Journal: Eur Heart J

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Abstract

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Aims
Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.
Methods and results
Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.
Conclusions
Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.
Trial registration
ClinicalTrials.gov number: NCT01947621.

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

Eur Heart J: 06 Sep 2020; 41:3255-3268
Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Eur Heart J: 06 Sep 2020; 41:3255-3268 | PMID: 32484517
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Abstract

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study.

Zabel M, Willems R, Lubinski A, Bauer A, ... Merkely B,
Aims
The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy.
Methods and results
We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537-0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class Conclusion
In contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.

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

Eur Heart J: 20 Sep 2020; 41:3437-3447
Zabel M, Willems R, Lubinski A, Bauer A, ... Merkely B,
Eur Heart J: 20 Sep 2020; 41:3437-3447 | PMID: 32372094
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Abstract

A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPA-LVH trial.

Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC
Aim
We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D).
Methods and results
We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of -2.82g [95% confidence interval (CI): -5.13 to -0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change -2.92g; 95% CI: -5.45 to -0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049).
Conclusion
Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin.
Clinicaltrials.gov identifier
NCT02956811.

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

Eur Heart J: 20 Sep 2020; 41:3421-3432
Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC
Eur Heart J: 20 Sep 2020; 41:3421-3432 | PMID: 32578850
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Abstract

Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization.

Cecelja M, Keehn L, Ye L, Spector TD, Hughes AD, Chowienczyk P
Aims
Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness.
Methods and results
We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001).
Conclusion
The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness.

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

Eur Heart J: 13 Sep 2020; 41:3314-3322
Cecelja M, Keehn L, Ye L, Spector TD, Hughes AD, Chowienczyk P
Eur Heart J: 13 Sep 2020; 41:3314-3322 | PMID: 32357239
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Abstract

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

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

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

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

Eur Heart J: 02 Nov 2020; epub ahead of print
Levey AS, Eckardt KU, Dorman NM, Christiansen SL, ... Jadoul M, Winkelmayer WC
Eur Heart J: 02 Nov 2020; epub ahead of print | PMID: 33141221
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Abstract

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

Simons SO, Elliott A, Sastry M, Hendriks JM, ... Crijns HJGM, Linz D

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

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

Eur Heart J: 17 Nov 2020; epub ahead of print
Simons SO, Elliott A, Sastry M, Hendriks JM, ... Crijns HJGM, Linz D
Eur Heart J: 17 Nov 2020; epub ahead of print | PMID: 33206945
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Abstract

Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy.

Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Aims
Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.
Method and results
Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.
Conclusion
H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

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

Eur Heart J: 20 Sep 2020; 41:3462-3474
Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Eur Heart J: 20 Sep 2020; 41:3462-3474 | PMID: 32657324
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Abstract

Interdisciplinary management of acute ischaemic stroke: Current evidence training requirements for endovascular stroke treatment.

Nardai S, Lanzer P, Abelson M, Baumbach A, ... Flodmark O, Widimsky P

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

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

Eur Heart J: 06 Nov 2020; epub ahead of print
Nardai S, Lanzer P, Abelson M, Baumbach A, ... Flodmark O, Widimsky P
Eur Heart J: 06 Nov 2020; epub ahead of print | PMID: 33160282
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Abstract

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease.

Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Lüscher TF

Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

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

Eur Heart J: 06 Nov 2020; epub ahead of print
Akhmedov A, Sawamura T, Chen CH, Kraler S, Vdovenko D, Lüscher TF
Eur Heart J: 06 Nov 2020; epub ahead of print | PMID: 33159784
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Abstract

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

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

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

Eur Heart J: 05 Nov 2020; epub ahead of print
Wang L, Wang F, Chen L, Geng Y, Yu S, Chen Z
Eur Heart J: 05 Nov 2020; epub ahead of print | PMID: 33156911
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Abstract

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

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

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

Eur Heart J: 19 Nov 2020; epub ahead of print
Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Collier TJ, Zannad F
Eur Heart J: 19 Nov 2020; epub ahead of print | PMID: 33215209
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Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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

Eur Heart J: 13 Oct 2020; 41:3856-3861
Packer M
Eur Heart J: 13 Oct 2020; 41:3856-3861 | PMID: 32460327
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Abstract

Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study.

