Journal: Eur Heart J

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Abstract

Valvular heart disease: shifting the focus to the myocardium.

Ajmone Marsan N, Delgado V, Shah DJ, Pellikka P, ... Treibel T, Cavalcante JL
Adverse cardiac remodelling is the main determinant of patient prognosis in degenerative valvular heart disease (VHD). However, to give an indication for valvular intervention, current guidelines include parameters of cardiac chamber dilatation or function which are subject to variability, do not directly reflect myocardial structural changes, and, more importantly, seem to be not sensitive enough in depicting early signs of myocardial dysfunction before irreversible myocardial damage has occurred. To avoid irreversible myocardial dysfunction, novel biomarkers are advocated to help refining indications for intervention and risk stratification. Advanced echocardiographic modalities, including strain analysis, and magnetic resonance imaging have shown to be promising in providing new tools to depict the important switch from adaptive to maladaptive myocardial changes in response to severe VHD. This review, therefore, summarizes the current available evidence on the role of these new imaging biomarkers in degenerative VHD, aiming at shifting the clinical perspective from a valve-centred to a myocardium-focused approach for patient management and therapeutic decision-making.

© 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 Sep 2022; epub ahead of print
Ajmone Marsan N, Delgado V, Shah DJ, Pellikka P, ... Treibel T, Cavalcante JL
Eur Heart J: 28 Sep 2022; epub ahead of print | PMID: 36167923
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Abstract

Association of anti-Ro seropositivity with cardiac rhythm and conduction disturbances.

Akuka A, Ben-Shabat N, Watad A, Tsur AM, ... Cohen AD, Amital H
Aims
Anti-Ro/La autoantibodies are especially prevalent in autoimmune diseases but are also relatively frequent in healthy adults. Their arrhythmogenic effect on the immature cardiac conductive system is well established, with substantial evidence demonstrating an increased risk for congenital atrioventricular block in neonates of seropositive mothers. Despite their wide distribution and their arrhythmogenic potential effect, there are no large population studies conducted in seropositive adults. Thus, this is the first large population-based study to examine the association of anti-Ro/La seropositivity with cardiac rhythm and conduction disturbances.
Methods and results
This cross-sectional designed study involved the electronic health records of the largest health maintenance organization in Israel. All subjects that were tested positive for anti-Ro/anti-La antibodies between the years 2002 and 2019 were included and were matched by age, gender, and place of residence, with controls. Rates of different cardiac rhythm and conduction disturbances were compared between groups. Sensitivity analyses were performed using propensity score matching. The study population included 17 231 anti-Ro/La seropositive subjects and 84 368 controls. Anti-Ro seropositive patients had higher rates of conduction disturbances (3.0 vs. 1.7%, P < 0.001) and rhythm disturbances (10.5 vs. 7.0%, P < 0.001). Patients who tested positive for anti-La alone did not demonstrate a significant association with arrhythmias. Multivariate logistic regression analysis, controlling for possible confounders, showed an increased risk for cardiac conduction disturbances [odds ratio (OR) 1.44, 95% confidence interval (CI) 1.25-1.66, P < 0.001], as well as for cardiac rhythm disturbances (OR 1.21, 95% CI 1.11-1.31, P < 0.001) among anti-Ro seropositive patients. However, the association with rhythm disturbances was more robust in certain subgroup analyses.
Conclusions
Anti-Ro seropositivity is positively associated with adult cardiac conduction disturbances and, to a lesser extent, cardiac rhythm disturbances, regardless of the presence of concurrent autoimmune 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: 23 Sep 2022; epub ahead of print
Akuka A, Ben-Shabat N, Watad A, Tsur AM, ... Cohen AD, Amital H
Eur Heart J: 23 Sep 2022; epub ahead of print | PMID: 36148481
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Abstract

Albuminuria as a marker of systemic congestion in patients with heart failure.

