead of print
Younis A, Goldberger JJ, Kutyifa V, Zareba W, ... Stein K, Goldenberg I
Eur Heart J: 07 Jan 2021; epub ahead of print | PMID: 33417692
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Impact:
Abstract

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, ... Mehta NN, Ridker PM
Aims
The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.
Methods and results
Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001).
Conclusion
The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.

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: 07 Jan 2021; epub ahead of print
Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, ... Mehta NN, Ridker PM
Eur Heart J: 07 Jan 2021; epub ahead of print | PMID: 33417682
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Impact:
Abstract

CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure.

Batkai S, Genschel C, Viereck J, Rump S, ... Gyöngyösi M, Thum T
Aims
Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI.
Methods and results
In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF.
Conclusion
Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure.

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

Eur Heart J: 06 Jan 2021; 42:192-201
Batkai S, Genschel C, Viereck J, Rump S, ... Gyöngyösi M, Thum T
Eur Heart J: 06 Jan 2021; 42:192-201 | PMID: 33089304
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Impact:
Abstract

Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.

Agarwal R, Kolkhof P, Bakris G, Bauersachs J, ... Wada T, Zannad F

This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.

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

Eur Heart J: 06 Jan 2021; 42:152-161
Agarwal R, Kolkhof P, Bakris G, Bauersachs J, ... Wada T, Zannad F
Eur Heart J: 06 Jan 2021; 42:152-161 | PMID: 33099609
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Impact:
Abstract

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

Verdonschot JAJ, Merlo M, Dominguez F, Wang P, ... Garcia-Pavia P, Heymans SRB
Aims
The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.
Methods and results
We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.
Conclusion
The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.

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

Eur Heart J: 06 Jan 2021; 42:162-174
Verdonschot JAJ, Merlo M, Dominguez F, Wang P, ... Garcia-Pavia P, Heymans SRB
Eur Heart J: 06 Jan 2021; 42:162-174 | PMID: 33156912
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Impact:
Abstract

Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study.

Täubel J, Hauke W, Rump S, Viereck J, ... Solomon SD, Thum T
Aims
Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405).
Methods and results
Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers.
Conclusion
This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF.

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

Eur Heart J: 06 Jan 2021; 42:178-188
Täubel J, Hauke W, Rump S, Viereck J, ... Solomon SD, Thum T
Eur Heart J: 06 Jan 2021; 42:178-188 | PMID: 33245749
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Impact:
Abstract

Lipoproteins in chronic kidney disease: from bench to bedside.

Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D
Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed \'uraemic dyslipidaemia\', which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.

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: 03 Jan 2021; epub ahead of print
Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D
Eur Heart J: 03 Jan 2021; epub ahead of print | PMID: 33393990
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Impact:
Abstract

Long-term cardiovascular disease mortality among 160 834 5-year survivors of adolescent and young adult cancer: an American population-based cohort study.

Wang L, Wang F, Chen L, Geng Y, Yu S, Chen Z
Aims 
Our aim was to assess the risk of cardiovascular disease (CVD) mortality in US 5-year survivors of adolescent and young adult (AYA) cancer compared with those of the general population and contemporaneous 5-year survivors of childhood cancer.
Methods and results 
A total of 160 834 5-year AYA cancer survivors (aged 15-39 years at diagnosis) were included, representing 2 239 390 person-years of follow-up. Overall, 2910 CVD deaths occurred, which was 1.4-fold [95% confidence interval (CI) 1.3-1.4] that expected in the general population, corresponding to 3.6 (95% CI 3.2-3.9) excess CVD deaths per 10 000 person-years. The highest risk of cardiac mortality was experienced after Hodgkin\'s lymphoma (HL), and the highest risk of cerebrovascular mortality was observed with central nervous system (CNS) tumours. Even survivors in their 6th and 7th decades of life, the risk of CVD mortality remained markedly higher than that of the matched general population. Competing risk analysis showed that the cumulative mortality of CVD was elevated among AYA cancer survivors compared with childhood cancer survivors during the whole study period.
Conclusion 
Long-term AYA cancer survivors have a greater risk of CVD mortality than the US general population and childhood cancer survivors. Vulnerable subgroups, especially survivors of HL and CNS tumours, require continued close follow-up care for cardiovascular conditions throughout survivorship.

