Journal: Eur Heart J

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Abstract

Inflammation drives residual risk in chronic kidney disease: a CANTOS substudy.

Ridker PM, Tuttle KR, Perkovic V, Libby P, MacFadyen JG
Aims
Hyperlipidaemia and inflammation jointly contribute to atherosclerotic disease. Yet, after the initiation of statin therapy, the relative contributions of these processes may differ in patient groups, such as those with and without impaired kidney function.
Methods and results
Among 9151 stable statin-treated post-myocardial infarction patients participating in the CANTOS trial, the contributions of residual cholesterol risk and residual inflammatory risk were evaluated as determinants of recurrent major adverse cardiovascular events (MACE) and total mortality, stratified by baseline estimated glomerular filtration rate (eGFR) above or below 60 mL/min/1.73 m2 using the race agnostic CKD-EPI 2021 formula (all participants had eGFR > 30 mL/min/1.73 m2). Analyses of residual inflammatory risk focused on high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) while analyses of residual cholesterol risk focused on LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C). Participants were followed for a period of up to 5 years (median 3.7 years). Median baseline levels of LDL-C and hsCRP were 81 mg/dL and 4.2 mg/L. Among participants with eGFR ≥ 60 mL/min/1.73 m2, increasing quartiles of plasma hsCRP, IL-6, LDL-C, and non-HDL-C all positively associated with risks of recurrent MACE [hazard ratios (HR) comparing the top to bottom quartile for hsCRP 1.45; for IL-6 2.48; for LDL-C 1.64; and for non-HDL-C 1.68] (all P < 0.0001). By contrast, among those with eGFR < 60 mL/min/1.73 m2, increasing quartiles of hsCRP and IL-6 significantly predicted recurrent MACE [HR comparing the top to bottom quartile for hsCRP 1.50 (P = 0.021); for IL-6 1.84 (P = 0.048)], whereas increasing quartiles of LDL-C and non-HDL-C did not [HR comparing the top to bottom quartile for LDL-C 1.04 (P = 0.80); for non-HDL-C 0.98 (P = 0.88)]. The predictive utility of hsCRP and IL-6 in the setting of eGFR < 60 mL/min/1.73 m2 remained significant after adjustment for a wide range of potential confounding factors including age, sex, smoking status, blood pressure, body mass index, and diabetes. For the endpoint of total mortality, both hsCRP (HR 1.77, P = 0.0021) and IL-6 (HR 2.15, P = 0.015) were significant predictors among those with eGFR < 60 mL/min/1.73 m2, whereas LDL-C (HR 0.91, P = 0.56) and non-HDL-C (HR 0.85, P = 0.31) were not. Similar effects were observed in analyses stratified by the albumin to creatinine ratio rather than eGFR.
Conclusion
Among atherosclerosis patients with impaired kidney function already aggressively treated with statin therapy, residual inflammatory risk plays a substantial role in determining the risk of recurrent cardiovascular events. These data have implications for risk stratification of individuals with chronic kidney disease and for the development of novel agents that target inflammatory processes in this high-risk group of patients.
Clinical trial registration
ClinicalTrials.gov: NCT01327846.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 09 Aug 2022; epub ahead of print
Ridker PM, Tuttle KR, Perkovic V, Libby P, MacFadyen JG
Eur Heart J: 09 Aug 2022; epub ahead of print | PMID: 35943897
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Abstract

Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

Chi C, Fu H, Li YH, Zhang GY, ... Li DJ, Wang P
Aims
Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored.
Methods and results
FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study.
Conclusion
FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 04 Aug 2022; epub ahead of print
Chi C, Fu H, Li YH, Zhang GY, ... Li DJ, Wang P
Eur Heart J: 04 Aug 2022; epub ahead of print | PMID: 35929617
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Abstract

Trends in survival after cardiac arrest: a Swedish nationwide study over 30 years.

Jerkeman M, Sultanian P, Lundgren P, Nielsen N, ... Herlitz J, Rawshani A
Aims
Trends in characteristics, management, and survival in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) were studied in the Swedish Cardiopulmonary Resuscitation Registry (SCRR).
Methods and results
The SCRR was used to study 106 296 cases of OHCA (1990-2020) and 30 032 cases of IHCA (2004-20) in whom resuscitation was attempted. In OHCA, survival increased from 5.7% in 1990 to 10.1% in 2011 and remained unchanged thereafter. Odds ratios [ORs, 95% confidence interval (CI)] for survival in 2017-20 vs. 1990-93 were 2.17 (1.93-2.43) overall, 2.36 (2.07-2.71) for men, and 1.67 (1.34-2.10) for women. Survival increased for all aetiologies, except trauma, suffocation, and drowning. OR for cardiac aetiology in 2017-20 vs. 1990-93 was 0.45 (0.42-0.48). Bystander cardiopulmonary resuscitation increased from 30.9% to 82.2%. Shockable rhythm decreased from 39.5% in 1990 to 17.4% in 2020. Use of targeted temperature management decreased from 42.1% (2010) to 18.2% (2020). In IHCA, OR for survival in 2017-20 vs. 2004-07 was 1.18 (1.06-1.31), showing a non-linear trend with probability of survival increasing by 46.6% during 2011-20. Myocardial ischaemia or infarction as aetiology decreased during 2004-20 from 67.4% to 28.3% [OR 0.30 (0.27-0.34)]. Shockable rhythm decreased from 37.4% to 23.0% [OR 0.57 (0.51-0.64)]. Approximately 90% of survivors (IHCA and OHCA) had no or mild neurological sequelae.
Conclusion
Survival increased 2.2-fold in OHCA during 1990-2020 but without any improvement in the final decade, and 1.2-fold in IHCA during 2004-20, with rapid improvement the last decade. Cardiac aetiology and shockable rhythms were halved. Neurological outcome has not improved.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 04 Aug 2022; epub ahead of print
Jerkeman M, Sultanian P, Lundgren P, Nielsen N, ... Herlitz J, Rawshani A
Eur Heart J: 04 Aug 2022; epub ahead of print | PMID: 35924401
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Abstract

Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial.

Dachs TM, Duca F, Rettl R, Binder-Rodriguez C, ... Kastner J, Bonderman D
Aims
The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF.
Methods and results
The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred.
Conclusion
The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 01 Aug 2022; epub ahead of print
Dachs TM, Duca F, Rettl R, Binder-Rodriguez C, ... Kastner J, Bonderman D
Eur Heart J: 01 Aug 2022; epub ahead of print | PMID: 35909264
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Abstract

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

Butler J, Anker SD, Lund LH, Coats AJS, ... Weir MR, Pitt B
Aims
To investigate the impact of patiromer on serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF).
Methods and results
A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of RAASi therapy (≥50% recommended dose of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist [MRA] spironolactone or eplerenone). Specified target doses of RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13, 43) weeks, the adjusted mean change in potassium was +0.03 mmol/L in the patiromer group and +0.13 mmol/L in the placebo group (difference in adjusted mean change between patiromer and placebo: -0.10 [95% confidence interval, CI -0.13, -0.07] mmol/L, P<0.001). Risk of hyperkalemia >5.5 mmol/L (hazard ratio [HR] 0.63; 95% CI 0.45, 0.87; P=0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P=0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P<0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P<0.001) and total RAASi use score (win ratio 1.25, P=0.048) favored the patiromer arm. Adverse events were similar between groups.
Conclusion
Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 28 Jul 2022; epub ahead of print
Butler J, Anker SD, Lund LH, Coats AJS, ... Weir MR, Pitt B
Eur Heart J: 28 Jul 2022; epub ahead of print | PMID: 35900838
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Abstract

Hypertension in children and adolescents.

de Simone G, Mancusi C, Hanssen H, Genovesi S, ... Weismann CG, Williams B
Definition and management of arterial hypertension in children and adolescents are uncertain, due to different positions of current guidelines. The European Society of Cardiology task-force, constituted by Associations and Councils with interest in arterial hypertension, has reviewed current literature and evidence, to produce a Consensus Document focused on aspects of hypertension in the age range of 6-16 years, including definition, methods of measurement of blood pressure, clinical evaluation, assessment of hypertension-mediated target organ damage, evaluation of possible vascular, renal and hormonal causes, assessment and management of concomitant risk factors with specific attention for obesity, and anti-hypertensive strategies, especially focused on life-style modifications. The Consensus Panel also suggests aspects that should be studied with high priority, including generation of multi-ethnic sex, age and height specific European normative tables, implementation of randomized clinical trials on different diagnostic and therapeutic aspects, and long-term cohort studies to link with adult cardiovascular risk. Finally, suggestions for the successful implementation of the contents of the present Consensus document are also given.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 27 Jul 2022; epub ahead of print
de Simone G, Mancusi C, Hanssen H, Genovesi S, ... Weismann CG, Williams B
Eur Heart J: 27 Jul 2022; epub ahead of print | PMID: 35896123
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Abstract

Phenotyping the hypertensive heart.

Tadic M, Cuspidi C, Marwick TH
Arterial hypertension remains the most frequent cardiovascular (CV) risk factor, and is responsible for a huge global burden of disease. Echocardiography is the first-line imaging method for the evaluation of cardiac damage in hypertensive patients and novel techniques, such as 2D and D speckle tracking and myocardial work, provide insight in subclinical left ventricular (LV) impairment that would not be possible to detect with conventional echocardiography. The structural, functional, and mechanical cardiac remodelling that are detected with imaging are intermediate stages in the genesis of CV events, and initiation or intensification of antihypertensive therapy in response to these findings may prevent or delay progressive remodelling and CV events. However, LV remodelling-especially LV hypertrophy-is not specific to hypertensive heart disease (HHD) and there are circumstances when other causes of hypertrophy such as athlete heart, aortic stenosis, or different cardiomyopathies need exclusion. Tissue characterization obtained by LV strain, cardiac magnetic resonance, or computed tomography might significantly help in the distinction of different LV phenotypes, as well as being sensitive to subclinical disease. Selective use of multimodality imaging may therefore improve the detection of HHD and guide treatment to avoid disease progression. The current review summarizes the advanced imaging tests that provide morphological and functional data about the hypertensive cardiac injury.

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Eur Heart J: 23 Jul 2022; epub ahead of print
Tadic M, Cuspidi C, Marwick TH
Eur Heart J: 23 Jul 2022; epub ahead of print | PMID: 35869979
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Abstract

Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification.

Kaiser Y, van der Toorn JE, Singh SS, Zheng KH, ... Boekholdt SM, Bos D
Aim
Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression.
Methods and results
A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9-14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2-37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15-1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02-1.65), but not with AVC progression (β: -71 AU for each 50 mg/dL higher Lp(a); 95% CI -117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001).
Conclusion
In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.

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Eur Heart J: 23 Jul 2022; epub ahead of print
Kaiser Y, van der Toorn JE, Singh SS, Zheng KH, ... Boekholdt SM, Bos D
Eur Heart J: 23 Jul 2022; epub ahead of print | PMID: 35869873
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Abstract

Effects of a comprehensive lifestyle intervention on cardiovascular health: the TANSNIP-PESA trial.

Garcia-Lunar I, van der Ploeg HP, Fernández Alvira JM, van Nassau F, ... van Mechelen W, Fuster V
Aims
To investigate the effectiveness of a 3-year worksite lifestyle intervention on cardiovascular metrics and to study whether outcomes are influenced by baseline subclinical atherosclerosis (SA) by non-invasive imaging.
Methods and results
A randomized controlled trial was performed to compare a lifestyle intervention with standard of care in asymptomatic middle-aged subjects, stratified by SA. The intervention consisted of nine motivational interviews during the first year, followed by three further sessions between Years 1 and 3. The primary outcome was the change in a pre-specified adaptation of the Fuster-BEWAT score (Blood pressure, Exercise, Weight, Alimentation, and Tobacco) between baseline and follow-up Years 1-3. A total of 1020 participants (mean age 50 ± 4 years) were enrolled, of whom 510 were randomly assigned to the intervention and 510 to the control group. The baseline adapted Fuster-BEWAT score was 16.2 ± 3.7 points in the intervention group and 16.5 ± 3.5 points in the control group. At Year 1, the score improved significantly in intervention participants compared with controls [estimate 0.83 (95% CI 0.52-1.15) points]. However, intervention effectiveness decreased to non-significant levels at Year 3 [0.24 (95% CI -0.10 to 0.59) points]. Over the 3-year period, the intervention was effective in participants having low baseline SA [0.61 (95% CI 0.30-0.93) points] but not in those with high baseline SA [0.19 (95% CI -0.26 to 0.64) points].
Conclusion
In middle-aged asymptomatic adults, a lifestyle intervention was associated with a significant improvement in cardiovascular health and behavioural metrics. The effect attenuated after 1 year as the intensity of the intervention was reduced.
Trial registration
ClinicalTrials.gov (NCT02561065).

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 23 Jul 2022; epub ahead of print
Garcia-Lunar I, van der Ploeg HP, Fernández Alvira JM, van Nassau F, ... van Mechelen W, Fuster V
Eur Heart J: 23 Jul 2022; epub ahead of print | PMID: 35869885
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Abstract

Sex-specific associations between potassium intake, blood pressure, and cardiovascular outcomes: the EPIC-Norfolk study.

Wouda RD, Boekholdt SM, Khaw KT, Wareham NJ, ... Rotmans JI, Vogt L
Aims
A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown.
Methods and results
An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex].
Conclusion
The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 21 Jul 2022; epub ahead of print
Wouda RD, Boekholdt SM, Khaw KT, Wareham NJ, ... Rotmans JI, Vogt L
Eur Heart J: 21 Jul 2022; epub ahead of print | PMID: 35863377
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Abstract

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

Tardif JC, Pfeffer MA, Kouz S, Koenig W, ... Dubé MP, dal-GenE Investigators
Aims
In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis.
Methods and results
dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98).
Conclusion
Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype.
Clinical trial registration
Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 20 Jul 2022; epub ahead of print
Tardif JC, Pfeffer MA, Kouz S, Koenig W, ... Dubé MP, dal-GenE Investigators
Eur Heart J: 20 Jul 2022; epub ahead of print | PMID: 35856777
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Abstract

Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial.

Chimenti C, Russo MA, Frustaci A
Aims
Long-term results of the Tailored IMmunosuppression in virus-negative Inflammatory Cardiomyopathy (TIMIC) trial protocol have been evaluated.
Methods and results
Eighty-five patients with endomyocardial biopsy-proven virus-negative chronic inflammatory cardiomyopathy were enrolled in the randomized, double-blind, placebo-controlled TIMIC trial and received prednisone and azathioprine (n = 43) vs. placebo (n = 42) for 6 months. Immunosuppressive treatment promoted an improvement in cardiac function in 88% of the cases compared with none of the patients in the placebo group, which were switched to a 6-month immunosuppressive therapy at the end of the 6-month study period. Long-term (up to 20 years) clinical outcomes of the whole cohort of 85 patients originally enrolled in the TIMIC trial (Group A) were compared with those of a 1:2 propensity score-matched control cohort of patients untreated with the TIMIC protocol (Group B) and followed for a comparable period of time. The primary outcome was a composite of cardiovascular death and heart transplantation. At long-term follow-up, the risk of cardiovascular death [hazard ratio (HR) 6.77; 95% confidence interval (CI) 2.36-19.45] and heart transplantation (HR 7.92; 95% CI 1.80-34.88) was significantly higher in Group B patients. Group A showed a persistent improvement in the left ventricular ejection fraction compared with Group B (HR 7.24; 95% CI 3.05-17.18). A higher number of Group B patients underwent implantable cardioverter defibrillator implantation. The incidence of recurrent myocarditis was similar between groups, and patients with evidence of a recurrent cardiac inflammatory process promptly responded to a TIMIC protocol application.
Conclusion
Virus-negative inflammatory cardiomyopathy benefits from immunosuppressive therapy even after long-term follow-up. Recurrence appears to respond to a new TIMIC protocol application.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 14 Jul 2022; epub ahead of print
Chimenti C, Russo MA, Frustaci A
Eur Heart J: 14 Jul 2022; epub ahead of print | PMID: 35831932
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Abstract

From supravalvular to valvular aortic stenosis: are statins contributing to the phenotypic shift in homozygous familial hypercholesterolaemia?