Kim J, Kang D, Park H, Kang M, ... Cho J, Hahn JY
Aims
To investigate the association between long-term β-blocker therapy and clinical outcomes in patients without heart failure (HF) after acute myocardial infarction (AMI).
Method and results
Between 2010 and 2015, a total of 28 970 patients who underwent coronary revascularization for AMI with β-blocker prescription at hospital discharge and were event-free from death, recurrent myocardial infarction (MI), or HF for 1 year were enrolled from Korean nationwide medical insurance data. The primary outcome was all-cause death. The secondary outcomes were recurrent MI, hospitalization for new HF, and a composite of all-cause death, recurrent MI, or hospitalization for new HF. Outcomes were compared between β-blocker therapy for ≥1 year (N = 22 707) and β-blocker therapy for <1 year (N = 6263) using landmark analysis at 1 year after index MI. Compared with patients receiving β-blocker therapy for <1 year, those receiving β-blocker therapy for ≥1 year had significantly lower risks of all-cause death [adjusted hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.72-0.91] and composite of all-cause death, recurrent MI, or hospitalization for new HF (adjusted HR 0.82; 95% CI 0.75-0.89), but not the risks of recurrent MI or hospitalization for new HF. The lower risk of all-cause death associated with persistent β-blocker therapy was observed beyond 2 years (adjusted HR 0.86; 95% CI 0.75-0.99) but not beyond 3 years (adjusted HR 0.87; 95% CI 0.73-1.03) after MI.
Conclusion
In this nationwide cohort, β-blocker therapy for ≥1 year after MI was associated with reduced all-cause death among patients with AMI without HF.

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

Eur Heart J: 30 Sep 2020; 41:3521-3529
Kim J, Kang D, Park H, Kang M, ... Cho J, Hahn JY
Eur Heart J: 30 Sep 2020; 41:3521-3529 | PMID: 32542362
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Abstract

An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.

Kunadian V, Chieffo A, Camici PG, Berry C, ... Capodanno D, Baumbach A

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA). Angina pectoris affects approximately 112 million people globally. Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms. INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment. INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation.

The article has been co-published with permission in the European Heart Journal and EuroIntervention. All rights reserved. © 2020 the Author(s). These articles are identical except for minor stylistic and spelling differences in keeping with each journal\'s style. Either citation can be used when citing this article.

Eur Heart J: 30 Sep 2020; 41:3504-3520
Kunadian V, Chieffo A, Camici PG, Berry C, ... Capodanno D, Baumbach A
Eur Heart J: 30 Sep 2020; 41:3504-3520 | PMID: 32626906
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Abstract

Validation of the European Society of Cardiology pre-test probability model for obstructive coronary artery disease.

Winther S, Schmidt SE, Rasmussen LD, Juárez Orozco LE, ... Knuuti J, Bøttcher M
Aims 
Estimation of pre-test probability (PTP) of disease in patients with suspected coronary artery disease (CAD) is a common challenge. Due to decreasing prevalence of obstructive CAD in patients referred for diagnostic testing, the European Society of Cardiology suggested a new PTP (2019-ESC-PTP) model. The aim of this study was to validate that model.
Methods and results 
Symptomatic patients referred for coronary computed tomography angiography (CTA) due to suspected CAD in a geographical uptake area of 3.3 million inhabitants were included. The reference standard was a combined endpoint of CTA and invasive coronary angiography (ICA) with obstructive CAD defined at ICA as a ≥50% diameter stenosis or fractional flow reserve ≤0.80 when performed. The 2019-ESC-PTP, 2013-ESC-PTP, and CAD Consortium basic PTP scores were calculated based on age, sex, and symptoms. Of the 42 328 identified patients, coronary stenosis was detected in 8.8% using the combined endpoint. The 2019-ESC-PTP and CAD Consortium basic scores classified substantially more patients into the low PTP groups (PTP < 15%) than did the 2013-ESC-PTP (64% and 65% vs. 16%, P < 0.001). Using the combined endpoint as reference, calibration of the 2019-ESC-PTP model was superior to the 2013-ESC-PTP and CAD Consortium basic score.
Conclusion 
The new 2019-ESC-PTP model is well calibrated and superior to the previously recommended models in predicting obstructive stenosis detected by a combined endpoint of CTA and ICA.