Boorsma EM, Ter Maaten JM, Damman K, van Essen BJ, ... Voors AA, Emmens JE
Aims
Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated.
Methods and results
Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumin-creatinine ratio (UACR) >30 mg/gCr and >300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4% and 10.0%, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P < 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95% confidence interval 0.35-0.53, P < 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings.
Conclusion
In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.

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

Eur Heart J: 23 Sep 2022; epub ahead of print
Boorsma EM, Ter Maaten JM, Damman K, van Essen BJ, ... Voors AA, Emmens JE
Eur Heart J: 23 Sep 2022; epub ahead of print | PMID: 36148485
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Abstract

Sex differences in arterial hypertension.

Gerdts E, Sudano I, Brouwers S, Borghi C, ... Parati G, de Simone G
There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension.

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

Eur Heart J: 22 Sep 2022; epub ahead of print
Gerdts E, Sudano I, Brouwers S, Borghi C, ... Parati G, de Simone G
Eur Heart J: 22 Sep 2022; epub ahead of print | PMID: 36136303
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Abstract

The search for optimal antithrombotic therapy in transcatheter aortic valve implantation: facts and uncertainties.

Ten Berg J, Rocca B, Angiolillo DJ, Hayashida K
Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure, which is used frequently in patients with symptomatic severe aortic valve stenosis. Most patients undergoing TAVI are over 80 years of age with a high bleeding as well as thrombotic risk. Despite the increasing safety of the procedure, thromboembolic events [stroke, (subclinical) valve thrombosis] remain prevalent. As a consequence, antithrombotic prophylaxis is routinely used and only recently new data on the efficacy and safety of antithrombotic drugs has become available. On the other hand, these antithrombotic drugs increase bleeding in a population with unique aortic stenosis-related bleeding characteristics (such as acquired von Willebrand factor defect and angiodysplasia). In this review, we discuss the impact of thromboembolic and bleeding events, the current optimal antithrombotic therapy based on registries and recent randomized controlled trials, as well as try to give a practical guide how to treat these high-risk patients. Finally, we discuss knowledge gaps and future research needed to fill these gaps.

© 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: 21 Sep 2022; epub ahead of print
Ten Berg J, Rocca B, Angiolillo DJ, Hayashida K
Eur Heart J: 21 Sep 2022; epub ahead of print | PMID: 36130256
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Abstract

Post-infarction ventricular septal defect: percutaneous or surgical management in the UK national registry.

Giblett JP, Matetic A, Jenkins D, Ng CY, ... Mamas MA, Calvert PA
Aims
Post-infarction ventricular septal defect (PIVSD) is a mechanical complication of acute myocardial infarction (AMI) with a poor prognosis. Surgical repair is the mainstay of treatment, although percutaneous closure is increasingly undertaken.
Methods and resuts
Patients treated with surgical or percutaneous repair of PIVSD (2010-2021) were identified at 16 UK centres. Case note review was undertaken. The primary outcome was long-term mortality. Patient groups were allocated based upon initial management (percutaneous or surgical). Three-hundred sixty-two patients received 416 procedures (131 percutaneous, 231 surgery). 16.1% of percutaneous patients subsequently had surgery. 7.8% of surgical patients subsequently had percutaneous treatment. Times from AMI to treatment were similar [percutaneous 9 (6-14) vs. surgical 9 (4-22) days, P = 0.18]. Surgical patients were more likely to have cardiogenic shock (62.8% vs. 51.9%, P = 0.044). Percutaneous patients were substantially older [72 (64-77) vs. 67 (61-73) years, P < 0.001] and more likely to be discussed in a heart team setting. There was no difference in long-term mortality between patients (61.1% vs. 53.7%, P = 0.17). In-hospital mortality was lower in the surgical group (55.0% vs. 44.2%, P = 0.048) with no difference in mortality after hospital discharge (P = 0.65). Cardiogenic shock [adjusted hazard ratio (aHR) 1.97 (95% confidence interval 1.37-2.84), P < 0.001), percutaneous approach [aHR 1.44 (1.01-2.05), P = 0.042], and number of vessels with coronary artery disease [aHR 1.22 (1.01-1.47), P = 0.043] were independently associated with long-term mortality.
Conclusion
Surgical and percutaneous repair are viable options for management of PIVSD. There was no difference in post-discharge long-term mortality between patients, although in-hospital mortality was lower for 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: 17 Sep 2022; epub ahead of print
Giblett JP, Matetic A, Jenkins D, Ng CY, ... Mamas MA, Calvert PA
Eur Heart J: 17 Sep 2022; epub ahead of print | PMID: 36124729
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Abstract