Bajaj A, Cuchel M
Graphical Abstract LLT, lipid lowering therapies; Lp(a), lipoprotein(a); VAS, valvular aortic stenosis; SVAS, supravalvular aortic stenosis.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 13 Jul 2022; epub ahead of print
Bajaj A, Cuchel M
Eur Heart J: 13 Jul 2022; epub ahead of print | PMID: 35822615
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Abstract

TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias.

Vandewiele F, Pironet A, Jacobs G, Kecskés M, ... Voets T, Vennekens R
Aims
Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear.
Methods and results
In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4-/- mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4-/- mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner.
Conclusion
The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 13 Jul 2022; epub ahead of print
Vandewiele F, Pironet A, Jacobs G, Kecskés M, ... Voets T, Vennekens R
Eur Heart J: 13 Jul 2022; epub ahead of print | PMID: 35822895
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Impact:
Abstract

Adding salt to foods and hazard of premature mortality.

Ma H, Xue Q, Wang X, Li X, ... Manson JE, Qi L
Aims
We analyzed whether the frequency of adding salt to foods was associated with the hazard of premature mortality and life expectancy.
Methods and results
A total of 501 379 participants from UK biobank who completed the questionnaire on the frequency of adding salt to foods at baseline. The information on the frequency of adding salt to foods (do not include salt used in cooking) was collected through a touch-screen questionnaire at baseline. We found graded relationships between higher frequency of adding salt to foods and higher concentrations of spot urinary sodium or estimated 24-h sodium excretion. During a median of 9.0 years of follow-up, 18 474 premature deaths were documented. The multivariable hazard ratios [95% confidence interval (CI)] of all-cause premature mortality across the increasing frequency of adding salt to foods were 1.00 (reference), 1.02 (0.99, 1.06), 1.07 (1.02, 1.11), and 1.28 (1.20, 1.35) (P-trend < 0.001). We found that intakes of fruits and vegetables significantly modified the associations between the frequency of adding salt to foods and all-cause premature mortality, which were more pronounced in participants with low intakes than those with high intakes of these foods (P-interaction = 0.02). In addition, compared with the never/rarely group, always adding salt to foods was related to 1.50 (95% CI, 0.72-2.30) and 2.28 (95% CI, 1.66-2.90) years lower life expectancy at the age of 50 years in women and men, respectively.
Conclusions
Our findings indicate that higher frequency of adding salt to foods is associated with a higher hazard of all-cause premature mortality and lower life expectancy.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 10 Jul 2022; epub ahead of print
Ma H, Xue Q, Wang X, Li X, ... Manson JE, Qi L
Eur Heart J: 10 Jul 2022; epub ahead of print | PMID: 35808995
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Abstract

Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications.

Omote K, Sorimachi H, Obokata M, Reddy YNV, ... Redfield MM, Borlaug BA
Aims
Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD.
Methods and results
Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV-PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch.
Conclusions
Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV-PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 07 Jul 2022; epub ahead of print
Omote K, Sorimachi H, Obokata M, Reddy YNV, ... Redfield MM, Borlaug BA
Eur Heart J: 07 Jul 2022; epub ahead of print | PMID: 35796488
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Impact:
Abstract

Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial.

Doehner W, Anker SD, Butler J, Zannad F, ... Januzzi JL, Packer M
Background
The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA.
Methods
The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA.
Results
Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28-2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35-2.91); all-cause mortality, HR 1.8 (95% CI 1.29-2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: -1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52-0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65-0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69-0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively).
Conclusion
Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 05 Jul 2022; epub ahead of print
Doehner W, Anker SD, Butler J, Zannad F, ... Januzzi JL, Packer M
Eur Heart J: 05 Jul 2022; epub ahead of print | PMID: 35788657
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Impact:
Abstract

Risk stratification of patients with cardiac sarcoidosis: the ILLUMINATE-CS registry.

Nabeta T, Kitai T, Naruse Y, Taniguchi T, ... Matsumoto S, Matsue Y
Aims
This study evaluated the prognosis and prognostic factors of patients with cardiac sarcoidosis (CS), an underdiagnosed disease.
Methods and results
Patients from a retrospective multicentre registry, diagnosed with CS between 2001 and 2017 based on the 2016 Japanese Circulation Society or 2014 Heart Rhythm Society criteria, were included. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, and documented fatal ventricular arrhythmia events (FVAE), each constituting exploratory endpoints. Among 512 registered patients, 148 combined events (56 heart failure hospitalizations, 99 documented FVAE, and 49 all-cause deaths) were observed during a median follow-up of 1042 (interquartile range: 518-1917) days. The 10-year estimated event rates for the primary endpoint, all-cause death, heart failure hospitalizations, and FVAE were 48.1, 18.0, 21.1, and 31.9%, respectively. On multivariable Cox regression, a history of ventricular tachycardia (VT) or fibrillation [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.59-4.00, P < 0.001], log-transformed brain natriuretic peptide (BNP) levels (HR 1.28, 95% CI 1.07-1.53, P = 0.008), left ventricular ejection fraction (LVEF) (HR 0.94 per 5% increase, 95% CI 0.88-1.00, P = 0.046), and post-diagnosis radiofrequency ablation for VT (HR 2.65, 95% CI 1.02-6.86, P = 0.045) independently predicted the primary endpoint.
Conclusion
Although mortality is relatively low in CS, adverse events are common, mainly due to FVAE. Patients with low LVEF, with high BNP levels, with VT/fibrillation history, and requiring ablation to treat VT are at high risk.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 04 Jul 2022; epub ahead of print
Nabeta T, Kitai T, Naruse Y, Taniguchi T, ... Matsumoto S, Matsue Y
Eur Heart J: 04 Jul 2022; epub ahead of print | PMID: 35781334
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Impact:
Abstract

Aortic stenosis in homozygous familial hypercholesterolaemia: a paradigm shift over a century.

Bélanger AM, Akioyamen LE, Ruel I, Hales L, Genest J
Aims
Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565).
Methods and results
MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted.
Conclusion
These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 01 Jul 2022; epub ahead of print
Bélanger AM, Akioyamen LE, Ruel I, Hales L, Genest J
Eur Heart J: 01 Jul 2022; epub ahead of print | PMID: 35776569
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Abstract

Association between hypotension during 24 h ambulatory blood pressure monitoring and reflex syncope: the SynABPM 1 study.

Rivasi G, Groppelli A, Brignole M, Soranna D, ... Fedorowski A, Parati G
Aims
Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. The study hypothesis was that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM.
Methods and results
ABPM data from reflex syncope patients and controls, matched by average 24 h SBP, age, sex, and hypertension were compared. Patients with constitutional hypotension, orthostatic hypotension, and predominant cardioinhibition during carotid sinus massage or prolonged electrocardiogram monitoring or competing causes of syncope were excluded. Daytime and nighttime SBP drops (<110, 100, 90, 80 mmHg) were assessed. Findings were validated in an independent sample. In the derivation sample, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drops <90 mmHg achieved 91% specificity and 32% sensitivity [odds ratio (OR) 4.6, P < 0.001]. Two or more daytime drops <100 mmHg achieved 84% specificity and 40% sensitivity (OR 3.5, P = 0.001). Results were confirmed in the validation sample of 164 syncope patients and 164 controls: one or more daytime SBP drops <90 mmHg achieved 94% specificity and 29% sensitivity (OR 6.2, P < 0.001), while two or more daytime SBP drops <100 mmHg achieved 83% specificity and 35% sensitivity (OR 2.6, P < 0.001).
Conclusion
SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 29 Jun 2022; epub ahead of print
Rivasi G, Groppelli A, Brignole M, Soranna D, ... Fedorowski A, Parati G
Eur Heart J: 29 Jun 2022; epub ahead of print | PMID: 35766175
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Impact:
Abstract

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.

Jordà P, Bosman LP, Gasperetti A, Mazzanti A, ... Krahn AD, Cadrin-Tourigny J
Aims
Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus.
Methods and results
In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%.
Conclusion
Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 29 Jun 2022; epub ahead of print
Jordà P, Bosman LP, Gasperetti A, Mazzanti A, ... Krahn AD, Cadrin-Tourigny J
Eur Heart J: 29 Jun 2022; epub ahead of print | PMID: 35766180
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Impact:
Abstract

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

Protonotarios A, Bariani R, Cappelletto C, Pavlou M, ... Bauce B, Elliott PM
Aims
To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).
Methods and results
The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function.
Conclusion
The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 29 Jun 2022; epub ahead of print
Protonotarios A, Bariani R, Cappelletto C, Pavlou M, ... Bauce B, Elliott PM
Eur Heart J: 29 Jun 2022; epub ahead of print | PMID: 35766183
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Impact:
Abstract

Post-operative atrial fibrillation and risk of heart failure hospitalization.

Goyal P, Kim M, Krishnan U, Mccullough SA, ... Safford MM, Kamel H
Aims
Post-operative atrial fibrillation (POAF) is associated with stroke and mortality. It is unknown if POAF is associated with subsequent heart failure (HF) hospitalization. This study aims to examine the association between POAF and incident HF hospitalization among patients undergoing cardiac and non-cardiac surgeries.
Methods and results
A retrospective cohort study was conducted using all-payer administrative claims data that included all non-federal emergency department visits and acute care hospitalizations across 11 states in the USA. The study population included adults aged at least 18 years hospitalized for surgery without a prior diagnosis of HF. Cox proportional hazards regression models were used to examine the association between POAF and incident HF hospitalization after making adjustment for socio-demographics and comorbid conditions. Among 76 536 patients who underwent cardiac surgery, 14 365 (18.8%) developed incident POAF. In an adjusted Cox model, POAF was associated with incident HF hospitalization [hazard ratio (HR) 1.33; 95% confidence interval (CI) 1.25-1.41]. In a sensitivity analysis excluding HF within 1 year of surgery, POAF remained associated with incident HF hospitalization (HR 1.15; 95% CI 1.01-1.31). Among 2 929 854 patients who underwent non-cardiac surgery, 23 763 (0.8%) developed incident POAF. In an adjusted Cox model, POAF was again associated with incident HF hospitalization (HR 2.02; 95% CI 1.94-2.10), including in a sensitivity analysis excluding HF within 1 year of surgery (HR 1.49; 95% CI 1.38-1.61).
Conclusions
Post-operative atrial fibrillation is associated with incident HF hospitalization among patients without prior history of HF undergoing both cardiac and non-cardiac surgeries. These findings reinforce the adverse prognostic impact of POAF and suggest that POAF may be a marker for identifying patients with subclinical HF and those at elevated risk for HF.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 28 Jun 2022; epub ahead of print
Goyal P, Kim M, Krishnan U, Mccullough SA, ... Safford MM, Kamel H
Eur Heart J: 28 Jun 2022; epub ahead of print | PMID: 35764099
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Impact:
Abstract

A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity.

Lu D, Chatterjee S, Xiao K, Riedel I, ... Bär C, Thum T
Aims
Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF.
Methods and results
The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity.
Conclusion
Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 27 Jun 2022; epub ahead of print
Lu D, Chatterjee S, Xiao K, Riedel I, ... Bär C, Thum T
Eur Heart J: 27 Jun 2022; epub ahead of print | PMID: 35758064
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Impact:
Abstract

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci.

Ghouse J, Tragante V, Muhammad A, Ahlberg G, ... Bundgaard H, Olesen MS
Aims
To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs).
Methods and results
A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits.
Conclusion
This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Jun 2022; epub ahead of print
Ghouse J, Tragante V, Muhammad A, Ahlberg G, ... Bundgaard H, Olesen MS
Eur Heart J: 25 Jun 2022; epub ahead of print | PMID: 35751511
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Impact:
Abstract

Rivaroxaban and aspirin vs. aspirin alone in Asian compared with non-Asian patients with chronic coronary artery disease or peripheral arterial disease: the COMPASS trial.

Hori M, Zhu J, Liang Y, Bhatt DL, ... Yusuf S, Eikelboom JW
Aims
It is unknown whether Asian and non-Asian patients with atherosclerotic vascular disease derive similar benefits from long-term antithrombotic therapy.
Methods and results
In patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in The Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, the effects of rivaroxaban 2.5 mg b.i.d. plus aspirin 100 mg o.d. were compared with those of aspirin 100 mg o.d. in Asian vs. non-Asian patients (race was self-identified). Asians (n = 4269) vs. non-Asians (n = 23 126) had similar rates of major adverse cardiovascular events (MACEs) (4.85% vs. 4.83%, P = 0.30) and modified International Society on Thrombosis and Haemostasis (ISTH) major bleeding (2.72% vs. 2.58%, P = 0.22), but higher rates of intracranial haemorrhage (ICH) (0.63% vs. 0.29%, P = 0.01) and minor bleeding (13.61% vs. 6.49%, P < 0.001). In Asians vs. non-Asians, the combination of rivaroxaban and aspirin compared with aspirin alone produced consistent reductions in MACE [Asians: hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.45-0.90; non-Asians: HR: 0.78, 95% CI: 0.67-0.90; P(heterogeneity) = 0.29], increases in modified ISTH major bleeding (Asians: HR 2.24, 95% CI: 1.40-3.58; non-Asians: HR: 1.60, 95% CI: 1.30-1.97; P = 0.20), and net clinical outcome (Asians: HR: 0.77, 95% CI: 0.56-1.05; non-Asians: HR: 0.81, 95% CI: 0.70-0.93, P = 0.78), but borderline higher rates of ICH (Asians: HR: 3.50, 95% CI: 0.98-12.56; non-Asians: HR: 0.81, 95% CI: 0.43, 1.53; P = 0.04).
Conclusion
Asian compared with non-Asian patients with chronic CAD and/or PAD have higher rates of ICH and minor bleeding. The combination of rivaroxaban and aspirin vs. aspirin alone produces similar effects for MACE, modified ISTH major bleeding, and net clinical outcome but may be associated with higher rates of ICH in Asian patients.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Jun 2022; epub ahead of print
Hori M, Zhu J, Liang Y, Bhatt DL, ... Yusuf S, Eikelboom JW
Eur Heart J: 25 Jun 2022; epub ahead of print | PMID: 35751528
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Impact:
Abstract

Modifiable risk factors associated with cardiovascular disease and mortality in China: a PURE substudy.