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

Eur Heart J: 31 Dec 2020; 42:101-109
Wang L, Wang F, Chen L, Geng Y, Yu S, Chen Z
Eur Heart J: 31 Dec 2020; 42:101-109 | PMID: 33156911
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Impact:
Abstract

Ventricular arrhythmia burden during the coronavirus disease 2019 (COVID-19) pandemic.

O\'Shea CJ, Thomas G, Middeldorp ME, Harper C, ... Campbell K, Sanders P
Aims
Our objective was to determine the ventricular arrhythmia burden in implantable cardioverter-defibrillator (ICD) patients during COVID-19.
Methods and results
In this multicentre, observational, cohort study over a 100-day period during the COVID-19 pandemic in the USA, we assessed ventricular arrhythmias in ICD patients from 20 centres in 13 states, via remote monitoring. Comparison was via a 100-day control period (late 2019) and seasonal control period (early 2019). The primary outcome was the impact of COVID-19 on ventricular arrhythmia burden. The secondary outcome was correlation with COVID-19 incidence. During the COVID-19 period, 5963 ICD patients underwent remote monitoring, with 16 942 episodes of treated ventricular arrhythmias (2.8 events per 100 patient-days). Ventricular arrhythmia burden progressively declined during COVID-19 (P < 0.001). The proportion of patients with ventricular arrhythmias amongst the high COVID-19 incidence states was significantly reduced compared with those in low incidence states [odds ratio 0.61, 95% confidence interval (CI) 0.54-0.69, P < 0.001]. Comparing patients remotely monitored during both COVID-19 and control periods (n = 2458), significantly fewer ventricular arrhythmias occurred during COVID-19 [incident rate ratio (IRR) 0.68, 95% CI 0.58-0.79, P < 0.001]. This difference persisted when comparing the 1719 patients monitored during both the COVID-19 and seasonal control periods (IRR 0.69, 95% CI 0.56-0.85, P < 0.001).
Conclusions
During COVID-19, there was a 32% reduction in ventricular arrhythmias needing device therapies, coinciding with measures of social isolation. There was a 39% reduction in the proportion of patients with ventricular arrhythmias in states with higher COVID-19 incidence. These findings highlight the potential role of real-life stressors in ventricular arrhythmia burden in individuals with ICDs.
Trial registration
Australian New Zealand Clinical Trial Registry; URL: https://www.anzctr.org.au/; Unique Identifier: ACTRN12620000641998.

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

Eur Heart J: 31 Dec 2020; 42:520-528
O'Shea CJ, Thomas G, Middeldorp ME, Harper C, ... Campbell K, Sanders P
Eur Heart J: 31 Dec 2020; 42:520-528 | PMID: 33321517
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Impact:
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

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

Wang Q, Oliver-Williams C, Raitakari OT, Viikari J, ... Holmes MV, Ala-Korpela M
Aims 
Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.
Methods and results 
Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.
Conclusions 
Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

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

Eur Heart J: 21 Dec 2020; epub ahead of print
Wang Q, Oliver-Williams C, Raitakari OT, Viikari J, ... Holmes MV, Ala-Korpela M
Eur Heart J: 21 Dec 2020; epub ahead of print | PMID: 33351885
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Abstract

Sodium intake, life expectancy, and all-cause mortality.

Messerli FH, Hofstetter L, Syrogiannouli L, Rexhaj E, ... Seiler C, Bangalore S
Aims 
Since dietary sodium intake has been identified as a risk factor for cardiovascular disease and premature death, a high sodium intake can be expected to curtail life span. We tested this hypothesis by analysing the relationship between sodium intake and life expectancy as well as survival in 181 countries worldwide.
Methods and results 
We correlated age-standardized estimates of country-specific average sodium consumption with healthy life expectancy at birth and at age of 60 years, death due to non-communicable diseases and all-cause mortality for the year of 2010, after adjusting for potential confounders such as gross domestic product per capita and body mass index. We considered global health estimates as provided by World Health Organization. Among the 181 countries included in this analysis, we found a positive correlation between sodium intake and healthy life expectancy at birth (β = 2.6 years/g of daily sodium intake, R2 = 0.66, P < 0.001), as well as healthy life expectancy at age 60 (β = 0.3 years/g of daily sodium intake, R2 = 0.60, P = 0.048) but not for death due to non-communicable diseases (β = 17 events/g of daily sodium intake, R2 = 0.43, P = 0.100). Conversely, all-cause mortality correlated inversely with sodium intake (β = -131 events/g of daily sodium intake, R2 = 0.60, P < 0.001). In a sensitivity analysis restricted to 46 countries in the highest income class, sodium intake continued to correlate positively with healthy life expectancy at birth (β = 3.4 years/g of daily sodium intake, R2 = 0.53, P < 0.001) and inversely with all-cause mortality (β = -168 events/g of daily sodium intake, R2 = 0.50, P < 0.001).
Conclusion 
Our observation of sodium intake correlating positively with life expectancy and inversely with all-cause mortality worldwide and in high-income countries argues against dietary sodium intake being a culprit of curtailing life span or a risk factor for premature death. These data are observational and should not be used as a base for nutritional interventions.