Small non-coding RNA therapeutics for cardiovascular disease.

Shah AM, Giacca M
Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.

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

Eur Heart J: 15 Sep 2022; epub ahead of print
Shah AM, Giacca M
Eur Heart J: 15 Sep 2022; epub ahead of print | PMID: 36106499
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Abstract

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines.

Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

The article has been co-published with permission in the European Heart Journal, the Journal of the American College of Cardiology, and Circulation. © The Author(s) 2022.

Eur Heart J: 14 Sep 2022; 43:3302-3311
Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B
Eur Heart J: 14 Sep 2022; 43:3302-3311 | PMID: 36100239
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Abstract

The collateral damage of COVID-19 to cardiovascular services: a meta-analysis.

Nadarajah R, Wu J, Hurdus B, Asma S, ... Mamas M, Gale CP
Aims
The effect of the COVID-19 pandemic on care and outcomes across non-COVID-19 cardiovascular (CV) diseases is unknown. A systematic review and meta-analysis was performed to quantify the effect and investigate for variation by CV disease, geographic region, country income classification and the time course of the pandemic.
Methods and results
From January 2019 to December 2021, Medline and Embase databases were searched for observational studies comparing a pandemic and pre-pandemic period with relation to CV disease hospitalisations, diagnostic and interventional procedures, outpatient consultations, and mortality. Observational data were synthesised by incidence rate ratios (IRR) and risk ratios (RR) for binary outcomes and weighted mean differences for continuous outcomes with 95% confidence intervals. The study was registered with PROSPERO (CRD42021265930). A total of 158 studies, covering 49 countries and 6 continents, were used for quantitative synthesis. Most studies (80%) reported information for high-income countries (HICs). Across all CV disease and geographies there were fewer hospitalisations, diagnostic and interventional procedures, and outpatient consultations during the pandemic. By meta-regression, in low-middle income countries (LMICs) compared to HICs the decline in ST-segment elevation myocardial infarction (STEMI) hospitalisations (RR 0.79, 95% confidence interval [CI] 0.66-0.94) and revascularisation (RR 0.73, 95% CI 0.62-0.87) was more severe. In LMICs, but not HICs, in-hospital mortality increased for STEMI (RR 1.22, 95% CI 1.10-1.37) and heart failure (RR 1.08, 95% CI 1.04-1.12). The magnitude of decline in hospitalisations for CV diseases did not differ between the first and second wave.
Conclusions
There was substantial global collateral CV damage during the COVID-19 pandemic with disparity in severity by country income classification.

© 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 Sep 2022; 43:3164-3178
Nadarajah R, Wu J, Hurdus B, Asma S, ... Mamas M, Gale CP
Eur Heart J: 01 Sep 2022; 43:3164-3178 | PMID: 36044988
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Abstract

Cardiovascular complications of immune checkpoint inhibitors for cancer.