Li S, Liu Z, Joseph P, Hu B, ... Yusuf S, Li W
Aims
To examine the incidence of cardiovascular disease (CVD) and mortality in China and in key subpopulations, and to estimate the population-level risks attributable to 12 common modifiable risk factors for each outcome.
Methods and results
In this prospective cohort of 47 262 middle-aged participants from 115 urban and rural communities in 12 provinces of China, it was examined how CVD incidence and mortality rates varied by sex, by urban-rural area, and by region. In participants without prior CVD, population-attributable fractions (PAFs) for CVD and for death related to 12 common modifiable risk factors were assessed: four metabolic risk factors (hypertension, diabetes, abdominal obesity, and lipids), four behavioural risk factors (tobacco, alcohol, diet quality, and physical activity), education, depression, grip strength, and household air pollution. The mean age of the cohort was 51.1 years. 58.2% were female, 49.2% were from urban areas, and 59.6% were from the eastern region of China. The median follow-up duration was 11.9 years. The CVD was the leading cause of death in China (36%). The rates of CVD and death were 8.35 and 5.33 per 1000 person-years, respectively, with higher rates in men compared with women and in rural compared with urban areas. Death rates were higher in the central and western regions of China compared with the eastern region. The modifiable risk factors studied collectively contributed to 59% of the PAF for CVD and 56% of the PAF for death in China. Metabolic risk factors accounted for the largest proportion of CVD (PAF of 41.7%), and hypertension was the most important risk factor (25.0%), followed by low education (10.2%), high non-high-density lipoprotein cholesterol (7.8%), and abdominal obesity (6.9%). The largest risk factors for death were hypertension (10.8%), low education (10.5%), poor diet (8.3%), tobacco use (7.5%), and household air pollution (6.1%).
Conclusion
Both CVD and mortality are higher in men compared with women, and in rural compared with urban areas. Large reductions in CVD could potentially be achieved by controlling metabolic risk factors and improving education. Lowering mortality rates will require strategies addressing a broader range of risk factors.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 22 Jun 2022; epub ahead of print
Li S, Liu Z, Joseph P, Hu B, ... Yusuf S, Li W
Eur Heart J: 22 Jun 2022; epub ahead of print | PMID: 35731140
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Abstract

Cardiovascular disease, mortality, and their associations with modifiable risk factors in a multi-national South Asia cohort: a PURE substudy.

Joseph P, Kutty VR, Mohan V, Kumar R, ... Gupta R, Yusuf S
Aim
To examine the incidence of cardiovascular disease (CVD), of death, and the comparative effects of 12 common modifiable risk factors for both outcomes in South Asia.
Methods and results
Prospective study of 33 583 individuals 35-70 years of age from India, Bangladesh, or Pakistan. Mean follow-up period was 11 years. Age and sex adjusted incidence of a CVD event and mortality rates were calculated for the overall cohort, by urban or rural location, by sex, and by country. For each outcome, mutually adjusted population attributable fractions (PAFs) were calculated in 32 611 individuals without prior CVD to compare risks associated with four metabolic risk factors (hypertension, diabetes, abdominal obesity, high non-HDL cholesterol), four behavioural risk factors (tobacco use, alcohol use, diet quality, physical activity), education, household air pollution, strength, and depression. Hazard ratios were calculated using Cox regression models, and average PAFs were calculated for each risk factor or groups of risk factors. Cardiovascular disease was the most common cause of death (35.5%) in South Asia. Rural areas had a higher incidence of CVD (5.41 vs. 4.73 per 1000 person-years) and a higher mortality rate (10.27 vs. 6.56 per 1000 person-years) compared with urban areas. Males had a higher incidence of CVD (6.42 vs. 3.91 per 1000 person-years) and a higher mortality rate (10.66 vs. 6.85 per 1000 person-years) compared with females. Between countries, CVD incidence was highest in Bangladesh, while the mortality rate was highest in Pakistan. The modifiable risk factors studied contributed to approximately 64% of the PAF for CVD and 69% of the PAF for death. Largest PAFs for CVD were attributable to hypertension (13.1%), high non-HDL cholesterol (11.1%), diabetes (8.9%), low education (7.7%), abdominal obesity (6.9%), and household air pollution (6.1%). Largest PAFs for death were attributable to low education (18.9%), low strength (14.6%), poor diet (6.4%), diabetes (5.8%), tobacco use (5.8%), and hypertension (5.5%).
Conclusion
In South Asia, both CVD and deaths are highest in rural areas and among men. Reducing CVD and premature mortality in the region will require investment in policies that target a broad range of health determinants.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 22 Jun 2022; epub ahead of print
Joseph P, Kutty VR, Mohan V, Kumar R, ... Gupta R, Yusuf S
Eur Heart J: 22 Jun 2022; epub ahead of print | PMID: 35731159
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Abstract

Implantable defibrillators in primary prevention of genetic arrhythmias. A shocking choice?

Corrado D, Link MS, Schwartz PJ
Many previously unexplained life-threatening ventricular arrhythmias and sudden cardiac deaths (SCDs) in young individuals are now recognized to be genetic in nature and are ascribed to a growing number of distinct inherited arrhythmogenic diseases. These include hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (VT), and short QT syndrome. Because of their lower frequency compared to coronary disease, risk factors for SCD are not very precise in patients with inherited arrhythmogenic diseases. As randomized studies are generally non-feasible and may even be ethically unjustifiable, especially in the presence of effective therapies, the risk assessment of malignant arrhythmic events such as SCD, cardiac arrest due to ventricular fibrillation (VF), appropriate implantable cardioverter defibrillator (ICD) interventions, or ICD therapy on fast VT/VF to guide ICD implantation is based on observational data and expert consensus. In this document, we review risk factors for SCD and indications for ICD implantation and additional therapies. What emerges is that, allowing for some important differences between cardiomyopathies and channelopathies, there is a growing and disquieting trend to create, and then use, semi-automated systems (risk scores, risk calculators, and, to some extent, even guidelines) which then dictate therapeutic choices. Their common denominator is a tendency to favour ICD implantation, sometime with reason, sometime without it. This contrasts with the time-honoured approach of selecting, among the available therapies, the best option (ICDs included) based on the clinical judgement for the specific patient and after having assessed the protection provided by optimal medical treatment.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 21 Jun 2022; epub ahead of print
Corrado D, Link MS, Schwartz PJ
Eur Heart J: 21 Jun 2022; epub ahead of print | PMID: 35725934
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Abstract

Hypertensive disorders of pregnant women with heart disease: the ESC EORP ROPAC Registry.

Ramlakhan KP, Malhamé I, Marelli A, Rutz T, ... Cornette J, Roos-Hesselink JW
Aims
Hypertensive disorders of pregnancy (HDP) occur in 10% of pregnancies in the general population, pre-eclampsia specifically in 3-5%. Hypertensive disorders of pregnancy may have a high prevalence in, and be poorly tolerated by, women with heart disease.
Methods and results
The prevalence and outcomes of HDP (chronic hypertension, gestational hypertension or pre-eclampsia) were assessed in the ESC EORP ROPAC (n = 5739), a worldwide prospective registry of pregnancies in women with heart disease.The overall prevalence of HDP was 10.3%, made up of chronic hypertension (5.9%), gestational hypertension (1.3%), and pre-eclampsia (3%), with significant differences between the types of underlying heart disease (P < 0.05). Pre-eclampsia rates were highest in women with pulmonary arterial hypertension (PAH) (11.1%), cardiomyopathy (CMP) (7.1%), and ischaemic heart disease (IHD) (6.3%). Maternal mortality was 1.4 and 0.6% in women with vs. without HDP (P = 0.04), and even 3.5% in those with pre-eclampsia. All pre-eclampsia-related deaths were post-partum and 50% were due to heart failure. Heart failure occurred in 18.5 vs. 10.6% of women with vs. without HDP (P < 0.001) and in 29.1% of those with pre-eclampsia. Perinatal mortality was 3.1 vs. 1.7% in women with vs. without HDP (P = 0.019) and 4.7% in those with pre-eclampsia.
Conclusion
Hypertensive disorders of pregnancy and pre-eclampsia rates were higher in women with CMP, IHD, and PAH than in the general population. Adverse outcomes were increased in women with HDP, and maternal mortality was strikingly high in women with pre-eclampsia. The combination of HDP and heart disease should prompt close surveillance in a multidisciplinary context and the diagnosis of pre-eclampsia requires hospital admission and continued monitoring during the post-partum period.

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Eur Heart J: 21 Jun 2022; epub ahead of print
Ramlakhan KP, Malhamé I, Marelli A, Rutz T, ... Cornette J, Roos-Hesselink JW
Eur Heart J: 21 Jun 2022; epub ahead of print | PMID: 35727736
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Abstract

Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy.

Perea-Gil I, Seeger T, Bruyneel AAN, Termglinchan V, ... Mercola M, Karakikes I
Aims
Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro.
Methods and results
Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Gö 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 (ATF4) and its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions.
Conclusions
A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM.

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Eur Heart J: 21 Jun 2022; epub ahead of print
Perea-Gil I, Seeger T, Bruyneel AAN, Termglinchan V, ... Mercola M, Karakikes I
Eur Heart J: 21 Jun 2022; epub ahead of print | PMID: 35728000
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Impact:
Abstract

Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.

Pandey AK, Bhatt DL, Cosentino F, Marx N, ... Butler J, Verma S
Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin-angiotensin-aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium-glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 17 Jun 2022; epub ahead of print
Pandey AK, Bhatt DL, Cosentino F, Marx N, ... Butler J, Verma S
Eur Heart J: 17 Jun 2022; epub ahead of print | PMID: 35713973
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Impact:
Abstract

Functional stress imaging to predict abnormal coronary fractional flow reserve: the PACIFIC 2 study.

Driessen RS, van Diemen PA, Raijmakers PG, Knuuti J, ... Danad I, Knaapen P
Aims
The diagnostic performance of non-invasive imaging in patients with prior coronary artery disease (CAD) has not been tested in prospective head-to-head comparative studies. The aim of this study was to compare the diagnostic performance of qualitative single-photon emission computed tomography (SPECT), quantitative positron emission tomography (PET), and qualitative magnetic resonance imaging (MRI) in patients with a prior myocardial infarction (MI) or percutaneous coronary intervention (PCI).
Methods and results
In this prospective clinical study, all patients with prior MI and/or PCI and new symptoms of ischaemic CAD underwent 99mTc-tetrofosmin SPECT, [15O]H2O PET, and MRI, followed by invasive coronary angiography with fractional flow reserve (FFR) in all coronary arteries. All modalities were interpreted by core laboratories. Haemodynamically significant CAD was defined by at least one coronary artery with an FFR ≤0.80. Among the 189 enrolled patients, 63% had significant CAD. Sensitivity was 67% (95% confidence interval 58-76%) for SPECT, 81% (72-87%) for PET, and 66% (56-75%) for MRI. Specificity was 61% (48-72%) for SPECT, 65% (53-76%) for PET, and 62% (49-74%) for MRI. Sensitivity of PET was higher than SPECT (P = 0.016) and MRI (P = 0.014), whereas specificity did not differ among the modalities. Diagnostic accuracy for PET (75%, 68-81%) did not statistically differ from SPECT (65%, 58-72%, P = 0.03) and MRI (64%, 57-72%, P = 0.052). Using FFR < 0.75 as a reference, accuracies increased to 69% (SPECT), 79% (PET), and 71% (MRI).
Conclusion
In this prospective head-to-head comparative study, SPECT, PET, and MRI did not show a significantly different accuracy for diagnosing FFR defined significant CAD in patients with prior PCI and/or MI. Overall diagnostic performances, however, were discouraging and the additive value of non-invasive imaging in this high-risk population is questionable.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 16 Jun 2022; epub ahead of print
Driessen RS, van Diemen PA, Raijmakers PG, Knuuti J, ... Danad I, Knaapen P
Eur Heart J: 16 Jun 2022; epub ahead of print | PMID: 35708168
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Abstract

Single versus multiple arterial grafting in diabetic patients at 10 years: the Arterial Revascularization Trial.

Taggart DP, Audisio K, Gerry S, Robinson NB, ... Gaudino M, ART Investigators
Aims
To evaluate the impact of multiple arterial grafting (MAG) vs. single arterial grafting (SAG) in a post hoc analysis of 10-year outcomes in patients with diabetes mellitus (DM) from the Arterial Revascularization Trial (ART).
Methods and results
The primary endpoint was all-cause mortality and the secondary endpoint was a composite of major adverse cardiac events (MACE) at 10-year follow-up. Patients were stratified by diabetes status (non-DM and DM) and grafting strategy (MAG vs. SAG). A total of 3020 patients were included in the analysis; 716 (23.7%) had DM. Overall, 55.8% non-DM patients received MAG and 44.2% received SAG, while 56.6% DM patients received MAG and 43.4% received SAG. The use of MAG compared with SAG was associated with lower 10-year mortality for both non-DM [17.7 vs. 21.0%, adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.72-1.06] and DM patients (21.5 vs. 29.9%, adjusted HR 0.65, 95% CI 0.48-0.89; P for interaction = 0.12). For both groups, the rate of 10-year MACE was also lower for MAG vs. SAG. Overall, deep sternal wound infections (DSWIs) were uncommon but more frequent in the MAG vs. SAG group in both non-DM (3.3 vs. 2.1%) and DM patients (7.9 vs. 4.8%). The highest rates of DSWI were in insulin-treated patients receiving MAG (9.6 vs. 6.3%, when compared with SAG).
Conclusion
In this post hoc analysis of the ART, MAG was associated with substantially lower mortality rates at 10 years after coronary artery bypass grafting in patients with DM. Patients with DM receiving MAG had a higher incidence of DSWI, especially if insulin dependent.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Eur Heart J: 14 Jun 2022; epub ahead of print
Taggart DP, Audisio K, Gerry S, Robinson NB, ... Gaudino M, ART Investigators
Eur Heart J: 14 Jun 2022; epub ahead of print | PMID: 35699416
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Abstract

Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled.

Ferreira JP, Zannad F, Butler J, Filipattos G, ... Anker SD, Packer M
Aims
Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF.
Methods and results
EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators\' reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74-0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48-0.81, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/l) was not significantly increased with empagliflozin.
Conclusions
Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 10 Jun 2022; epub ahead of print
Ferreira JP, Zannad F, Butler J, Filipattos G, ... Anker SD, Packer M
Eur Heart J: 10 Jun 2022; epub ahead of print | PMID: 35687107
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Impact:
Abstract

A new score for life-threatening ventricular arrhythmias and sudden cardiac death in adults with transposition of the great arteries and a systemic right ventricle.

Ladouceur M, Van De Bruaene A, Kauling R, Budts W, ... Wong T, Gatzoulis MA
Aims
To investigate the incidence of major adverse ventricular arrhythmias and related events (MAREs) and to develop a stratification tool predicting MAREs in adults with a systemic right ventricle (sRV).
Methods and results
In a multicentre approach, all adults (≥16 years old) with a sRV undergoing follow-up between 2000 and 2018 were identified. The incidence of MAREs, defined as sudden cardiac death, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) therapy, was analysed. The association of MAREs with clinical, electrical, and echocardiographic parameters was evaluated. A total of 1184 patients (median age 27.1 years; interquartile range 19.9-34.9 years; 59% male; 70% with atrial switch repair for D-transposition of the great arteries) were included. The incidence of MAREs was 6.3 per 1000 patient-years. On multivariate analysis, age, history of heart failure, syncope, QRS duration, severe sRV dysfunction and at least moderate left ventricular outflow tract obstruction were retained in the final model with a C-index of 0.78 [95% confidence interval (CI) 0.72-0.83] and a calibration slope of 0.93 (95% CI 0.64-1.21). For every five ICDs implanted in patients with a 5-year MARE risk >10%, one patient may potentially be spared from a MARE.
Conclusion
Sudden cardiac death remains a devastating cause of death in a contemporary adult cohort with a sRV. A prediction model based on clinical, electrocardiographic, and echocardiographic parameters was devised to estimate MARE risk and to identify high-risk patients who may benefit from primary prevention ICD implantation.

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Eur Heart J: 08 Jun 2022; epub ahead of print
Ladouceur M, Van De Bruaene A, Kauling R, Budts W, ... Wong T, Gatzoulis MA
Eur Heart J: 08 Jun 2022; epub ahead of print | PMID: 35673927
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Abstract

Outcomes of culture-negative vs. culture-positive infective endocarditis: the ESC-EORP EURO-ENDO registry.