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

Eur Heart J: 11 Nov 2020; epub ahead of print
Winther S, Schmidt SE, Rasmussen LD, Juárez Orozco LE, ... Knuuti J, Bøttcher M
Eur Heart J: 11 Nov 2020; epub ahead of print | PMID: 33180904
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Impact:
Abstract

Current use and safety of novel oral anticoagulants in adults with congenital heart disease: results of a nationwide analysis including more than 44 000 patients.

Freisinger E, Gerß J, Makowski L, Marschall U, ... Koeppe J, Diller GP
Aims
To evaluate the use of novel oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) in adult congenital heart disease (ACHD) and assess outcome in a nationwide analysis.
Methods and results
Using data from one of Germany\'s largest Health Insurers, all ACHD patients treated with VKAs or NOACs were identified and changes in prescription patterns were assessed. Furthermore, the association between anticoagulation regimen and complications including mortality was studied. Between 2005 and 2018, the use of oral anticoagulants in ACHD increased from 6.3% to 12.4%. Since NOACs became available their utilization increased constantly, accounting for 45% of prescribed anticoagulants in ACHD in 2018. Adult congenital heart disease patients on NOACs had higher thromboembolic (3.8% vs. 2.8%), MACE (7.8% vs. 6.0%), bleeding rates (11.7% vs. 9.0%), and all-cause mortality (4.0% vs. 2.8%; all P < 0.05) after 1 year of therapy compared with VKAs. After comprehensive adjustment for patient characteristics, NOACs were still associated with increased risk of MACE (hazard rate-HR 1.22; 95% CI 1.09-1.36) and increased all-cause mortality (HR 1.43; 95% CI 1.24-1.65; both P < 0.001), but also bleeding (HR 1.16; 95% CI 1.04-1.29; P = 0.007) during long-term follow-up.
Conclusion
Despite the lack of prospective studies in ACHD, NOACs are increasingly replacing VKAs and now account for almost half of all oral anticoagulant prescriptions. Particularly, NOACs were associated with excess long-term risk of MACE, and mortality in this nationwide analysis, emphasizing the need for prospective studies before solid recommendations for their use in ACHD can be provided.

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

Eur Heart J: 12 Nov 2020; epub ahead of print
Freisinger E, Gerß J, Makowski L, Marschall U, ... Koeppe J, Diller GP
Eur Heart J: 12 Nov 2020; epub ahead of print | PMID: 33184662
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Impact:
Abstract

Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin.

Ferrannini G, Gerstein H, Colhoun HM, Dagenais GR, ... Sheu WH, Rydén L
Objective 
Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial.
Research design and methods 
Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection.
Results 
Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81-1.05) vs. 0.78 (CI 0.61-0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin.
Conclusion 
This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.

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

Eur Heart J: 15 Nov 2020; epub ahead of print
Ferrannini G, Gerstein H, Colhoun HM, Dagenais GR, ... Sheu WH, Rydén L
Eur Heart J: 15 Nov 2020; epub ahead of print | PMID: 33197271
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Impact:
Abstract

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

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

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

Eur Heart J: 18 Nov 2020; epub ahead of print
Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL
Eur Heart J: 18 Nov 2020; epub ahead of print | PMID: 33211823
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Impact:
Abstract

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

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

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

Eur Heart J: 16 Nov 2020; epub ahead of print
Sun S, Cao W, Ge Y, Ran J, ... Tian L, Wellenius GA
Eur Heart J: 16 Nov 2020; epub ahead of print | PMID: 33205210
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Impact:
Abstract

Long-term outcomes after myocardial infarction in middle-aged and older patients with congenital heart disease-a nationwide study.