Thuny F, Naidoo J, Neilan TG
Over the last decade or so, there has been a paradigm shift in the oncologic care of patients with a range of solid tumour and haematologic malignancies, away from traditional cytotoxic chemotherapy and towards personalized cancer treatments, using both targeted therapy and immunotherapy. This shift has contributed to the remarkable and sustained increase in the number of cancer survivors and the longevity of patients with a cancer diagnosis. This review will focus on the cardiovascular effects of immune checkpoint inhibitors and will present a background on immune checkpoint inhibition for cancer, the epidemiology, potential mechanisms, the potential insights into cardiovascular biology, and a diagnostic and therapeutic approach to potential cases. Our understanding of the cardiovascular effects of immune checkpoint inhibitors needs to improve. However, the evolution necessarily needs to be rapid. Initial observations noted that immune checkpoint inhibitor therapy can lead to a fulminant myocarditis. Recent reports have expanded the effect of immune checkpoint inhibitor therapy on the cardiovascular system to include an increase in cardiac dysfunction without myocarditis, arrhythmias, venous thromboembolic disease, accelerated atherosclerosis, and atherosclerosis-related cardiovascular events. The association between immune checkpoint inhibitor therapy and an increase in these cardiovascular events is not only limited to events occurring within the first few weeks after starting therapy but can also include events that occur months to years after therapy. The latter observation is especially of relevance in those treated with adjuvant or neoadjuvant therapy. There needs to be a shift from recognition of an increase in cardiovascular events to currently approved immune checkpoint inhibitor therapies to understanding the mechanisms that lead to adverse cardiovascular effects, understanding who is at risk, and understanding what we can do about it.

© 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: 30 Aug 2022; epub ahead of print
Thuny F, Naidoo J, Neilan TG
Eur Heart J: 30 Aug 2022; epub ahead of print | PMID: 36040835
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Abstract

Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST - AFNET 4 trial.

Eckardt L, Sehner S, Suling A, Borof K, ... Metzner A, Kirchhof P
Background
A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known which aspects of ERC contribute to outcome reduction.
Methods
Using the EAST - AFNET 4 trial data set, potential mediators of the effect of early rhythm control were identified in the total study population at 12-month follow-up and further interrogated by use of a 4-way decomposition of the treatment effect in an exponential model predicting future primary outcome events.
Results
Fourteen potential mediators of ERC were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect of ERC compared to usual care during the remainder of follow-up (4.1 years). In patients not in sinus rhythm at 12 months, ERC did not reduce future cardiovascular outcomes (hazard ratio 0.94, 95% confidence interval 0.65-1.67). Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%, respectively. There was no difference in outcomes in patients who underwent AF ablation compared to those who did not undergo AF ablation.
Conclusions
The effectiveness of early rhythm control therapy is mediated by the presence of sinus rhythm at 12 months in the EAST - AFNET 4 trial. Clinicians implementing early rhythm control should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities.Funded by AFNET, DZHK, EHRA, Deutsche Herzstiftung (DHS), Abbott Laboratories, Sanofi. EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010 -021258-20.

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

Eur Heart J: 29 Aug 2022; epub ahead of print
Eckardt L, Sehner S, Suling A, Borof K, ... Metzner A, Kirchhof P
Eur Heart J: 29 Aug 2022; epub ahead of print | PMID: 36036648
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Abstract

Highly malignant disease in childhood-onset arrhythmogenic right ventricular cardiomyopathy.

Smedsrud MK, Chivulescu M, Forså MI, Castrini I, ... Früh A, Haugaa KH
Aims
This study aimed to explore the incidence of severe cardiac events in paediatric arrhythmogenic right ventricular cardiomyopathy (ARVC) patients and ARVC penetrance in paediatric relatives. Furthermore, the phenotype in childhood-onset ARVC was described.
Methods
Consecutive ARVC paediatric patients and genotype positive relatives ≤18 years of age were followed with electrocardiographic, structural and arrhythmic characteristics according to the 2010 revised Task Force Criteria. Penetrance of ARVC disease was defined as fulfilling definite ARVC criteria and severe cardiac events were defined as cardiac death, heart transplantation (HTx) or severe ventricular arrhythmias. Childhood-onset disease was defined as meeting definite ARVC criteria ≤12 years of age.
Results
Among 62 individuals (age 9.8 [5.0-14.0] years, 11 probands), 20 (32%) fulfilled definite ARVC diagnosis, of which 8 (40%) had childhood-onset disease. The incidence of severe cardiac events was 23% (n = 14) by last follow-up and half of them occurred in patients ≤12 years of age. Among the 8 patients with childhood-onset disease, 5 had biventricular involvement needing HTx and 3 had severe arrhythmic events.Among the 51 relatives, 6% (n = 3) met definite ARVC criteria at time of genetic diagnosis, increasing to 18% (n = 9) at end of follow-up.
Conclusions
In a paediatric ARVC cohort, there was a high incidence of severe cardiac events and half of them occurred in children ≤12 years of age. The ARVC penetrance in genotype positive paediatric relatives was 18%. These findings of a high-malignant phenotype in childhood-onset ARVC indicate a need for ARVC family screening at younger age than currently recommended.