Kong WKF, Salsano A, Giacobbe DR, Popescu BA, ... Habib G, Lancellotti P
Aim
Fatality of infective endocarditis (IE) is high worldwide, and its diagnosis remains a challenge. The objective of the present study was to compare the clinical characteristics and outcomes of patients with culture-positive (CPIE) vs. culture-negative IE (CNIE).
Methods and results
This was an ancillary analysis of the ESC-EORP EURO-ENDO registry. Overall, 3113 patients who were diagnosed with IE during the study period were included in the present study. Of these, 2590 (83.2%) had CPIE, whereas 523 (16.8%) had CNIE. As many as 1488 (48.1%) patients underwent cardiac surgery during the index hospitalization, 1259 (48.8%) with CPIE and 229 (44.5%) with CNIE. The CNIE was a predictor of 1-year mortality [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.04-1.56], whereas surgery was significantly associated with survival (HR 0.49, 95% CI 0.41-0.58). The 1-year mortality was significantly higher in CNIE than CPIE patients in the medical subgroup, but it was not significantly different in CNIE vs. CPIE patients who underwent surgery.
Conclusion
The present analysis of the EURO-ENDO registry confirms a higher long-term mortality in patients with CNIE compared with patients with CPIE. This difference was present in patients receiving medical therapy alone and not in those who underwent surgery, with surgery being associated with reduced mortality. Additional efforts are required both to improve the aetiological diagnosis of IE and identify CNIE cases early before progressive disease potentially contraindicates surgery.

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Eur Heart J: 08 Jun 2022; epub ahead of print
Kong WKF, Salsano A, Giacobbe DR, Popescu BA, ... Habib G, Lancellotti P
Eur Heart J: 08 Jun 2022; epub ahead of print | PMID: 35695691
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Impact:
Abstract

Early and late-onset syncope: insight into mechanisms.

Torabi P, Rivasi G, Hamrefors V, Ungar A, ... Brignole M, Fedorowski A
Aims
Unexplained syncope is an important clinical challenge. The influence of age at first syncope on the final syncope diagnosis is not well studied.
Methods and results
Consecutive head-up tilt patients (n = 1928) evaluated for unexplained syncope were stratified into age groups <30, 30-59, and ≥60 years based on age at first syncope. Clinical characteristics and final syncope diagnosis were analysed in relation to age at first syncope and age at investigation. The age at first syncope had a bimodal distribution with peaks at 15 and 70 years. Prodromes (64 vs. 26%, P < 0.001) and vasovagal syncope (VVS, 59 vs. 19%, P < 0.001) were more common in early-onset (<30 years) compared with late-onset (≥60 years) syncope. Orthostatic hypotension (OH, 3 vs. 23%, P < 0.001), carotid sinus syndrome (CSS, 0.6 vs. 9%, P < 0.001), and complex syncope (>1 concurrent diagnosis; 14 vs. 26%, P < 0.001) were more common in late-onset syncope. In patients aged ≥60 years, 12% had early-onset and 70% had late-onset syncope; older age at first syncope was associated with higher odds of OH (+31% per 10-year increase, P < 0.001) and CSS (+26%, P = 0.004). Younger age at first syncope was associated with the presence of prodromes (+23%, P < 0.001) and the diagnoses of VVS (+22%, P < 0.001) and complex syncope (+9%, P = 0.018).
Conclusion
In patients with unexplained syncope, first-ever syncope incidence has a bimodal lifetime pattern with peaks at 15 and 70 years. The majority of older patients present only recent syncope; OH and CSS are more common in this group. In patients with early-onset syncope, prodromes, VVS, and complex syncope are more common.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 06 Jun 2022; 43:2116-2123
Torabi P, Rivasi G, Hamrefors V, Ungar A, ... Brignole M, Fedorowski A
Eur Heart J: 06 Jun 2022; 43:2116-2123 | PMID: 35139180
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Impact:
Abstract

Subcutaneous implantable cardioverter-defibrillators: long-term results of the EFFORTLESS study.

Lambiase PD, Theuns DA, Murgatroyd F, Barr C, ... Knops R, Boersma LVA
Aims
To report 5-year outcomes of EFFORTLESS registry patients with early generation subcutaneous implantable cardioverter-defibrillator (S-ICD) devices.
Methods and results
Kaplan-Meier, trend and multivariable analyses were performed for mortality and late (years 2-5) complications, appropriate shock (AS) and inappropriate shock (IAS) rates. Nine hundred and eighty-four of 994 enrolled patients with diverse diagnoses (28% female, 48 ± 17 years, body mass index 27 ± 6 kg/m2, ejection fraction 43 ± 18%) underwent S-ICD implantation. Median follow-up was 5.1 years (interquartile range 4.7-5.5 years). All-cause mortality was 9.3% (95% confidence interval 7.2-11.3%) at 5 years; 703 patients remained in follow-up on study completion, 171 withdrew including 87 (8.8%) with device explanted, and 65 (6.6%) lost to follow-up. Of the explants, only 20 (2.0%) patients needed a transvenous device for pacing indications. First and final shock efficacy for discrete ventricular arrhythmias was consistent at 90% and 98%, respectively, with storm episode final shock efficacy at 95.2%. Time to therapy remained unaltered. Overall 1- and 5-year complication rates were 8.9% and 15.2%, respectively. Early complications did not predict later complications. There were no structural lead failures. Inappropriate shock rates at 1 and 5 years were 8.7% and 16.9%, respectively. Self-terminating inappropriately sensed episodes predicted late IAS. Predictors of late AS included self-terminating appropriately sensed episodes and earlier AS.
Conclusion
In this diverse S-ICD registry population, spontaneous shock efficacy was consistently high over 5 years. Very few patients underwent S-ICD replacement with a transvenous device for pacing indications. Treated and self-terminating arrhythmic episodes predict future shock events, which should encourage more personalized device optimization.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 01 Jun 2022; 43:2037-2050
Lambiase PD, Theuns DA, Murgatroyd F, Barr C, ... Knops R, Boersma LVA
Eur Heart J: 01 Jun 2022; 43:2037-2050 | PMID: 35090007
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Impact:
Abstract

Cardiopulmonary exercise testing and efficacy of percutaneous coronary intervention: a substudy of the ORBITA trial.

Ganesananthan S, Rajkumar CA, Foley M, Thompson D, ... Howard J, Al-Lamee R
Aims
Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine the relationship between CPET parameters, myocardial ischaemia and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to percutaneous coronary intervention (PCI).
Methods and results
Patients with severe single-vessel coronary artery disease (CAD) were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE) and symptom assessment. These assessments were repeated at the end of a 6-week blinded follow-up period.A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (-0.07; 95% CI: -0.12 to -0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI.
Conclusion
Although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 26 May 2022; epub ahead of print
Ganesananthan S, Rajkumar CA, Foley M, Thompson D, ... Howard J, Al-Lamee R
Eur Heart J: 26 May 2022; epub ahead of print | PMID: 35639660
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Abstract

Critical appraisal of artificial intelligence-based prediction models for cardiovascular disease.

van Smeden M, Heinze G, Van Calster B, Asselbergs FW, ... Boulesteix AL, Moons KGM
The medical field has seen a rapid increase in the development of artificial intelligence (AI)-based prediction models. With the introduction of such AI-based prediction model tools and software in cardiovascular patient care, the cardiovascular researcher and healthcare professional are challenged to understand the opportunities as well as the limitations of the AI-based predictions. In this article, we present 12 critical questions for cardiovascular health professionals to ask when confronted with an AI-based prediction model. We aim to support medical professionals to distinguish the AI-based prediction models that can add value to patient care from the AI that does not.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 26 May 2022; epub ahead of print
van Smeden M, Heinze G, Van Calster B, Asselbergs FW, ... Boulesteix AL, Moons KGM
Eur Heart J: 26 May 2022; epub ahead of print | PMID: 35639667
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Impact:
Abstract

Three-dimensional printing, holograms, computational modelling, and artificial intelligence for adult congenital heart disease care: an exciting future.

Chessa M, Van De Bruaene A, Farooqi K, Valverde I, ... Little SH, Gatzoulis MA
Congenital heart disease (CHD) is often comprised of complex three-dimensional (3D) anatomy that must be well understood to assess the pathophysiological consequences and guide therapy. Thus, detailed cardiac imaging for early detection and planning of interventional and/or surgical treatment is paramount. Advanced technologies have revolutionized diagnostic and therapeutic practice in CHD, thus playing an increasing role in its management. Traditional reliance on standard imaging modalities including echocardiography, cardiac computed tomography (CT) and magnetic resonance imaging (MRI) has been augmented by the use of recent technologies such as 3D printing, virtual reality, augmented reality, computational modelling, and artificial intelligence because of insufficient information available with these standard imaging techniques. This has created potential opportunities of incorporating these technologies into routine clinical practice to achieve the best outcomes through delivery of personalized medicine. In this review, we provide an overview of these evolving technologies and a new approach enabling physicians to better understand their real-world application in adult CHD as a prelude to clinical workflow implementation.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 24 May 2022; epub ahead of print
Chessa M, Van De Bruaene A, Farooqi K, Valverde I, ... Little SH, Gatzoulis MA
Eur Heart J: 24 May 2022; epub ahead of print | PMID: 35608227
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Abstract

Characteristics and natural history of early-stage cardiac transthyretin amyloidosis.

Law S, Bezard M, Petrie A, Chacko L, ... Fontana M, Gillmore JD
Aims
Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly diagnosed at an early stage of the disease natural history, defined as National Amyloidosis Centre (NAC) ATTR Stage I. The natural history of early-stage ATTR-CM remains poorly characterized.
Methods and results
A retrospective multi-centre observational study of 879 patients with ATTR-CM, either wild-type TTR genotype or carrying the p.V142I TTR variant, and NAC ATTR Stage I biomarkers at the time of diagnosis who did not receive disease-modifying therapy for amyloidosis. Disease characteristics at diagnosis that were independently associated with mortality by Cox regression analysis were N-terminal pro-B-type natriuretic peptide (NT-proBNP), TTR genotype, and troponin T. Patients were categorized into NAC ATTR Stage Ia, defined as a furosemide equivalent diuretic requirement of <0.75 mg/kg and an NT-proBNP ≤500 ng/L or ≤1000 ng/L in the presence of atrial fibrillation, and NAC ATTR Stage Ib comprising all remaining Stage I patients. Median estimated survival among the 88% NAC ATTR Stage Ib patients was 75 (95% CI 57-93) months compared with >100 months in the 12% with Stage Ia disease [hazard ratio for death 5.06 (95% confidence interval 1.23-20.87); P = 0.025] despite significant cardiovascular morbidity at the time of diagnosis which increased during follow-up, including among patients diagnosed in NAC ATTR Stage Ia. Estimated survival among UK NAC ATTR Stage Ia patients was comparable to UK general population controls (P = 0.297).
Conclusion
Patients with NAC ATTR Stage I ATTR-CM can be further stratified according to NT-proBNP concentration and diuretic requirement at diagnosis. Patients with Stage Ia ATTR-CM have significant cardiovascular morbidity despite good short- and mid-term survival.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 24 May 2022; epub ahead of print
Law S, Bezard M, Petrie A, Chacko L, ... Fontana M, Gillmore JD
Eur Heart J: 24 May 2022; epub ahead of print | PMID: 35608040
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Impact:
Abstract

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

Metra M, Pagnesi M, Claggett BL, Díaz R, ... Malik FI, Teerlink JR
Aim
Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF).
Methods and results
The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo.
Conclusion
In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 22 May 2022; epub ahead of print
Metra M, Pagnesi M, Claggett BL, Díaz R, ... Malik FI, Teerlink JR
Eur Heart J: 22 May 2022; epub ahead of print | PMID: 35675469
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Impact:
Abstract

Apixaban vs. standard of care after transcatheter aortic valve implantation: the ATLANTIS trial.

Collet JP, Van Belle E, Thiele H, Berti S, ... Montalescot G, ATLANTIS Investigators of the ACTION Group
Aims
The respective roles of oral anticoagulation or antiplatelet therapy following transcatheter aortic valve implantation (TAVI) remain debated. ATLANTIS is an international, randomized, open-label, superiority trial comparing apixaban to the standard of care.
Methods and results
After successful TAVI, 1500 patients were randomized (1:1) to receive apixaban 5 mg (2.5 mg if impaired renal function or concomitant antiplatelet therapy) (n = 749) twice daily, or standard of care (n = 751). Randomization was stratified by the need for chronic anticoagulation therapy. Standard-of-care patients received a vitamin K antagonist (VKA) (Stratum 1) or antiplatelet therapy (Stratum 2) if there was an indication for anticoagulation or not, respectively. The primary endpoint was the composite of death, myocardial infarction, stroke or transient ischaemic attack, systemic embolism, intracardiac or bioprosthesis thrombosis, deep vein thrombosis or pulmonary embolism, and life-threatening, disabling, or major bleeding over 1-year follow-up. The primary safety endpoint was major, disabling, or life-threatening bleeding. The primary outcome occurred in 138 (18.4%) and 151 (20.1%) patients receiving apixaban or standard of care, respectively [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.73-1.16] and there was no evidence of interaction between treatment and stratum (Pinteraction = 0.57). The primary safety endpoint was similar in both groups (HR 1.02; 95% CI 0.72-1.44). In Stratum 1 (n = 451), an exploratory analysis showed no difference for all endpoints between apixaban and VKA. In Stratum 2 (n = 1049), the primary outcome and primary safety endpoint did not differ, but obstructive valve thrombosis was reduced with apixaban vs. antiplatelet therapy (HR 0.19; 95% CI 0.08-0.46), while a signal of higher non-cardiovascular mortality was observed with apixaban.
Conclusion
After TAVI, apixaban was not superior to the standard of care, irrespective of an indication for oral anticoagulation.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 18 May 2022; epub ahead of print
Collet JP, Van Belle E, Thiele H, Berti S, ... Montalescot G, ATLANTIS Investigators of the ACTION Group
Eur Heart J: 18 May 2022; epub ahead of print | PMID: 35583186
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Impact:
Abstract

Duration of Antiplatelet Therapy After Complex Percutaneous Coronary Intervention In Patients at High Bleeding Risk: a MASTER DAPT trial sub-analysis.

Valgimigli M, Smits PC, Frigoli E, Bongiovanni D, ... Vranckx P, MASTER DAPT Investigators
Aims
To assess the effects of 1- or ≥3-month dual antiplatelet therapy (DAPT) in high bleeding risk (HBR) patients who received biodegradable-polymer sirolimus-eluting stents for complex percutaneous coronary intervention (PCI) and/or acute coronary syndrome (ACS).
Methods and results
In the MASTER DAPT trial, 3383 patients underwent noncomplex (abbreviated DAPT, n = 1707; standard DAPT, n = 1676) and 1196 complex (abbreviated DAPT, n = 588; standard DAPT, n = 608) PCI. Co-primary outcomes at 335 days were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, stroke, and Bleeding Academic Research Consortium [BARC] 3 or 5 bleeding events); major adverse cardiac or cerebral events (MACCE; all-cause death, myocardial infarction, and stroke); and type 2, 3, or 5 BARC bleeding.NACE and MACCE did not differ with abbreviated versus standard DAPT among patients with complex (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 0.69-1.52, and HR: 1.24, 95% CI: 0.79-1.92, respectively) and noncomplex PCI (HR: 0.90, 95% CI: 0.71-1.15, and HR: 0.91, 95% CI: 0.69-1.21; Pinteraction = 0.60 and 0.26, respectively). BARC 2, 3 or 5 was reduced with abbreviated DAPT in patients with and without complex PCI (HR: 0.64; 95% CI: 0.42-0.98, and HR: 0.70; 95% CI: 0.55-0.89; Pinteraction = 0.72). Among the 2,816 patients with complex PCI and/or ACS, NACE and MACCE did not differ and BARC 2, 3 or 5 was lower with abbreviated DAPT.
Conclusion
In HBR patients free from recurrent ischemic events at 1 month, DAPT discontinuation was associated with similar NACE and MACCE and lower bleeding rates compared with standard DAPT, regardless of PCI or patient complexity.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 17 May 2022; epub ahead of print
Valgimigli M, Smits PC, Frigoli E, Bongiovanni D, ... Vranckx P, MASTER DAPT Investigators
Eur Heart J: 17 May 2022; epub ahead of print | PMID: 35580836
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Abstract

Twitter promotion is associated with higher citation rates of cardiovascular articles: the ESC Journals Randomized Study.