Fedchenko M, Mandalenakis Z, Giang KW, Rosengren A, Eriksson P, Dellborg M
Aims 
We aimed to describe the risk of myocardial infarction (MI) in middle-aged and older patients with congenital heart disease (ACHD) and to evaluate the long-term outcomes after index MI in patients with ACHD compared with controls.
Methods and results 
A search of the Swedish National Patient Register identified 17 189 patients with ACHD (52.2% male) and 180 131 age- and sex-matched controls randomly selected from the general population who were born from 1930 to 1970 and were alive at 40 years of age; all followed up until December 2017 (mean follow-up 23.2 ± 11.0 years). Patients with ACHD had a 1.6-fold higher risk of MI compared with controls [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.5-1.7, P < 0.001] and the cumulative incidence of MI by 65 years of age was 7.4% in patients with ACHD vs. 4.4% in controls. Patients with ACHD had a 1.4-fold increased risk of experiencing a composite event after the index MI compared with controls (HR 1.4, 95% CI 1.3-1.6, P < 0.001), driven largely by the occurrence of new-onset heart failure in 42.2% (n = 537) of patients with ACHD vs. 29.5% (n = 2526) of controls.
Conclusion 
Patients with ACHD had an increased risk of developing MI and of recurrent MI, new-onset heart failure, or death after the index MI, compared with controls, mainly because of a higher incidence of newly diagnosed heart failure in patients with ACHD. Recognizing and managing the modifiable cardiovascular risk factors should be of importance to reduce morbidity and mortality in patients with ACHD.

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

Eur Heart J: 20 Nov 2020; epub ahead of print
Fedchenko M, Mandalenakis Z, Giang KW, Rosengren A, Eriksson P, Dellborg M
Eur Heart J: 20 Nov 2020; epub ahead of print | PMID: 33219678
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Impact:
Abstract

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

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

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

Eur Heart J: 25 Nov 2020; epub ahead of print
Wartolowska KA, Webb AJS
Eur Heart J: 25 Nov 2020; epub ahead of print | PMID: 33238300
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Impact:
Abstract

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

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

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

Eur Heart J: 26 Nov 2020; epub ahead of print
Saucy A, Schäffer B, Tangermann L, Vienneau D, Wunderli JM, Röösli M
Eur Heart J: 26 Nov 2020; epub ahead of print | PMID: 33245107
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Impact:
Abstract

Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction.

Sorimachi H, Obokata M, Takahashi N, Reddy YNV, ... Jensen MD, Borlaug BA
Aims 
Central obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. We hypothesized that sex-specific differences in visceral adipose tissue (VAT) content would differentially relate to haemodynamic severity of HFpEF in women and men.
Methods and results 
Abdominal computed tomography (CT) and invasive haemodynamic exercise testing were performed in 105 subjects with HFpEF (63 women) and 105 age-, sex-, and body mass index-matched controls. Visceral adipose tissue area was quantified by CT. As compared with control women, VAT area was 34% higher in women with HFpEF (186 ± 112 vs. 139 ± 72 cm2, P = 0.006), while VAT area was not significantly different in men with or without HFpEF (294 ± 158 vs. 252 ± 92 cm2, P = 0.1). During exercise, pulmonary capillary wedge pressure (PCWP) increased markedly and to similar extent in both men and women with HFpEF. Women with increased VAT area displayed 33% higher PCWP during exercise compared with women with normal VAT area (28 ± 10 vs. 21 ± 10 mmHg, P = 0.001), whereas exercise PCWP was similar in men with or without excess VAT (24 ± 9 vs. 25 ± 6, P = 0.89). In women, each 100 cm2 increase in VAT area was associated with a 4.0 mmHg higher PCWP (95% CI 2.1, 6.0 mmHg; P < 0.0001), but there was no such relationship in men (interaction P = 0.009).
Conclusions 
These data suggest that accumulation of excess VAT plays a distinct and important role in the pathophysiology of HFpEF preferentially in women. Further research is needed to better understand the mechanisms and treatment implications for visceral fat in HFpEF.

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

Eur Heart J: 22 Nov 2020; epub ahead of print
Sorimachi H, Obokata M, Takahashi N, Reddy YNV, ... Jensen MD, Borlaug BA
Eur Heart J: 22 Nov 2020; epub ahead of print | PMID: 33227126
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Impact:
Abstract

Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention.

Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, ... Levin E, Stroes ESG
Aims
In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort.
Methods and results
Using the proximity extension assay, 368 proteins were measured in a nested case-control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001).
Conclusion
In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention.