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

Eur Heart J: 29 Aug 2022; epub ahead of print
Smedsrud MK, Chivulescu M, Forså MI, Castrini I, ... Früh A, Haugaa KH
Eur Heart J: 29 Aug 2022; epub ahead of print | PMID: 36036653
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Abstract

Empagliflozin in acute Myocardial Infarction: the EMMY trial.

von Lewinski D, Kolesnik E, Tripolt NJ, Pferschy PN, ... Oulhaj A, Sourij H
Background:
and aims
Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalisation for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking.
Methods
In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 U/L) were randomly assigned to empagliflozin 10 mg or matching placebo once-daily within 72 hours of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters.
Results
Baseline median (interquartile range) NT-proBNP was 1,294 (757-2,246) pg/ml. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower (95% confidence interval [CI] -4.4% to -23.6%) after adjusting for baseline NT-proBNP, sex and diabetes status (p = 0.026). Absolute left ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2% to 2.9%, p = 0.029), mean E/e\' reduction was 6.8% (95% CI 1.3% to 11.3%, p = 0.015) greater, and left ventricular end-systolic and end-diastolic volumes were lower by 7.5 ml (95% CI 3.4 to 11.5 ml, p = 0.0003) and 9.7 ml (95% CI 3.7 to 15.7 ml, p = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalised for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups.
Conclusions
In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters.

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

Eur Heart J: 29 Aug 2022; epub ahead of print
von Lewinski D, Kolesnik E, Tripolt NJ, Pferschy PN, ... Oulhaj A, Sourij H
Eur Heart J: 29 Aug 2022; epub ahead of print | PMID: 36036746
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Abstract

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

Kronenberg F, Mora S, Stroes ESG, Ference BA, ... Tokgözoğlu LS, Catapano AL
This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

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

Eur Heart J: 29 Aug 2022; epub ahead of print
Kronenberg F, Mora S, Stroes ESG, Ference BA, ... Tokgözoğlu LS, Catapano AL
Eur Heart J: 29 Aug 2022; epub ahead of print | PMID: 36036785
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Abstract

Device-related complications in the subcutaneous and transvenous ICD: a secondary analysis of the PRAETORIAN trial.

Knops RE, Pepplinkhuizen S, Delnoy PPHM, Boersma LVA, ... Wilde AAM, Olde Nordkamp LRA
Background
The subcutaneous ICD (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial.
Methods
The PRAETORIAN trial is an international, multicenter, randomised trial in which 849 patients with an indication for ICD therapy were randomised to receive an SICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections and the need for invasive interventions.
Results
Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group 49 complications occurred in 44 patients of which lead-dysfunction was most frequent (HR 0.69; P =0.11). In both groups half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared to the TV-ICD group (P <0.001, P =0.03 respectively). Significantly more complications required invasive interventions in the TV-ICD group compared to the S-ICD group (8.3% vs. 4.3%, HR 0.59; P =0.047).
Conclusions
This secondary analysis shows that, lead-related complications and systemic infections are more prevalent in the TV-ICD group compared to the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision making in clinical practice.