Ladeiras-Lopes R, Vidal-Perez R, Santos-Ferreira D, Alexander M, ... Crea F, Lüscher TF
The association between the dissemination of scientific articles on Twitter and online visibility (as assessed by the Altmetric Score) is still controversial, and the impact on citation rates has never been rigorously addressed for cardiovascular medicine journals using a randomized design. The ESC Journals Study randomized 695 papers published in the ESC Journal Family (March 2018-May 2019) for promotion on Twitter or to a control arm (with no active tweeting from ESC channels) and aimed to assess whether Twitter promotion was associated with an increase in citation rates (primary endpoint) and of the Altmetric Score. This is the final analysis including 694 articles (one paper excluded due to retraction). After a median follow-up of 994 days (interquartile range: 936-1063 days), Twitter promotion of articles was associated with a 1.12 (95% confidence interval: 1.08-1.15) higher rate of citations, and this effect was independent of the type of article. Altmetric Attention Score and number of users tweeting were positive predictors for the number of citations. A social media strategy of Twitter promotion for cardiovascular medicine papers seems to be associated with increased online visibility and higher numbers of citations.

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Eur Heart J: 14 May 2022; 43:1794-1798
Ladeiras-Lopes R, Vidal-Perez R, Santos-Ferreira D, Alexander M, ... Crea F, Lüscher TF
Eur Heart J: 14 May 2022; 43:1794-1798 | PMID: 35567549
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Abstract

Vascular dysfunction and increased cardiovascular risk in hypospadias.

Lucas-Herald AK, Montezano AC, Alves-Lopes R, Haddow L, ... Ahmed SF, Touyz RM
Aims
Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease.
Methods and results
Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02).
Conclusion
Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 14 May 2022; 43:1832-1845
Lucas-Herald AK, Montezano AC, Alves-Lopes R, Haddow L, ... Ahmed SF, Touyz RM
Eur Heart J: 14 May 2022; 43:1832-1845 | PMID: 35567552
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Abstract

Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques.

Edsfeldt A, Swart M, Singh P, Dib L, ... Goncalves I, Monaco C
Aims
Inflammation is a key factor in atherosclerosis. The transcription factor interferon regulatory factor-5 (IRF5) drives macrophages towards a pro-inflammatory state. We investigated the role of IRF5 in human atherosclerosis and plaque stability.
Methods and results
Bulk RNA sequencing from the Carotid Plaque Imaging Project biobank were used to mine associations between major macrophage associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were used for validation. The effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE-/- mice was studied in an inducible model of plaque rupture. Interferon regulatory factor-5 and ITGAX/CD11c were identified as the macrophage associated genes with the strongest associations with symptomatic carotid disease. Expression of IRF5 and ITGAX/CD11c correlated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and with each other. Macrophages were the predominant CD11c-expressing immune cells in the plaque by CyTOF and immunohistochemistry. Interferon regulatory factor-5 immunopositive areas were predominantly found within CD11c+ areas with a predilection for the shoulder region, the area of the human plaque most prone to rupture. Accordingly, an inducible plaque rupture model of ApoE-/-Irf5-/- mice had significantly lower frequencies of carotid plaque ruptures, smaller necrotic cores, and less CD11c+ macrophages than their IRF5-competent counterparts.
Conclusion
Using complementary evidence from data from human carotid endarterectomies and a murine model of inducible rupture of carotid artery plaque in IRF5-deficient mice, we demonstrate a mechanistic link between the pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and its vulnerability to rupture.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 14 May 2022; 43:1864-1877
Edsfeldt A, Swart M, Singh P, Dib L, ... Goncalves I, Monaco C
Eur Heart J: 14 May 2022; 43:1864-1877 | PMID: 35567557
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Impact:
Abstract

Targeting the CCL2-CCR2 axis for atheroprotection.

Georgakis MK, Bernhagen J, Heitman LH, Weber C, Dichgans M
Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome-interleukin-1β-interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2-CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2-CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2-CCR2 axis in human atherosclerotic disease.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 14 May 2022; 43:1799-1808
Georgakis MK, Bernhagen J, Heitman LH, Weber C, Dichgans M
Eur Heart J: 14 May 2022; 43:1799-1808 | PMID: 35567558
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Abstract

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

Devesa A, Lobo-González M, Martínez-Milla J, Oliva B, ... Ibanez B, Fuster V
Aims
Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis.
Methods and results
Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden).
Conclusion
In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 14 May 2022; 43:1809-1828
Devesa A, Lobo-González M, Martínez-Milla J, Oliva B, ... Ibanez B, Fuster V
Eur Heart J: 14 May 2022; 43:1809-1828 | PMID: 35567559
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Impact:
Abstract

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

Kraler S, Wenzl FA, Georgiopoulos G, Obeid S, ... Akhmedov A, Lüscher TF
Aims
The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS).
Methods and results
Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031).
Conclusion
Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD.
Clinical trial registration
NCT01000701.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 14 May 2022; 43:1849-1860
Kraler S, Wenzl FA, Georgiopoulos G, Obeid S, ... Akhmedov A, Lüscher TF
Eur Heart J: 14 May 2022; 43:1849-1860 | PMID: 35567560
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Abstract

Timing of cardiac surgery during pregnancy: a patient-level meta-analysis.

van Steenbergen GJ, Tsang QHY, van der Heijden OWH, Vart P, ... Li WWL, Verhagen AFTM
Aims
To investigate the association between the timing of cardiac surgery during pregnancy and both maternal and foetal outcomes.
Methods and results
Studies published up to 6 February 2021 on maternal and/or foetal mortality after cardiac surgery during pregnancy that included individual patient data were identified. Maternal and foetal mortality was analysed per trimester for the total population and stratified for patients who underwent caesarean section (CS) prior to cardiac surgery (Caesarean section (CaeSe) group) vs. patients who did not (Cardiac surgery (CarSu) group). Multivariable logistic regression analysis was performed to evaluate predictors of both maternal and foetal mortality. In total, 179 studies were identified including 386 patients of which 120 underwent CS prior to cardiac surgery. Maternal mortality was 7.3% and did not differ significantly among trimesters of pregnancy (P = 0.292) nor between subgroup CaeSe and CarSu (P = 0.671). Overall foetal mortality was 26.5% and was lowest when cardiac surgery was performed during the third trimester (10.3%, P < 0.01). CS prior to surgery was significantly associated with a reduced risk of foetal mortality in a multivariable model [odds ratio 0.19, 95% confidence interval [0.06-0.56)]. Trimester was not identified as an independent predictor for foetal nor maternal mortality.
Conclusion
Maternal mortality after cardiac surgery during pregnancy is not associated with the trimester of pregnancy. Cardiac surgery is associated with high foetal mortality but is significantly lower in women where CS is performed prior to cardiac surgery. When the foetus is viable, CS prior to cardiac surgery might be safe. When CS is not feasible, trimester stage does not seem to influence foetal mortality.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Eur Heart J: 13 May 2022; epub ahead of print
van Steenbergen GJ, Tsang QHY, van der Heijden OWH, Vart P, ... Li WWL, Verhagen AFTM
Eur Heart J: 13 May 2022; epub ahead of print | PMID: 35560020
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Impact:
Abstract

Integrated care for optimizing the management of stroke and associated heart disease: a position paper of the European Society of Cardiology Council on Stroke.

Lip GYH, Lane DA, Lenarczyk R, Boriani G, ... Ntaios G, Potpara T
The management of patients with stroke is often multidisciplinary, involving various specialties and healthcare professionals. Given the common shared risk factors for stroke and cardiovascular disease, input may also be required from the cardiovascular teams, as well as patient caregivers and next-of-kin. Ultimately, the patient is central to all this, requiring a coordinated and uniform approach to the priorities of post-stroke management, which can be consistently implemented by different multidisciplinary healthcare professionals, as part of the patient \'journey\' or \'patient pathway,\' supported by appropriate education and tele-medicine approaches. All these aspects would ultimately aid delivery of care and improve patient (and caregiver) engagement and empowerment. Given the need to address the multidisciplinary approach to holistic or integrated care of patients with heart disease and stroke, the European Society of Cardiology Council on Stroke convened a Task Force, with the remit to propose a consensus on Integrated care management for optimizing the management of stroke and associated heart disease. The present position paper summarizes the available evidence and proposes consensus statements that may help to define evidence gaps and simple practical approaches to assist in everyday clinical practice. A post-stroke ABC pathway is proposed, as a more holistic approach to integrated stroke care, would include three pillars of management: • A: Appropriate Antithrombotic therapy. • B: Better functional and psychological status. • C: Cardiovascular risk factors and Comorbidity optimization (including lifestyle changes).

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 13 May 2022; epub ahead of print
Lip GYH, Lane DA, Lenarczyk R, Boriani G, ... Ntaios G, Potpara T
Eur Heart J: 13 May 2022; epub ahead of print | PMID: 35552401
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Abstract

Sex-related differences in treatment and outcome of chronic limb-threatening ischaemia: a real-world cohort.

Makowski L, Köppe J, Engelbertz C, Kühnemund L, ... Reinecke H, Feld J
Aims
The prevalence of chronic limb-threatening ischaemia (CLTI) is increasing and available data often derive from cohorts with various selection criteria. In the present study, we included CLTI patients and studied sex-related differences in their risk profile, vascular procedures, and long-term outcome.
Methods and results
We analysed 199 953 unselected patients of the largest public health insurance in Germany (AOK: Local healthcare funds), hospitalized between 2010 and 2017 for a main diagnosis of CLTI. A baseline period of 2 years before index hospitalization to assess comorbidities and previous procedures, and a follow-up period until 2018 were included. Female CLTI patients were older (median 81.4 vs. 73.8 years in males; P < 0.001) and more often diagnosed with hypertension, atrial fibrillation, chronic heart failure, and chronic kidney disease. Male patients suffered more frequently from diabetes mellitus, dyslipidaemia, smoking, cerebrovascular disease, and chronic coronary syndrome (all P < 0.001). Within hospitalized CLTI patients, females represent the minority (43% vs. 57%; P < 0.001) and during index hospitalization, women underwent less frequently diagnostic angiographies (67 vs. 70%) and revascularization procedures (61 vs. 65%; both P < 0.001). Moreover, women received less frequently guideline-recommended drugs like statins (35 vs. 43%) and antithrombotic therapy (48 vs. 53%; both P < 0.001) at baseline. Interestingly, after including age and comorbidities in a Cox regression analysis, female sex was associated with increased overall-survival (OS) [hazard ratio (HR) 0.95; 95% confidence interval (CI) 0.94-0.96] and amputation-free survival (AFS) (HR 0.84; 95% CI 0.83-0.85; both P < 0.001).
Conclusion
Female patients with CLTI were older, underwent less often vascular procedures, and received less frequently guideline-recommended medication. Nevertheless, female sex was independently associated with better OS and AFS during follow-up.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 07 May 2022; 43:1759-1770
Makowski L, Köppe J, Engelbertz C, Kühnemund L, ... Reinecke H, Feld J
Eur Heart J: 07 May 2022; 43:1759-1770 | PMID: 35134893
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Abstract

Autopsy in the era of advanced cardiovascular imaging.

Basso C, Stone JR
Historically, autopsy contributed to our current knowledge of cardiovascular anatomy, physiology, and pathology. Major advances in the understanding of cardiovascular diseases, including atherosclerosis and coronary artery disease, congenital heart diseases, and cardiomyopathies, were possible through autopsy investigations and clinicopathological correlations. In this review, the importance of performing clinical autopsies in people dying from cardiovascular disease, even in the era of advanced cardiovascular imaging is addressed. Autopsies are most helpful in the setting of sudden unexpected deaths, particularly when advanced cardiovascular imaging has not been performed. In this setting, the autopsy is often the only chance to make the correct diagnosis. In previously symptomatic patients who had undergone advanced cardiovascular imaging, autopsies still play many roles. Post-mortem examinations are important for furthering the understanding of key issues related to the underlying diseases. Autopsy can help to increase the knowledge of the sensitivity and specificity of advanced cardiovascular imaging modalities. Autopsies are particularly important to gain insights into both the natural history of cardiovascular diseases as well as less common presentations and therapeutic complications. Finally, autopsies are a key tool to quickly understand the cardiac pathology of new disorders, as emphasized during the recent coronavirus disease 2019 pandemic.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 06 May 2022; epub ahead of print
Basso C, Stone JR
Eur Heart J: 06 May 2022; epub ahead of print | PMID: 35514073
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Abstract

Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials.

Kite TA, Kurmani SA, Bountziouka V, Cooper NJ, ... McCann GP, Ladwiniec A
Aims
The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis.
Methods and results
A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78-1.04], MI (RR: 0.86, 95% CI: 0.63-1.16), admission for HF (RR: 0.66, 95% CI: 0.43-1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88-1.23), major bleeding (RR: 0.86, 95% CI: 0.68-1.09), or stroke (RR: 0.95, 95% CI: 0.59-1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40-0.81) and length of stay (median difference: -22 h, 95% CI: -36.7 to -7.5 h) were reduced with an early IS.
Conclusion
In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 06 May 2022; epub ahead of print
Kite TA, Kurmani SA, Bountziouka V, Cooper NJ, ... McCann GP, Ladwiniec A
Eur Heart J: 06 May 2022; epub ahead of print | PMID: 35514079
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Abstract

The European Heart Journal: fulfilling the mission.

Crea F, Badimon L, Berry C, De Caterina R, ... Tybjaerg-Hansen A, EHJ Editorial Board
In September 2020, the new Editors of the European Heart Journal (EHJ) wrote the following in their inaugural editorial: \"The fundamental mission of the Journal remains the reduction of the global burden of cardiovascular disease. We aspire to advance this aim by worldwide teamwork to communicate practice-changing research, inspire clinical cardiologists, and pursue rigour and transparency in the application of science at the service of human health. The Journal will strive to lead the field in its impact, influence, and reach\". After more than one year of experience the Editors hope the cardiological community will agree that they are fulfilling this mission. As stewards of the EHJ, the Editor\'s primary goal is not solely to achieve a high Impact Factor (which attests to the scientific quality and influence of our publications) but also to elevate the practice of cardiovascular medicine worldwide. Accordingly, various initiatives of the EHJ strive to strengthen further links among Editors, Authors, Reviewers and Readers through a series of coordinated and diverse activities, including webinars, active social media presence, and active participation at congresses worldwide. The Editors are proud to serve one of the most important scientific journals in cardiovascular medicine.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 05 May 2022; epub ahead of print
Crea F, Badimon L, Berry C, De Caterina R, ... Tybjaerg-Hansen A, EHJ Editorial Board
Eur Heart J: 05 May 2022; epub ahead of print | PMID: 35512309
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Abstract

Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies.