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: 21 Dec 2020; epub ahead of print
Messerli FH, Hofstetter L, Syrogiannouli L, Rexhaj E, ... Seiler C, Bangalore S
Eur Heart J: 21 Dec 2020; epub ahead of print | PMID: 33351135
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Abstract

Nomenclature for kidney function and disease-executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference.

Levey AS, Eckardt KU, Dorman NM, Christiansen SL, ... Jadoul M, Winkelmayer WC

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a consensus conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used by journals in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centred, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use \'kidney\' rather than \'renal\' or \'nephro\' when referring to kidney disease and kidney function; (ii) to use \'kidney failure\' with appropriate descriptions of the presence or absence of symptoms, signs, and treatment rather than \'end-stage\' kidney disease; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI) rather than alternative descriptions to define and classify the severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify the severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate, rather than \'abnormal or reduced kidney function\' to describe alterations in kidney structure and function. A proposed five-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary but considered that standardizing scientific nomenclature is essential for improving communication.

© KDIGO 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 20 Dec 2020; 41:4592-4598
Levey AS, Eckardt KU, Dorman NM, Christiansen SL, ... Jadoul M, Winkelmayer WC
Eur Heart J: 20 Dec 2020; 41:4592-4598 | PMID: 33141221
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Abstract

Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.

Kyaw T, Loveland P, Kanellakis P, Cao A, ... Toh BH, Bobik A
Aims 
Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI.
Methods and results 
We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis.
Conclusion 
Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

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: 17 Dec 2020; epub ahead of print
Kyaw T, Loveland P, Kanellakis P, Cao A, ... Toh BH, Bobik A
Eur Heart J: 17 Dec 2020; epub ahead of print | PMID: 33338208
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Abstract

High-sugar feeding and increasing cholesterol levels in infants.

Zubin Maslov P, Hill JA, Lüscher TF, Narula J
Hypercholesterolaemia is an important risk factor for cardiovascular disease. Both total and LDL cholesterol levels are three-fold higher at the end of the first year of life and about four-fold higher in adulthood compared with the neonatal period. In the USA, only 25% of infants are exclusively breastfed and simple carbohydrate-rich formulas are preferentially consumed. Spikes in fasting glucose and insulin have been reported in formula-fed infants and are associated with higher levels of proprotein convertase subtilisin/kexin type 9, suggesting a potential link between high simple sugar intake and consequent increase in LDL cholesterol in early childhood.

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: 15 Dec 2020; epub ahead of print
Zubin Maslov P, Hill JA, Lüscher TF, Narula J
Eur Heart J: 15 Dec 2020; epub ahead of print | PMID: 33326580
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Abstract

Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study.

Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Aims
Accumulating evidence shows that atrial fibrillation (AF) is associated with an increased risk of dementia. Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving the quality of life. We investigated the association of catheter ablation for AF with the occurrence of dementia.
Methods and results
Using the Korean National Health Insurance Service database, among 194 928 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, we studied 9119 patients undergoing ablation and 17 978 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score-matching was used to correct for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed lower incidence and risk of overall dementia (8.1 and 5.6 per 1000 person-years, respectively; hazard ratio 0.73, 95% confidence interval 0.58-0.93). The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (hazard ratio 0.76, 95% confidence interval 0.61-0.95) and more pronounced in cases of ablation success whereas no significant differences observed in cases of ablation failure. Ablation was associated with lower risks of dementia subtypes including Alzheimer\'s disease and vascular dementia.
Conclusion
In this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders.