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

Eur Heart J: 28 Aug 2022; epub ahead of print
Knops RE, Pepplinkhuizen S, Delnoy PPHM, Boersma LVA, ... Wilde AAM, Olde Nordkamp LRA
Eur Heart J: 28 Aug 2022; epub ahead of print | PMID: 36030464
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Abstract

Last year of life of adults with congenital heart diseases: causes of death and patterns of care.

Van Bulck L, Goossens E, Morin L, Luyckx K, ... Moons P, BELCODAC consortium
Background:
and aims
Although life expectancy in adults with congenital heart diseases (CHD) has increased dramatically over the past five decades, still a substantial number of patients dies prematurely. To gain understanding in the trajectories of dying in adults with CHD, the last year of life warrants further investigation. Therefore, our study aimed to (i) define the causes of death, and (ii) describe the patterns of healthcare utilisation in the last year of life of adults with CHD.
Methods and results
This retrospective mortality follow-back study used healthcare claims and clinical data from BELCODAC, which includes patients with CHD from Belgium. Healthcare utilisation comprises cardiovascular procedures, CHD physician contacts, general practitioner visits, hospitalisations, emergency department (ED) visits, intensive care unit (ICU) admissions, and specialist palliative care and was identified using nomenclature codes. Of the 390 included patients, almost half of the study population (45%) died from a cardiovascular cause. In the last year of life, 87% of patients were hospitalised, 78% of patients had an ED visit, and 19% of patients had an ICU admission. Specialist palliative care was provided to 17% of patients, and to only 4% when looking at the patients with cardiovascular causes of death.
Conclusions
There is a high use of intensive and potentially avoidable care at the end of life. This may imply that end-of-life care provision can be improved. Future studies should further examine end-of-life care provision in the light of patient\'s needs and preferences, and how the healthcare system can adequately respond.

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

Eur Heart J: 28 Aug 2022; epub ahead of print
Van Bulck L, Goossens E, Morin L, Luyckx K, ... Moons P, BELCODAC consortium
Eur Heart J: 28 Aug 2022; epub ahead of print | PMID: 36030410
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Abstract

Dapagliflozin for heart failure according to body mass index: the DELIVER trial.

Adamson C, Kondo T, Jhund P, de Boer RA, ... Solomon SD, McMurray JJ
Background:
and aims
Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in DELIVER.
Methods
BMI was analyzed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines.
Results
BMI ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (SD ± 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); class I obesity 1574 (25.2%); class II obesity 798 (12.8%); class III obesity 415 (6.6%). Compared to placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval) 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002).
Conclusions
Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared to those without, and has the additional benefit of causing modest weight loss.

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

Eur Heart J: 27 Aug 2022; epub ahead of print
Adamson C, Kondo T, Jhund P, de Boer RA, ... Solomon SD, McMurray JJ
Eur Heart J: 27 Aug 2022; epub ahead of print | PMID: 36029309
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Abstract

Predicting stroke in heart failure and reduced ejection fraction without atrial fibrillation.

Kondo T, Abdul-Rahim AH, Talebi A, Abraham WT, ... Jhund PS, McMurray JJ
Background:
and aims
Patients with heart failure with reduced ejection fraction (HFrEF) are at significant risk of stroke. Anticoagulation reduces this risk in patients with and without atrial fibrillation (AF), but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy.
Methods
In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level), was validated.
Results
Of the 20,159 patients included, 12,751 patients did not have AF at baseline. Among patients without AF, 346 (2.7%) experienced a stroke over a median follow-up of 2.0 years (rate 11.7 per 1000 patient-years). The risk for stroke increased with increasing risk score: fourth quintile HR 2.35 (95%CI 1.60-3.45); fifth quintile HR 3.73 (2.58-5.38), with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years).Model discrimination was good with a C-index of 0.84 (0.75-0.91).
Conclusions
It is possible to identify a subset of HFrEF patients without AF with a stroke risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively.