Frantz S, Hundertmark MJ, Schulz-Menger J, Bengel FM, Bauersachs J
Most patients survive acute myocardial infarction (MI). Yet this encouraging development has certain drawbacks: heart failure (HF) prevalence is increasing and patients affected tend to have more comorbidities worsening economic strain on healthcare systems and impeding effective medical management. The heart\'s pathological changes in structure and/or function, termed myocardial remodelling, significantly impact on patient outcomes. Risk factors like diabetes, chronic obstructive pulmonary disease, female sex, and others distinctly shape disease progression on the \'road to HF\'. Despite the availability of HF drugs that interact with general pathways involved in myocardial remodelling, targeted drugs remain absent, and patient risk stratification is poor. Hence, in this review, we highlight the pathophysiological basis, current diagnostic methods and available treatments for cardiac remodelling following MI. We further aim to provide a roadmap for developing improved risk stratification and novel medical and interventional therapies.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 04 May 2022; epub ahead of print
Frantz S, Hundertmark MJ, Schulz-Menger J, Bengel FM, Bauersachs J
Eur Heart J: 04 May 2022; epub ahead of print | PMID: 35511857
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Abstract

Cardiac magnetic resonance identifies raised left ventricular filling pressure: prognostic implications.

Garg P, Gosling R, Swoboda P, Jones R, ... Alabed S, Swift AJ
Aims
Non-invasive imaging is routinely used to estimate left ventricular (LV) filling pressure (LVFP) in heart failure (HF). Cardiovascular magnetic resonance (CMR) is emerging as an important imaging tool for sub-phenotyping HF. However, currently, LVFP cannot be estimated from CMR. This study sought to investigate (i) if CMR can estimate LVFP in patients with suspected HF and (ii) if CMR-modelled LVFP has prognostic power.
Methods and results
Suspected HF patients underwent right heart catheterization (RHC), CMR and transthoracic echocardiography (TTE) (validation cohort only) within 24 h of each other. Right heart catheterization measured pulmonary capillary wedge pressure (PCWP) was used as a reference for LVFP. At follow-up, death was considered as the primary endpoint. We enrolled 835 patients (mean age: 65 ± 13 years, 40% male). In the derivation cohort (n = 708, 85%), two CMR metrics were associated with RHC PCWP:LV mass and left atrial volume. When applied to the validation cohort (n = 127, 15%), the correlation coefficient between RHC PCWP and CMR-modelled PCWP was 0.55 (95% confidence interval: 0.41-0.66, P < 0.0001). Cardiovascular magnetic resonance-modelled PCWP was superior to TTE in classifying patients as normal or raised filling pressures (76 vs. 25%). Cardiovascular magnetic resonance-modelled PCWP was associated with an increased risk of death (hazard ratio: 1.77, P < 0.001). At Kaplan-Meier analysis, CMR-modelled PCWP was comparable to RHC PCWP (≥15 mmHg) to predict survival at 7-year follow-up (35 vs. 37%, χ2 = 0.41, P  = 0.52).
Conclusion
A physiological CMR model can estimate LVFP in patients with suspected HF. In addition, CMR-modelled LVFP has a prognostic role.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 04 May 2022; epub ahead of print
Garg P, Gosling R, Swoboda P, Jones R, ... Alabed S, Swift AJ
Eur Heart J: 04 May 2022; epub ahead of print | PMID: 35512290
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Abstract

Characteristics, management, and outcomes of patients with multiple native valvular heart disease: a substudy of the EURObservational Research Programme Valvular Heart Disease II Survey.

Tribouilloy C, Bohbot Y, Kubala M, Ruschitzka F, ... Vahanian A, Iung B
Aims
To assess the characteristics, management, and survival of patients with multiple native valvular heart disease (VHD).
Methods and results
Among the 5087 patients with ≥1 severe left-sided native VHD included in the EURObservational VHD II Survey (maximum 3-month recruitment period per centre between January and August 2017 with a 6-month follow-up), 3571 had a single left-sided VHD (Group A, 70.2%), 363 had one severe left-sided VHD with moderate VHD of the other ipsilateral valve (Group B, 7.1%), and 1153 patients (22.7%) had ≥2 severe native VHDs (left-sided and/or tricuspid regurgitation, Group C). Patients with multiple VHD (Groups B and C) were more often women, had greater congestive heart failure (CHF) and comorbidity, higher left atrial volumes and pulmonary pressures, and lower ejection fraction than Group A patients (all P ≤ 0.01). During the index hospitalization, 36.7% of Group A (n = 1312), 26.7% of Group B (n = 97), and 32.7% of Group C (n = 377) underwent valvular intervention (P < 0.001). Six-month survival was better for Group A than for Group B or C (both P < 0.001), even after adjustment for age, sex, body mass index, and Charlson index [hazard ratio (HR) 95% confidence interval (CI) 1.62 (1.10-2.38) vs. Group B and HR 95% CI 1.72 (1.32-2.25) vs. Group C]. Groups B and C had more CHF at 6 months than Group A (both P < 0.001). Factors associated with mortality in Group C were age, CHF, and comorbidity (all P < 0.010).
Conclusion
Multiple VHD is common, encountered in nearly 30% of patients with left-sided native VHD, and associated with greater cardiac damage and leads to higher mortality and more heart failure at 6 months than single VHD, yet with lower rates of surgery.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 02 May 2022; epub ahead of print
Tribouilloy C, Bohbot Y, Kubala M, Ruschitzka F, ... Vahanian A, Iung B
Eur Heart J: 02 May 2022; epub ahead of print | PMID: 35511056
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Abstract

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study.

Valerio L, Mavromanoli AC, Barco S, Abele C, ... Rosenkranz S, FOCUS Investigators
Aims
To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria.
Methods and results
A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI.
Conclusion
In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 28 Apr 2022; epub ahead of print
Valerio L, Mavromanoli AC, Barco S, Abele C, ... Rosenkranz S, FOCUS Investigators
Eur Heart J: 28 Apr 2022; epub ahead of print | PMID: 35484821
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Abstract

Which patients with aortic stenosis should be referred to surgery rather than transcatheter aortic valve implantation?

Windecker S, Okuno T, Unbehaun A, Mack M, Kapadia S, Falk V
Transcatheter aortic valve implantation (TAVI) has matured into a standard treatment option for patients with severe symptomatic aortic valve stenosis (AS) across the whole spectrum of risk. The advances in the interventional treatment of AS raise the question of which patients with severe AS should be referred to surgery. The myriad of clinical permutations does not allow providing a single, uniform treatment strategy. Rather, the advent of TAVI along with established surgical aortic valve replacement (SAVR) fundamentally enforces the role of the multidisciplinary heart team for decision-making recommending the best individual choice of the two options based on a thorough review of clinical and anatomical factors as well as lifetime management considerations. Involvement of the informed patient expressing treatment preferences is a key for a shared decision-making process. Herein, we provide an in-depth review of evidence informing the decision-making process between TAVI and SAVR and key elements for treatment selection. Special attention is given to the populations that have been excluded from randomized clinical trials, and also lifetime management strategies of patients with severe AS are proposed.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Apr 2022; epub ahead of print
Windecker S, Okuno T, Unbehaun A, Mack M, Kapadia S, Falk V
Eur Heart J: 25 Apr 2022; epub ahead of print | PMID: 35466382
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Abstract

Accelerated and personalized therapy for heart failure with reduced ejection fraction.

Shen L, Jhund PS, Docherty KF, Vaduganathan M, ... Zhang X, McMurray JJV
Aims
Previously, guidelines recommended initiating therapy in patients with heart failure and reduced ejection fraction (HFrEF) in a sequence that follows the chronological order in which trials were conducted, with cautious up-titration of each treatment. It remains unclear whether this historical approach is optimal and alternative approaches may improve patient outcomes.
Methods and results
The potential reductions in events that might result from (i) more rapid up-titration of therapies used in the conventional order (based on the chronology of the trials), and (ii) accelerated up-titration and using treatments in different orders than is conventional were modelled using data from six pivotal trials in HFrEF. Over the first 12 months from starting therapy, using a rapid up-titration schedule led to 23 fewer patients per 1000 patients experiencing the composite of heart failure hospitalization or cardiovascular death and seven fewer deaths from any cause. In addition to accelerating up-titration of treatments, optimized alternative ordering of the drugs used resulted in a further reduction of 24 patients experiencing the composite outcome and six fewer deaths at 12 months. The optimal alternative sequences included sodium-glucose cotransporter 2 inhibition and a mineralocorticoid receptor antagonist as the first two therapies.
Conclusion
Modelling of accelerated up-titration schedule and optimized ordering of treatment suggested that at least 14 deaths and 47 patients experiencing the composite outcome per 1000 treated might be prevented over the first 12 months after starting therapy. Standard treatment guidance may not lead to the best patient outcomes in HFrEF, though these findings should be tested in clinical trials.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Apr 2022; epub ahead of print
Shen L, Jhund PS, Docherty KF, Vaduganathan M, ... Zhang X, McMurray JJV
Eur Heart J: 25 Apr 2022; epub ahead of print | PMID: 35467706
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Abstract

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

Eckhardt CM, Balte PP, Barr RG, Bertoni AG, ... Yende S, Oelsner EC
Aims
The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF).
Methods and results
Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking.
Conclusion
Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 25 Apr 2022; epub ahead of print
Eckhardt CM, Balte PP, Barr RG, Bertoni AG, ... Yende S, Oelsner EC
Eur Heart J: 25 Apr 2022; epub ahead of print | PMID: 35467708
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Abstract

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond.

Odening KE, van der Linde HJ, Ackerman MJ, Volders PGA, Ter Bekke RMA
An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation-contraction coupling. However, the mutual influencing of excitation-contraction and mechano-electrical feedback in the beating heart, here designated \'electromechanical reciprocity\', remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed-by volume loading during the rapid filling phase-when repolarization is still ongoing. This creates a \'sensitized\' electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 21 Apr 2022; epub ahead of print
Odening KE, van der Linde HJ, Ackerman MJ, Volders PGA, Ter Bekke RMA
Eur Heart J: 21 Apr 2022; epub ahead of print | PMID: 35445703
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Abstract

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

Cadrin-Tourigny J, Bosman LP, Nozza A, Wang W, ... Te Riele ASJM, James CA
Aims
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.
Methods and results
Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001).
Conclusion
Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

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

Eur Heart J: 20 Apr 2022; epub ahead of print
Cadrin-Tourigny J, Bosman LP, Nozza A, Wang W, ... Te Riele ASJM, James CA
Eur Heart J: 20 Apr 2022; epub ahead of print | PMID: 35441664
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Abstract

Data standards for heart failure: the European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart).

Aktaa S, Batra G, Cleland JGF, Coats A, ... Gale CP, Heart Failure Association of the European Society of Cardiology
Standardized data definitions are essential for assessing the quality of care and patient outcomes in observational studies and randomized controlled trials. The European Unified Registries for Heart Care Evaluation and Randomized Trials (EuroHeart) project of the European Society of Cardiology (ESC) aims to create contemporary pan-European data standards for cardiovascular diseases, including heart failure (HF). We followed the EuroHeart methodology for cardiovascular data standard development. A Working Group including experts in HF registries, representatives from the Heart Failure Association of the ESC, and the EuroHeart was formed. Using Embase and Medline (2016-21), we conducted a systematic review of the literature on data standards, registries, and trials to identify variables pertinent to HF. A modified Delphi method was used to reach a consensus on the final set of variables. For each variable, the Working Group developed data definitions and agreed on whether it was mandatory (Level 1) or additional (Level 2). In total, 84 Level 1 and 79 Level 2 variables were selected for nine domains of HF care. These variables were reviewed by an international Reference Group with the Level 1 variables providing the dataset for registration of patients with HF on the EuroHeart IT platform. By means of a structured process and interaction with international stakeholders, harmonized data standards for HF have been developed. In the context of the EuroHeart, this will facilitate quality improvement, international observational research, registry-based randomized trials, and post-marketing surveillance of devices and pharmacotherapies across Europe.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 20 Apr 2022; epub ahead of print
Aktaa S, Batra G, Cleland JGF, Coats A, ... Gale CP, Heart Failure Association of the European Society of Cardiology
Eur Heart J: 20 Apr 2022; epub ahead of print | PMID: 35443059
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Abstract

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

Crespo-Leiro MG, Costanzo MR, Gustafsson F, Khush KK, ... Zuckermann A, Mehra MR
Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 20 Apr 2022; epub ahead of print
Crespo-Leiro MG, Costanzo MR, Gustafsson F, Khush KK, ... Zuckermann A, Mehra MR
Eur Heart J: 20 Apr 2022; epub ahead of print | PMID: 35441654
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Abstract

Adult T-cells impair neonatal cardiac regeneration.

Dolejsi T, Delgobo M, Schuetz T, Tortola L, ... Campos Ramos G, Haubner BJ
Aims
Newborn mice and humans display transient cardiac regenerative potential that rapidly declines postnatally. Patients who survive a myocardial infarction (MI) often develop chronic heart failure due to the heart\'s poor regeneration capacity. We hypothesized that the cardiac \'regenerative-to-scarring\' transition might be driven by the perinatal shifts observed in the circulating T-cell compartment.
Methods and results
Post-MI immune responses were characterized in 1- (P1) vs. 7-day-old (P7) mice subjected to left anterior descending artery ligation. Myocardial infarction induced robust early inflammatory responses (36 h post-MI) in both age groups, but neonatal hearts exhibited rapid resolution of inflammation and full functional recovery. The perinatal loss of myocardial regenerative capacity was paralleled by a baseline increase in αβ-T cell (CD4+ and CD8+) numbers. Strikingly, P1-infarcted mice reconstituted with adult T-cells shifted to an adult-like healing phenotype, marked by irreversible cardiac functional impairment and increased fibrosis. Infarcted neonatal mice harbouring adult T-cells also had more monocyte-derived macrophage recruitment, as typically seen in adults. At the transcriptome level, infarcted P1 hearts that received isolated adult T-cells showed enriched gene sets linked to fibrosis, inflammation, and interferon-gamma (IFN-γ) signalling. In contrast, newborn mice that received isolated Ifng-/- adult T-cells prior to MI displayed a regenerative phenotype that resembled that of its age-matched untreated controls.
Conclusion
Physiological T-cell development or adoptive transfer of adult IFN-γ-producing T-cells into neonates contributed to impaired cardiac regeneration and promoted irreversible structural and functional cardiac damage. These findings reveal a trade-off between myocardial regenerative potential and the development of T-cell competence.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 13 Apr 2022; epub ahead of print
Dolejsi T, Delgobo M, Schuetz T, Tortola L, ... Campos Ramos G, Haubner BJ
Eur Heart J: 13 Apr 2022; epub ahead of print | PMID: 35417553
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Abstract

Effects of aspirin on dementia and cognitive function in diabetic patients: the ASCEND trial.