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

Eur Heart J: 31 Oct 2020; 41:3998-4007
Hoogeveen RM, Pereira JPB, Nurmohamed NS, Zampoleri V, ... Levin E, Stroes ESG
Eur Heart J: 31 Oct 2020; 41:3998-4007 | PMID: 32808014
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Impact:
Abstract

Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention.

Juul Rasmussen I, Rasmussen KL, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R
Aims
Dementia is a major global challenge for health and social care in aging populations. A third of all dementia may be preventable due to cardiovascular risk factors. Intensive multi-domain intervention trials targeting primarily cardiovascular risk factors show improved cognitive function in people at risk. Such interventions will, however, be expensive to implement in all individuals at risk and will represent unrealistic economic tasks for most societies. Therefore, a risk score identifying high-risk individuals is warranted.
Methods and results
In 61 664 individuals from two prospective cohorts of the Danish general population, we generated 10-year absolute risk scores for all-cause dementia from cardiovascular risk factors and genetics. In both sexes, 10-year absolute risk of all-cause dementia increased with increasing age, number of apolipoprotein E (APOE) ɛ4 alleles, number of genome-wide association studies (GWAS) risk alleles, and cardiovascular risk factors. The highest 10-year absolute risks of all-cause dementia seen in smoking women with diabetes, low education, APOE ɛ44 genotype, and 22-31 GWAS risk alleles were 6%, 23%, 48%, and 66% in those aged 50-59, 60-69, 70-79, and 80-100, respectively. Corresponding values for men were 5%, 19%, 42%, and 60%, respectively.
Conclusion
Ten-year absolute risk of all-cause dementia increased with age, APOE ɛ4 alleles, GWAS risk alleles, diabetes, low education, and smoking in both women and men. Ten-year absolute risk charts for dementia will facilitate identification of high-risk individuals, those who likely will benefit the most from an early intervention against cardiovascular risk factors.

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

Eur Heart J: 31 Oct 2020; 41:4024-4033
Juul Rasmussen I, Rasmussen KL, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R
Eur Heart J: 31 Oct 2020; 41:4024-4033 | PMID: 33022702
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Impact:
Abstract

Prevalence, incidence, and outcomes across cardiovascular diseases in homeless individuals using national linked electronic health records.

Nanjo A, Evans H, Direk K, Hayward AC, Story A, Banerjee A
Aims
The risk and burden of cardiovascular disease (CVD) are higher in homeless than in housed individuals but population-based analyses are lacking. The aim of this study was to investigate prevalence, incidence and outcomes across a range of specific CVDs among homeless individuals.
Methods and results 
Using linked UK primary care electronic health records (EHRs) and validated phenotypes, we identified homeless individuals aged ≥16 years between 1998 and 2019, and age- and sex-matched housed controls in a 1:5 ratio. For 12 CVDs (stable angina; unstable angina; myocardial infarction; sudden cardiac death or cardiac arrest; unheralded coronary death; heart failure; transient ischaemic attack; ischaemic stroke; subarachnoid haemorrhage; intracerebral haemorrhage; peripheral arterial disease; abdominal aortic aneurysm), we estimated prevalence, incidence, and 1-year mortality post-diagnosis, comparing homeless and housed groups. We identified 8492 homeless individuals (32 134 matched housed individuals). Comorbidities and risk factors were more prevalent in homeless people, e.g. smoking: 78.1% vs. 48.3% and atrial fibrillation: 9.9% vs. 8.6%, P < 0.001. CVD prevalence (11.6% vs. 6.5%), incidence (14.7 vs. 8.1 per 1000 person-years), and 1-year mortality risk [adjusted hazard ratio 1.64, 95% confidence interval (CI) 1.29-2.08, P < 0.001] were higher, and onset was earlier (difference 4.6, 95% CI 2.8-6.3 years, P < 0.001), in homeless, compared with housed people. Homeless individuals had higher CVD incidence in all three arterial territories than housed people.
Conclusion 
CVD in homeless individuals has high prevalence, incidence, and 1-year mortality risk post-diagnosis with earlier onset, and high burden of risk factors. Inclusion health and social care strategies should reflect this high preventable and treatable burden, which is increasingly important in the current COVID-19 context.