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: 13 Dec 2020; 41:4483-4493
Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Eur Heart J: 13 Dec 2020; 41:4483-4493 | PMID: 33022705
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Abstract

Vegetarians, fish, poultry, and meat-eaters: who has higher risk of cardiovascular disease incidence and mortality? A prospective study from UK Biobank.

Petermann-Rocha F, Parra-Soto S, Gray S, Anderson J, ... Celis-Morales C, Pell JP
Aims 
To compare the incidence and mortality risk for cardiovascular diseases (CVD) [CVD and also ischaemic heart disease (IHD), myocardial infarction (MI), stroke, and heart failure (HF)] among people with different types of diets-including vegetarians, fish eaters, fish and poultry eaters, and meat-eaters-using data from UK Biobank.
Methods and results 
A total of 422 791 participants (55.4% women) were included in this prospective analysis. Using data from a food frequency questionnaire, four types of diets were derived. Associations between types of diets and health outcomes were investigated using Cox proportional hazard models. Meat-eaters comprised 94.7% of the cohort and were more likely to be obese than other diet groups. After a median follow-up of 8.5 years, fish eaters, compared with meat-eaters, had lower risks of incident CVD {hazard ratios (HR): 0.93 [95% confidence intervals (CI): 0.88-0.97]}, IHD [HR: 0.79 (95% CI: 0.70-0.88)], MI [HR: 0.70 (95% CI: 0.56-0.88)], stroke [HR: 0.79 (95% CI: 0.63-0.98)] and HF [HR: 0.78 (95% CI: 0.63-0.97)], after adjusting for confounders. Vegetarians had lower risk of CVD incidence [HR: 0.91 (95% CI: 0.86-0.96)] relative to meat-eaters. In contrast, the risk of adverse outcomes was not different in fish and poultry eaters compared with meat-eaters. No associations were identified between types of diets and CVD mortality.
Conclusion 
Eating fish rather than meat or poultry was associated with a lower risk of a range of adverse cardiovascular outcomes. Vegetarianism was only associated with a lower risk of CVD incidence.

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: 13 Dec 2020; epub ahead of print
Petermann-Rocha F, Parra-Soto S, Gray S, Anderson J, ... Celis-Morales C, Pell JP
Eur Heart J: 13 Dec 2020; epub ahead of print | PMID: 33313747
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Abstract

Coronavirus disease 2019 in adults with congenital heart disease: a position paper from the ESC working group of adult congenital heart disease, and the International Society for Adult Congenital Heart Disease.

Diller GP, Gatzoulis MA, Broberg CS, Aboulhosn J, ... Kovacs AH, Roos-Hesselink J
We are witnessing an unparalleled pandemic caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) associated with coronavirus disease 2019 (COVID-19). Current data show that SARS-CoV-2 results in mild flu-like symptoms in the majority of healthy and young patients affected. Nevertheless, the severity of COVID-19 respiratory syndrome and the risk of adverse or catastrophic outcomes are increased in patients with pre-existing cardiovascular disease. Patients with adult congenital heart disease (ACHD)-by definition-have underlying cardiovascular disease. Many patients with ACHD are also afflicted with residual haemodynamic lesions such as valve dysfunction, diminished ventricular function, arrhythmias or cyanosis, have extracardiac comorbidities, and face additional challenges regarding pregnancy. Currently, there are emerging data of the effect of COVID-19 on ACHD patients, but many aspects, especially risk stratification and treatment considerations, remain unclear. In this article, we aim to discuss the broad impact of COVID-19 on ACHD patients, focusing specifically on pathophysiology, risk stratification for work, self-isolation, hospitalization, impact on pregnancy, psychosocial health, and longer-term implications for the provision of ACHD care.

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: 11 Dec 2020; epub ahead of print
Diller GP, Gatzoulis MA, Broberg CS, Aboulhosn J, ... Kovacs AH, Roos-Hesselink J
Eur Heart J: 11 Dec 2020; epub ahead of print | PMID: 33313664
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Abstract

The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study.

D\'Souza M, Nielsen D, Svane IM, Iversen K, ... Torp-Pedersen C, Schou M
Aims
The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma.
Methods and results
The study included consecutive patients with lung cancer or malignant melanoma in 2011-17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8-12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8-11.3) and 7.5% (3.7-11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50-3.05) in patients with lung cancer and 4.30 (1.38-13.42) and 4.93 (2.45-9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27-4.02) for patients with lung cancer and 3.48 (1.91-6.35) for patients with malignant melanoma and CTLA-4i.
Conclusions
Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).