Parish S, Mafham M, Offer A, Barton J, ... Armitage J, ASCEND Study Collaborative Group
Aims
Aspirin is widely used in cardiovascular disease prevention but is also associated with an increased risk of bleeding. The net effect of aspirin on dementia and cognitive impairment is uncertain.
Methods and results
In the ASCEND trial, 15 480 people from the UK with diabetes and no history of cardiovascular disease were randomized to aspirin 100 mg daily or matching placebo for a mean of 7.4 years. The 15 427 ASCEND participants with no recorded dementia prior to baseline were included in this cognitive study with a primary pre-specified outcome of \'broad dementia\', comprising dementia, cognitive impairment, or confusion. This was ascertained through participant, carer, or general practitioner report or hospital admission diagnosis, by 31 March 2019 (∼2 years beyond the scheduled treatment period). The broad dementia outcome occurred in a similar percentage of participants in the aspirin group and placebo group: 548 participants (7.1%) vs. 598 (7.8%), rate ratio 0.91 [95% confidence interval (CI), 0.81-1.02]. Thus, the CI excluded proportional hazards of >2% and proportional benefits of >19%.
Conclusion
Aspirin does not have a large proportional effect on the risk of dementia. Trials or meta-analyses with larger total numbers of incident dementia cases to increase statistical power are needed to assess whether any modest proportional 10-15% benefits of 5-7 years of aspirin use on dementia exist.
Clinical trial registration
Current Controlled Trials number, ISRCTN60635500; ClinicalTrials.gov number: NCT00135226.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 08 Apr 2022; epub ahead of print
Parish S, Mafham M, Offer A, Barton J, ... Armitage J, ASCEND Study Collaborative Group
Eur Heart J: 08 Apr 2022; epub ahead of print | PMID: 35393614
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Abstract

Global disparities in prescription of guideline-recommended drugs for heart failure with reduced ejection fraction.

Tromp J, Ouwerkerk W, Teng TK, Cleland JGF, ... Filippatos G, Lam CSP
Background
Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction (HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines.
Methods and results
This analysis assessed prescription rates and doses of renin-angiotensin system (RAS) inhibitors, β-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and β-blockers were independently associated with better 1-year survival, regardless of country income level.
Conclusion
Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 08 Apr 2022; epub ahead of print
Tromp J, Ouwerkerk W, Teng TK, Cleland JGF, ... Filippatos G, Lam CSP
Eur Heart J: 08 Apr 2022; epub ahead of print | PMID: 35393622
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Abstract

Twitter promotion is associated with higher citation rates of cardiovascular articles: the ESC Journals Randomized Study.

Ladeiras-Lopes R, Vidal-Perez R, Santos-Ferreira D, Alexander M, ... Crea F, Lüscher TF
The association between the dissemination of scientific articles on Twitter and online visibility (as assessed by the Altmetric Score) is still controversial, and the impact on citation rates has never been rigorously addressed for cardiovascular medicine journals using a randomized design. The ESC Journals Study randomized 695 papers published in the ESC Journal Family (March 2018-May 2019) for promotion on Twitter or to a control arm (with no active tweeting from ESC channels) and aimed to assess whether Twitter promotion was associated with an increase in citation rates (primary endpoint) and of the Altmetric Score. This is the final analysis including 694 articles (one paper excluded due to retraction). After a median follow-up of 994 days (interquartile range: 936-1063 days), Twitter promotion of articles was associated with a 1.12 (95% confidence interval: 1.08-1.15) higher rate of citations, and this effect was independent of the type of article. Altmetric Attention Score and number of users tweeting were positive predictors for the number of citations. A social media strategy of Twitter promotion for cardiovascular medicine papers seems to be associated with increased online visibility and higher numbers of citations.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 07 Apr 2022; epub ahead of print
Ladeiras-Lopes R, Vidal-Perez R, Santos-Ferreira D, Alexander M, ... Crea F, Lüscher TF
Eur Heart J: 07 Apr 2022; epub ahead of print | PMID: 35388421
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Abstract

Data standards for acute coronary syndrome and percutaneous coronary intervention: the European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart).

Association of Cardiovascular Nursing and Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), EURObservational Research Programme (EORP), ... Casadei B, Gale CP
Standardized data definitions are essential for monitoring and benchmarking the quality of care and patient outcomes in observational studies and randomized controlled trials. There are no contemporary pan-European data standards for the acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) project of the European Society of Cardiology (ESC) aimed to develop such data standards for ACS and PCI. Following a systematic review of the literature on ACS and PCI data standards and evaluation of contemporary ACS and PCI registries, we undertook a modified Delphi process involving clinical and registry experts from 11 European countries, as well as representatives from relevant ESC Associations, including the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and Acute CardioVascular Care (ACVC). This resulted in final sets of 68 and 84 \'mandatory\' variables and several catalogues of optional variables for ACS and PCI, respectively. Data definitions were provided for these variables, which have been programmed as the basis for continuous registration of individual patient data in the online EuroHeart IT platform. By means of a structured process and the interaction with major stakeholders, internationally harmonized data standards for ACS and PCI have been developed. In the context of the EuroHeart project, this will facilitate country-level quality of care improvement, international observational research, registry-based randomized trials, and post-marketing surveillance of devices and pharmacotherapies.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 05 Apr 2022; epub ahead of print
Association of Cardiovascular Nursing and Allied Professions (ACNAP), Association for Acute CardioVascular Care (ACVC), European Association of Percutaneous Cardiovascular Interventions (EAPCI), EURObservational Research Programme (EORP), ... Casadei B, Gale CP
Eur Heart J: 05 Apr 2022; epub ahead of print | PMID: 35380662
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Abstract

Survival of patients undergoing cardiac resynchronization therapy with or without defibrillator: the RESET-CRT project.

Hadwiger M, Dagres N, Haug J, Wolf M, ... Frielitz FS, Hindricks G
Aims
Cardiac resynchronization therapy (CRT) is an established treatment for heart failure. There is contradictory evidence whether defibrillator capability improves prognosis in patients receiving CRT. We compared the survival of patients undergoing de novo implantation of a CRT with defibrillator (CRT-D) option and CRT with pacemaker (CRT-P) in a large health claims database.
Methods and results
Using health claims data of a major German statutory health insurance, we analysed patients with de novo CRT implantation from 2014 to 2019 without indication for defibrillator implantation for secondary prevention of sudden cardiac death. We performed age-adjusted Cox proportional hazard regression and entropy balancing to calculate weights to control for baseline imbalances. The analysis comprised 847 CRT-P and 2722 CRT-D patients. Overall, 714 deaths were recorded during a median follow-up of 2.35 years. A higher cumulative incidence of all-cause death was observed in the initial unadjusted Kaplan-Meier time-to-event analysis [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.38-1.92]. After adjustment for age, HR was 1.13 (95% CI: 0.95-1.35) and after entropy balancing 0.99 (95% CI: 0.81-1.20). No survival differences were found in different age groups. The results were robust in sensitivity analyses.
Conclusion
In a large health claims database of CRT implantations performed in a contemporary setting, CRT-P treatment was not associated with inferior survival compared with CRT-D. Age differences accounted for the greatest part of the survival difference that was observed in the initial unadjusted analysis.
Key question
Is the defibrillator capability needed in cardiac resynchronization therapy (CRT)?Aim: Compare survival of patients receiving de novo CRT with and without defibrillator option between 2014 and 2019.Health claims data, same inclusion and exclusion criteria as in RESET-CRT randomized trial.
Key finding
CRT-P patients 6.7 years older than CRT-D patients.Comparable aetiology of heart failure.Median follow-up 2.35 years: 203 (24%) deaths in CRT-P and 511 (19%) deaths in CRT-D patients.Age differences accounted for the greatest part of the survival difference.
Take-home message
No survival differences between CRT-D and CRT-P after adjustment for age and entropy balancing.Results corroborate the hypothesis of the RESET-CRT randomized clinical trial.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 03 Apr 2022; epub ahead of print
Hadwiger M, Dagres N, Haug J, Wolf M, ... Frielitz FS, Hindricks G
Eur Heart J: 03 Apr 2022; epub ahead of print | PMID: 35366320
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Abstract

Importance of genetic testing in unexplained cardiac arrest.

Grondin S, Davies B, Cadrin-Tourigny J, Steinberg C, ... Krahn AD, Tadros R
Aims
Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES).
Methods and results
Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of \'explained\' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest.
Conclusions
Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 30 Mar 2022; epub ahead of print
Grondin S, Davies B, Cadrin-Tourigny J, Steinberg C, ... Krahn AD, Tadros R
Eur Heart J: 30 Mar 2022; epub ahead of print | PMID: 35352813
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Abstract

Middle age serum sodium levels in the upper part of normal range and risk of heart failure.

Dmitrieva NI, Liu D, Wu CO, Boehm M
Aims
With increasing prevalence of heart failure (HF) owing to the ageing population, identification of modifiable risk factors is important. In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. Here, we evaluate the association of serum sodium at middle age as a measure of hydration habits with risk to develop HF.
Methods and results
We analysed data from Atherosclerosis Risk in Communities study with middle age enrolment (45-66 years) and 25 years of follow-up. Participants without water balance dysregulation were selected: serum sodium within normal range (135-146 mmol/L), not diabetic, not obese and free of HF at baseline (N = 11 814). In time-to-event analysis, HF risk was increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to 1% body weight water deficit [hazard ratio 1.39, 95% confidence interval (CI) 1.14-1.70]. In a retrospective case-control analysis performed on 70- to 90-year-old attendees of Visit 5 (N = 4961), serum sodium of 142.5-143 mmol/L was associated with 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62, 95% CI 1.03-2.55]. Serum sodium above 143 mmol/L was associated with 107% increase in odds of LVH (OR 2.07, 95% CI 1.30-3.28) and 54% increase in odds of HF (OR 1.54, 95% CI 1.06-2.23). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium.
Conclusion
Middle age serum sodium above 142 mmol is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down decline in cardiac function and decrease prevalence of HF.

Published by Oxford University Press on behalf of European Society of Cardiology 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Eur Heart J: 29 Mar 2022; epub ahead of print
Dmitrieva NI, Liu D, Wu CO, Boehm M
Eur Heart J: 29 Mar 2022; epub ahead of print | PMID: 35348651
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Abstract

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

Kraler S, Wenzl FA, Georgiopoulos G, Obeid S, ... Akhmedov A, Lüscher TF
Aims
The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS).
Methods and results
Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031).
Conclusion
Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD.
Clinical trial registration
NCT01000701.
Key question
Experimental evidence has implicated the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] in atherosclerosis. The aim was to study the relationship of sLOX-1 with mortality and plaque progression in patients with acute coronary syndromes (ACS).
Key finding
Acute coronary syndrome patients displayed elevated sLOX-1 levels, with those in the highest tertile being at increased multivariable-adjusted risk of death from any [hazard ratio (HR) 2.04; P = 0.0098] and cardiovascular causes (HR, 2.29; P = 0.0148). Dynamics of sLOX-1 showed good discrimination for predicting plaque progression.
Take-home message
Plasma levels of sLOX-1 are increased during ACS and predict fatal events beyond established risk factors. Trajectories of sLOX-1 mirror coronary plaque progression after the index ACS. Soluble LOX-1 is a novel biomarker of coronary plaque vulnerability and progression.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 24 Mar 2022; epub ahead of print
Kraler S, Wenzl FA, Georgiopoulos G, Obeid S, ... Akhmedov A, Lüscher TF
Eur Heart J: 24 Mar 2022; epub ahead of print | PMID: 35325132
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Abstract

Risk factors, cardiovascular disease, and mortality in South America: a PURE substudy.

Lopez-Jaramillo P, Joseph P, Lopez-Lopez JP, Lanas F, ... Islam S, Yusuf S
Aims
In a multinational South American cohort, we examined variations in CVD incidence and mortality rates between subpopulations stratified by country, by sex and by urban or rural location. We also examined the contributions of 12 modifiable risk factors to CVD development and to death.
Methods and results
This prospective cohort study included 24 718 participants from 51 urban and 49 rural communities in Argentina, Brazil, Chile, and Colombia. The mean follow-up was 10.3 years. The incidence of CVD and mortality rates were calculated for the overall cohort and in subpopulations. Hazard ratios and population attributable fractions (PAFs) for CVD and for death were examined for 12 common modifiable risk factors, grouped as metabolic (hypertension, diabetes, abdominal obesity, and high non-HDL cholesterol), behavioural (tobacco, alcohol, diet quality, and physical activity), and others (education, household air pollution, strength, and depression). Leading causes of death were CVD (31.1%), cancer (30.6%), and respiratory diseases (8.6%). The incidence of CVD (per 1000 person-years) only modestly varied between countries, with the highest incidence in Brazil (3.86) and the lowest in Argentina (3.07). There was a greater variation in mortality rates (per 1000 person-years) between countries, with the highest in Argentina (5.98) and the lowest in Chile (4.07). Men had a higher incidence of CVD (4.48 vs. 2.60 per 1000 person-years) and a higher mortality rate (6.33 vs. 3.96 per 1000 person-years) compared with women. Deaths were higher in rural compared to urban areas. Approximately 72% of the PAF for CVD and 69% of the PAF for deaths were attributable to 12 modifiable risk factors. For CVD, largest PAFs were due to hypertension (18.7%), abdominal obesity (15.4%), tobacco use (13.5%), low strength (5.6%), and diabetes (5.3%). For death, the largest PAFs were from tobacco use (14.4%), hypertension (12.0%), low education (10.5%), abdominal obesity (9.7%), and diabetes (5.5%).
Conclusions
Cardiovascular disease, cancer, and respiratory diseases account for over two-thirds of deaths in South America. Men have consistently higher CVD and mortality rates than women. A large proportion of CVD and premature deaths could be averted by controlling metabolic risk factors and tobacco use, which are common leading risk factors for both outcomes in the region.
Key questions
How do the rates of cardiovascular disease (CVD) and death vary within South America, and what are the predominant risk factors for each?
Key findings
Cardiovascular disease and death rates were both higher in men compared with women. Death rates were higher in rural compared with urban areas. Hypertension, obesity, diabetes, and tobacco use were leading risk factors for both CVD and death.
Take-home message
A large proportion of CVD and premature deaths in South America could be averted by policies aimed at controlling metabolic risk factors and tobacco use.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 23 Mar 2022; epub ahead of print
Lopez-Jaramillo P, Joseph P, Lopez-Lopez JP, Lanas F, ... Islam S, Yusuf S
Eur Heart J: 23 Mar 2022; epub ahead of print | PMID: 35325078
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Abstract

Influence of atrial fibrillation on efficacy and safety of omecamtiv mecarbil in heart failure: the GALACTIC-HF trial.

Solomon SD, Claggett BL, Miao ZM, Diaz R, ... Malik FI, Teerlink JR
Aims
In GALACTIC-HF, the cardiac myosin activator omecamtiv mecarbil compared with placebo reduced the risk of heart failure events or cardiovascular death in patients with heart failure with reduced ejection fraction. We explored the influence of atrial fibrillation or flutter (AFF) on the effectiveness of omecamtiv mecarbil.
Methods and results
GALACTIC-HF enrolled patients with New York Heart Association (NYHA) Class II-IV heart failure, left ventricular ejection fraction ≤35%, and elevated natriuretic peptides. We assessed whether the presence or absence of AFF, a pre-specified subgroup, modified the treatment effect for the primary and secondary outcomes, and additionally explored effect modification in patients who were or were not receiving digoxin. Patients with AFF (n = 2245, 27%) were older, more likely to be randomized as an inpatient, less likely to have a history of ischaemic aetiology or myocardial infarction, had a worse NYHA class, worse quality of life, lower estimated glomerular filtration rate, and higher N-terminal pro-B-type natriuretic peptide. The treatment effect of omecamtiv mecarbil was modified by baseline AFF (interaction P = 0.012), with patients without AFF at baseline deriving greater benefit. The worsening of the treatment effect by baseline AFF was significantly more pronounced in digoxin users than in non-users (interaction P = 0.007); there was minimal evidence of effect modification in those patients not using digoxin (P = 0.47) or in digoxin users not in AFF.
Conclusion
Patients in AFF at baseline were less likely to benefit from omecamtiv mecarbil than patients without AFF, although the attenuation of the treatment effect was disproportionally concentrated in patients with AFF who were also receiving digoxin.Clinical Trial Registration: NCT02929329.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 23 Mar 2022; epub ahead of print
Solomon SD, Claggett BL, Miao ZM, Diaz R, ... Malik FI, Teerlink JR
Eur Heart J: 23 Mar 2022; epub ahead of print | PMID: 35325102
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Abstract

Leadless vs. transvenous single-chamber ventricular pacing in the Micra CED study: 2-year follow-up.