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

Eur Heart J: 26 Aug 2022; epub ahead of print
Kondo T, Abdul-Rahim AH, Talebi A, Abraham WT, ... Jhund PS, McMurray JJ
Eur Heart J: 26 Aug 2022; epub ahead of print | PMID: 36017729
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Impact:
Abstract

Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program.

Zannad F, Ferreira JP, Butler J, Filippatos G, ... Anker SD, Packer M
Background
Sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study.
Aims
To explore the effect of empagliflozin on circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.
Methods
Over 1250 circulating proteins were measured at baseline, week 12 and week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs placebo), which were then linked to demonstrated biological actions in the heart and kidneys.
Results
At week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e., their levels were changed by ≥10% with a false discovery rate < 1% (empagliflozin vs placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to week 52 were generally concordant with the changes from baseline to week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at week 52, but not at week 12. The most common biological action of differentially-expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially-expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.
Conclusions
Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport.

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

Eur Heart J: 26 Aug 2022; epub ahead of print
Zannad F, Ferreira JP, Butler J, Filippatos G, ... Anker SD, Packer M
Eur Heart J: 26 Aug 2022; epub ahead of print | PMID: 36017745
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Abstract

Left bundle branch area pacing outcomes: the multicentre European MELOS study.

Jastrzębski M, Kiełbasa G, Cano O, Curila K, ... Zanon F, Vernooy K
Aims
Permanent transseptal left bundle branch area pacing (LBBAP) is a promising new pacing method for both bradyarrhythmia and heart failure indications. However, data regarding safety, feasibility and capture type are limited to relatively small, usually single centre studies. In this large multicentre international collaboration, outcomes of LBBAP were evaluated.
Methods and results
This is a registry-based observational study that included patients in whom LBBAP device implantation was attempted at 14 European centres, for any indication. The study comprised 2533 patients (mean age 73.9 years, female 57.6%, heart failure 27.5%). LBBAP lead implantation success rate for bradyarrhythmia and heart failure indications was 92.4% and 82.2%, respectively. The learning curve was steepest for the initial 110 cases and plateaued after 250 cases. Independent predictors of LBBAP lead implantation failure were heart failure, broad baseline QRS and left ventricular end-diastolic diameter. The predominant LBBAP capture type was left bundle fascicular capture (69.5%), followed by left ventricular septal capture (21.5%) and proximal left bundle branch capture (9%). Capture threshold (0.77 V) and sensing (10.6 mV) were stable during mean follow-up of 6.4 months. The complication rate was 11.7%. Complications specific to the ventricular transseptal route of the pacing lead occurred in 209 patients (8.3%).
Conclusions
LBBAP is feasible as a primary pacing technique for both bradyarrhythmia and heart failure indications. Success rate in heart failure patients and safety need to be improved. For wider use of LBBAP, randomized trials are necessary to assess clinical outcomes.

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

Eur Heart J: 18 Aug 2022; epub ahead of print
Jastrzębski M, Kiełbasa G, Cano O, Curila K, ... Zanon F, Vernooy K
Eur Heart J: 18 Aug 2022; epub ahead of print | PMID: 35979843
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Impact:
Abstract

A polygenic risk score predicts atrial fibrillation in cardiovascular disease.

Marston NA, Garfinkel AC, Kamanu FK, Melloni GM, ... Sabatine MS, Ruff CT
Aims
Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear.
Methods and results
A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan-Meier event rates, adjusted hazard ratios (HRs), C-indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32-1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99-3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C-index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS.
Conclusion
In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP.

© 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 Aug 2022; epub ahead of print
Marston NA, Garfinkel AC, Kamanu FK, Melloni GM, ... Sabatine MS, Ruff CT
Eur Heart J: 18 Aug 2022; epub ahead of print | PMID: 35980763
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Impact:
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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Impact:
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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Impact:
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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Impact:
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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Impact:
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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Impact:
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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Impact:
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.

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

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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Impact:
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.

© 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 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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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.

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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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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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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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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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Impact:

This program is still in alpha version.