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: 08 Dec 2020; epub ahead of print
D'Souza M, Nielsen D, Svane IM, Iversen K, ... Torp-Pedersen C, Schou M
Eur Heart J: 08 Dec 2020; epub ahead of print | PMID: 33291147
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Abstract

Metoprolol exerts a non-class effect against ischaemia-reperfusion injury by abrogating exacerbated inflammation.

Clemente-Moragón A, Gómez M, Villena-Gutiérrez R, Lalama DV, ... Oliver E, Ibáñez B
Aims
Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous β-blockers.
Methods and results
Mice undergoing 45 min/24 h ischaemia-reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of β-blockers on the conformation of the β1 adrenergic receptor was studied in silico. Of the tested β-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular β1 adrenergic receptor conformational changes when bound to metoprolol than to the other two β-blockers.
Conclusions
Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of β-blockers may be related to distinct conformational changes in the β1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous β-blocker of choice for patients with ongoing infarction.

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

Eur Heart J: 06 Dec 2020; 41:4425-4440
Clemente-Moragón A, Gómez M, Villena-Gutiérrez R, Lalama DV, ... Oliver E, Ibáñez B
Eur Heart J: 06 Dec 2020; 41:4425-4440 | PMID: 33026079
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Abstract

Association of β-blocker use with survival and pulmonary function in patients with chronic obstructive pulmonary and cardiovascular disease: a systematic review and meta-analysis.

Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL
Aims
The aim of this study was to clarify the effect of β-blockers (BBs) on respiratory function and survival in patients with chronic obstructive pulmonary disease with cardiovascular disease (CVD), as well as the difference between the effects of cardioselective and noncardioselective BBs.
Methods and results
We searched for relevant literature in four electronic databases, namely, PubMed, EMBASE, Cochrane Library, and Web of Science, and compared the differences in various survival indicators between patients with chronic obstructive pulmonary disease taking BBs and those not taking BBs. Forty-nine studies were included, with a total sample size of 670 594. Among these, 12 studies were randomized controlled trials (RCTs; seven crossover and five parallel RCTs) and 37 studies were observational (including four post hoc analyses of data from RCTs). The hazard ratios (HRs) of chronic obstructive pulmonary disease exacerbation between patients with chronic obstructive pulmonary disease who were not treated with BBs and those who were treated with BBs, cardioselective BBs, and noncardioselective BBs were 0.77 [95% confidence interval (CI) 0.67, 0.89], 0.72 [95% CI 0.56, 0.94], and 0.98 [95% CI 0.71, 1.34, respectively] (HRs <1 indicate favouring BB therapy). The HRs of all-cause mortality between patients with chronic obstructive pulmonary disease who were not treated with BBs and those who were treated with BBs, cardioselective BBs, and noncardioselective BBs were 0.70 [95% CI 0.59, 0.83], 0.60 [95% CI 0.48, 0.76], and 0.74 [95% CI 0.60, 0.90], respectively (HRs <1 indicate favouring BB therapy). Patients with Chronic obstructive pulmonary disease treated with cardioselective BBs showed no difference in ventilation effect after the use of an agonist, in comparison with placebo. The difference in mean change in forced expiratory volume in 1 s was 0.06 [95% CI -0.02, 0.14].
Conclusion
The use of BBs in patients with chronic obstructive pulmonary disease is not only safe but also reduces their all-cause and in-hospital mortality. Cardioselective BBs may even reduce chronic obstructive pulmonary disease exacerbations. In addition, cardioselective BBs do not affect the action of bronchodilators. Importantly, BBs reduce the heart rate acceleration caused by bronchodilators. BBs should be prescribed freely when indicated in patients with chronic obstructive pulmonary disease and heart disease.

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

Eur Heart J: 06 Dec 2020; 41:4415-4422
Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL
Eur Heart J: 06 Dec 2020; 41:4415-4422 | PMID: 33211823
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Abstract

The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.

Li L, Fu W, Gong X, Chen Z, ... Wang WE, Zeng C
Aims
G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI.
Methods and results
We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers.
Conclusion
GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

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: 05 Dec 2020; epub ahead of print
Li L, Fu W, Gong X, Chen Z, ... Wang WE, Zeng C
Eur Heart J: 05 Dec 2020; epub ahead of print | PMID: 33280021
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This program is still in alpha version.