El-Chami MF, Bockstedt L, Longacre C, Higuera L, ... Kowal RC, Piccini JP
Aims 
Clinical trials have demonstrated the safety and efficacy of the Micra leadless VVI pacemaker; however, longer-term outcomes in a large, real-world population with a contemporaneous comparison to transvenous VVI pacemakers have not been examined. We compared reinterventions, chronic complications, and all-cause mortality at 2 years between leadless VVI and transvenous VVI implanted patients.
Methods and results 
The Micra Coverage with Evidence Development study is a continuously enrolling, observational, cohort study of leadless VVI pacemakers in the US Medicare fee-for-service population. Patients implanted with a leadless VVI pacemaker between March 9, 2017, and December 31, 2018, were identified using Medicare claims data linked to manufacturer device registration data (n = 6219). All transvenous VVI patients from facilities with leadless VVI implants during the study period were obtained directly from Medicare claims (n = 10 212). Cox models were used to compare 2-year outcomes between groups. Compared to transvenous VVI, patients with leadless VVI had more end-stage renal disease (12.0% vs. 2.3%) and a higher Charlson comorbidity index (5.1 vs. 4.6). Leadless VVI patients had significantly fewer reinterventions [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45-0.85, P = 0.003] and chronic complications (adjusted HR 0.69, 95% CI 0.60-0.81, P < 0.0001) compared with transvenous VVI patients. Adjusted all-cause mortality at 2 years was not different between the two groups (adjusted HR 0.97, 95% CI 0.91-1.04, P = 0.37).
Conclusion 
In a real-world study of US Medicare patients, the Micra leadless VVI pacemaker was associated with a 38% lower adjusted rate of reinterventions and a 31% lower adjusted rate of chronic complications compared with transvenous VVI pacing. There was no difference in adjusted all-cause mortality at 2 years.

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

Eur Heart J: 21 Mar 2022; 43:1207-1215
El-Chami MF, Bockstedt L, Longacre C, Higuera L, ... Kowal RC, Piccini JP
Eur Heart J: 21 Mar 2022; 43:1207-1215 | PMID: 34788416
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Impact:
Abstract

Risk of sports-related sudden cardiac death in women.

Rajan D, Garcia R, Svane J, Tfelt-Hansen J
Sudden cardiac death (SCD) is a tragic incident accountable for up to 50% of deaths from cardiovascular disease. Sports-related SCD (SrSCD) is a phenomenon which has previously been associated with both competitive and recreational sport activities. SrSCD has been found to occur 5-33-fold less frequently in women than in men, and the sex difference persists despite a rapid increase in female participation in sports. Establishing the reasons behind this difference could pinpoint targets for improved prevention of SrSCD. Therefore, this review summarizes existing knowledge on epidemiology, characteristics, and causes of SrSCD in females, and elaborates on proposed mechanisms behind the sex differences. Although literature concerning the aetiology of SrSCD in females is limited, proposed mechanisms include sex-specific variations in hormones, blood pressure, autonomic tone, and the presentation of acute coronary syndromes. Consequently, these biological differences impact the degree of cardiac hypertrophy, dilation, right ventricular remodelling, myocardial fibrosis, and coronary atherosclerosis, and thereby the occurrence of ventricular arrhythmias in male and female athletes associated with short- and long-term exercise. Finally, cardiac examinations such as electrocardiograms and echocardiography are useful tools allowing easy differentiation between physiological and pathological cardiac adaptations following exercise in women. However, as a significant proportion of SrSCD causes in women are non-structural or unexplained after autopsy, channelopathies may play an important role, encouraging attention to prodromal symptoms and family history. These findings will aid in the identification of females at high risk of SrSCD and development of targeted prevention for female sport participants.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J: 21 Mar 2022; 43:1198-1206
Rajan D, Garcia R, Svane J, Tfelt-Hansen J
Eur Heart J: 21 Mar 2022; 43:1198-1206 | PMID: 34894223
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Abstract

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy: a translational study.

Cerrone M, Marrón-Liñares GM, van Opbergen CJM, Costa S, ... Te Riele ASJM, Delmar M
Aims
Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls.
Methods and results
Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls.
Conclusions
We speculate that exercise challenges a cardiomyocyte \"desmosomal reserve\" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J: 21 Mar 2022; 43:1251-1264
Cerrone M, Marrón-Liñares GM, van Opbergen CJM, Costa S, ... Te Riele ASJM, Delmar M
Eur Heart J: 21 Mar 2022; 43:1251-1264 | PMID: 34932122
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Abstract

Sudden cardiac death in congenital heart disease.

Khairy P, Silka MJ, Moore JP, DiNardo JA, ... Gatzoulis MA, Ladouceur M
Sudden cardiac death (SCD) accounts for up to 25% of deaths in patients with congenital heart disease (CHD). To date, research has largely been driven by observational studies and real-world experience. Drawbacks include varying definitions, incomplete taxonomy that considers SCD as a unitary diagnosis as opposed to a terminal event with diverse causes, inconsistent outcome ascertainment, and limited data granularity. Notwithstanding these constraints, identified higher-risk substrates include tetralogy of Fallot, transposition of the great arteries, cyanotic heart disease, Ebstein anomaly, and Fontan circulation. Without autopsies, it is often impossible to distinguish SCD from non-cardiac sudden deaths. Asystole and pulseless electrical activity account for a high proportion of SCDs, particularly in patients with heart failure. High-quality cardiopulmonary resuscitation is essential to improve outcomes. Pulmonary hypertension and CHD complexity are associated with lower likelihood of successful resuscitation. Risk stratification for primary prevention implantable cardioverter-defibrillators (ICDs) should consider the probability of SCD due to a shockable rhythm, competing causes of mortality, complications of ICD therapy, and associated costs. Risk scores to better estimate probabilities of SCD and CHD-specific guidelines and consensus-based recommendations have been proposed. The subcutaneous ICD has emerged as an attractive alternative to transvenous systems in those with vascular access limitations, prior device infections, intra-cardiac shunts, or a Fontan circulation. Further improving SCD-related outcomes will require a multidimensional approach to research that addresses disease processes and triggers, taxonomy to better reflect underlying pathophysiology, high-risk features, early warning signs, access to high-quality cardiopulmonary resuscitation and specialized care, and preventive therapies tailored to underlying mechanisms.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 18 Mar 2022; epub ahead of print
Khairy P, Silka MJ, Moore JP, DiNardo JA, ... Gatzoulis MA, Ladouceur M
Eur Heart J: 18 Mar 2022; epub ahead of print | PMID: 35302168
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Abstract

Cardiac sympathetic denervation in the prevention of genetically mediated life-threatening ventricular arrhythmias.

Schwartz PJ, Ackerman MJ
Proper management of patients affected by genetic disorders causing life-threatening arrhythmias is important for several reasons, including even societal ones, given the predominantly young age of those affected. Incorrect management often has dire consequences, ranging from unnecessary psychologic damage for the patients whose life becomes too limited by the fear of sudden death to equally avoidable tragedies when the entire armamentarium of effective therapies is not fully utilized. In this review, we focus primarily on long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) and deal specifically with the clinical impact of the most commonly used cardiac sympathetic denervation (CSD), namely left cardiac sympathetic denervation (LCSD). The two of us have used LCSD in the management of our patients with either LQTS or CPVT for a very long time and have been involved in ∼500 such interventions. It is on the basis of this personal and direct experience that we wish to share our views with clinical cardiologists and electrophysiologists, adult and paediatric, and with genetic cardiologists. We will begin by reviewing the history and rationale underlying sympathetic denervation therapy and will continue with a disease-specific intensification of therapy, and then with a discussion on how the impressive efficacy of LCSD should translate into guideline-directed therapy in both current and future guidelines, in order to upgrade the quality of care in the era of precision medicine.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 18 Mar 2022; epub ahead of print
Schwartz PJ, Ackerman MJ
Eur Heart J: 18 Mar 2022; epub ahead of print | PMID: 35301528
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Abstract

P2Y12 inhibitor adherence trajectories in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prognostic implications.

Turgeon RD, Koshman SL, Dong Y, Graham MM
Aims
Post-acute coronary syndrome (ACS) P2Y12 inhibitor non-adherence is common and associated with greater risk of major adverse cardiovascular events (MACEs). Non-adherence can follow different trajectories from an inability to initiate, implement, or continue therapy for the intended duration. We aimed to evaluate P2Y12 inhibitor adherence trajectories among ACS patients treated with percutaneous coronary intervention (PCI), their frequency, and association with MACE.
Methods and results
We conducted a cohort study of adults discharged alive after PCI for ACS (2012-16) using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry linked with administrative data. The primary outcome was P2Y12 inhibitor adherence trajectory in the year after PCI assessed using group-based trajectory modelling. We used logistic regression and Cox proportional-hazards regression to assess associations of trajectories with risk factors and MACE, respectively. We included 12 844 patients (mean age 62.4 years, 23.6% female). Five trajectories were identified: early consistent non-adherence (11.0%), rapid decline (7.7%), delayed initiation (6.0%), gradual decline (20.5%), and persistent adherence (54.8%). Compared with persistent adherence, rapid decline [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01-1.49] and delayed initiation (HR 1.41, 95% CI 1.12-1.78) were associated with higher MACE in the overall cohort, whereas early consistent non-adherence was associated with higher MACE only in the subgroup receiving a drug-eluting stent (HR 2.44, 95% CI 1.60-3.71).
Conclusion
After PCI for ACS, patients followed one of five distinct P2Y12 inhibitor adherence trajectories. Rapid decline and delayed initiation were associated with a higher risk of MACE, whereas early consistent non-adherence was only associated with higher MACE risk in patients with a drug-eluting stent.
Key questions

Key findings

Take-home message


© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 17 Mar 2022; epub ahead of print
Turgeon RD, Koshman SL, Dong Y, Graham MM
Eur Heart J: 17 Mar 2022; epub ahead of print | PMID: 35296876
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Abstract

Vascular dysfunction and increased cardiovascular risk in hypospadias.

Lucas-Herald AK, Montezano AC, Alves-Lopes R, Haddow L, ... Ahmed SF, Touyz RM
Aims
Hypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease.
Methods and results
Our human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4-5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5-11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7-114.3, P = 0.02).
Conclusion
Hypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.
Key question
Is hypospadias associated with vascular dysfunction?
Key finding
Boys with hypospadias have evidence of hypercontractility and impaired vasodilation secondary to increased Rho kinase activation and oxidative stress. This leads to raised systolic blood pressure in adolescence and increased risk of admission to hospital for cardiovascular diseases in adulthood.
Take-home message
Hypospadias is a risk factor for cardiovascular dysfunction in males.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Eur Heart J: 17 Mar 2022; epub ahead of print
Lucas-Herald AK, Montezano AC, Alves-Lopes R, Haddow L, ... Ahmed SF, Touyz RM
Eur Heart J: 17 Mar 2022; epub ahead of print | PMID: 35296881
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Abstract

The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway.

Farina FM, Serio S, Hall IF, Zani S, ... Quintavalle M, Elia L
Aims
Histone H3 dimethylation at lysine 79 is a key epigenetic mark uniquely induced by methyltransferase disruptor of telomeric silencing 1-like (DOT1L). We aimed to determine whether DOT1L modulates vascular smooth muscle cell (VSMC) phenotype and how it might affect atherosclerosis in vitro and in vivo, unravelling the related mechanism.
Methods and results
Gene expression screening of VSMCs stimulated with the BB isoform of platelet-derived growth factor led us to identify Dot1l as an early up-regulated epigenetic factor. Mouse and human atherosclerotic lesions were assessed for Dot1l expression, which resulted specifically localized in the VSMC compartment. The relevance of Dot1l to atherosclerosis pathogenesis was assessed through deletion of its gene in the VSMCs via an inducible, tissue-specific knock-out mouse model crossed with the ApoE-/- high-fat diet model of atherosclerosis. We found that the inactivation of Dot1l significantly reduced the progression of the disease. By combining RNA- and H3K79me2-chromatin immunoprecipitation-sequencing, we found that DOT1L and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and -2, master modulators of inflammation, which in turn induce the expression of CCL5 and CXCL10, cytokines fundamentally involved in atherosclerosis development. Finally, a correlation between coronary artery disease and genetic variations in the DOT1L gene was found because specific polymorphisms are associated with increased mRNA expression.
Conclusion
DOT1L plays a key role in the epigenetic control of VSMC gene expression, leading to atherosclerosis development. Results identify DOT1L as a potential therapeutic target for vascular diseases.
Key question
Epigenetics plays an important role in the regulation of atherosclerosis development. Its role in vascular smooth muscle cell biology and immune cell recruitment is not yet fully understood.
Key finding
Inhibition of the epigenetic enzyme disruptor of telomeric silencing 1-like (DOT1L) in vascular smooth muscle cells significantly reduces atherosclerosis progression, directly modulating Nfκb1 and Nfκb2 transcription. These genes are master regulators of inflammation, able to induce the expression of CCL5 and CXCL10 cytokines, which play a fundamental role in atherosclerosis development.
Take home message
DOT1L could be a promising therapeutic target since its inhibition reduces plaque progression.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Eur Heart J: 15 Mar 2022; epub ahead of print
Farina FM, Serio S, Hall IF, Zani S, ... Quintavalle M, Elia L
Eur Heart J: 15 Mar 2022; epub ahead of print | PMID: 35292818
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Abstract

ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2-care pathways, treatment, and follow-up.

Task Force for the management of COVID-19 of the European Society of Cardiology
Aims
Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular (CV) disease in association with COVID-19.
Methods and results
A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, which was reported previously, focused on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. This second part addresses the topics of: care pathways and triage systems and management and treatment pathways, both of the most commonly encountered CV conditions and of COVID-19; and information that may be considered useful to help patients with CV disease (CVD) to avoid exposure to COVID-19.
Conclusion
This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.

This article has been co-published with permission in the European Heart Journal and Cardiovascular Research. © The European Society of Cardiology 2021. All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Eur Heart J: 14 Mar 2022; 43:1059-1103
Task Force for the management of COVID-19 of the European Society of Cardiology
Eur Heart J: 14 Mar 2022; 43:1059-1103 | PMID: 34791154
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Impact:
Abstract

European Society of Cardiology guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 1-epidemiology, pathophysiology, and diagnosis.

Task Force for the management of COVID-19 of the European Society of Cardiology
Aims
Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two-part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular disease (CVD) in association with COVID-19.
Methods and results
A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, reported here, focuses on the epidemiology, pathophysiology, and diagnosis of cardiovascular (CV) conditions that may be manifest in patients with COVID-19. The second part, which will follow in a later edition of the journal, addresses the topics of care pathways, treatment, and follow-up of CV conditions in patients with COVID-19.
Conclusion
This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.

This article has been co-published with permission in the European Heart Journal and Cardiovascular Research. © The European Society of Cardiology 2021. All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Eur Heart J: 14 Mar 2022; 43:1033-1058
Task Force for the management of COVID-19 of the European Society of Cardiology
Eur Heart J: 14 Mar 2022; 43:1033-1058 | PMID: 34791157
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Impact:
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