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

Eur Heart J: 31 Oct 2020; 41:4011-4020
Nanjo A, Evans H, Direk K, Hayward AC, Story A, Banerjee A
Eur Heart J: 31 Oct 2020; 41:4011-4020 | PMID: 33205821
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Impact:
Abstract

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

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

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

Eur Heart J: 25 Nov 2020; epub ahead of print
Assmus B, Cremer S, Kirschbaum K, Culmann D, ... Dimmeler S, Zeiher AM
Eur Heart J: 25 Nov 2020; epub ahead of print | PMID: 33241418
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Impact:
Abstract

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

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

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

Eur Heart J: 10 Nov 2020; epub ahead of print
Täubel J, Hauke W, Rump S, Viereck J, ... Solomon SD, Thum T
Eur Heart J: 10 Nov 2020; epub ahead of print | PMID: 33245749
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Impact:
Abstract

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

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

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

Eur Heart J: 29 Nov 2020; epub ahead of print
Silvain J, Zeitouni M, Paradies V, Zheng HL, ... Bulluck H, Hausenloy DJ
Eur Heart J: 29 Nov 2020; epub ahead of print | PMID: 33257958
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Impact:
Abstract

Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Mass General Brigham YOUNG-MI registry.

DeFilippis EM, Collins BL, Singh A, Biery DW, ... Bhatt DL, Blankstein R
Aims
There are sex differences in presentation, treatment, and outcomes of myocardial infarction (MI) but less is known about these differences in a younger patient population. The objective of this study was to investigate sex differences among individuals who experience their first MI at a young age.
Methods and results
Consecutive patients presenting to two large academic medical centres with a Type 1 MI at ≤50 years of age between 2000 and 2016 were included. Cause of death was adjudicated using electronic health records and death certificates. In total, 2097 individuals (404 female, 19%) had an MI (mean age 44 ± 5.1 years, 73% white). Risk factor profiles were similar between men and women, although women were more likely to have diabetes (23.7% vs. 18.9%, P = 0.028). Women were less likely to undergo invasive coronary angiography (93.5% vs. 96.7%, P = 0.003) and coronary revascularization (82.1% vs. 92.6%, P < 0.001). Women were significantly more likely to have MI with non-obstructive coronary disease on angiography (10.2% vs. 4.2%, P < 0.001). They were less likely to be discharged with aspirin (92.2% vs. 95.0%, P = 0.027), beta-blockers (86.6% vs. 90.3%, P = 0.033), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (53.4% vs. 63.7%, P < 0.001), and statins (82.4% vs. 88.4%, P < 0.001). There was no significant difference in in-hospital mortality; however, women who survived to hospital discharge experienced a higher all-cause mortality rate (adjusted HR = 1.63, P = 0.01; median follow-up 11.2 years) with no significant difference in cardiovascular mortality (adjusted HR = 1.14, P = 0.61).
Conclusions
Women who experienced their first MI under the age of 50 were less likely to undergo coronary revascularization or be treated with guideline-directed medical therapies. Women who survived hospitalization experienced similar cardiovascular mortality with significantly higher all-cause mortality than men. A better understanding of the mechanisms underlying these differences is warranted.

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

Eur Heart J: 12 Oct 2020; epub ahead of print
DeFilippis EM, Collins BL, Singh A, Biery DW, ... Bhatt DL, Blankstein R
Eur Heart J: 12 Oct 2020; epub ahead of print | PMID: 33049774
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Abstract

Management of non-culprit coronary plaques in patients with acute coronary syndrome.

Montone RA, Niccoli G, Crea F, Jang IK

Approximately 50% of patients with ST-segment elevation myocardial infarction (STEMI) have multivessel coronary artery disease, a condition associated with an increased incidence of recurrent ischaemic events and higher mortality. Based on recent evidences, a strategy of staged percutaneous coronary intervention (PCI) of obstructive non-culprit lesions should be considered the gold standard for the management of these patients. However, several issues remain still unresolved. Indeed, what is the optimal timing of staged PCI is not completely defined. Moreover, assessment of intermediate non-culprit lesions represent still a clinical conundrum, as pressure-wire indexes do not seem able to correctly identify those patients in whom deferral is safe. Intracoronary imaging may help to identify untreated non-culprit lesions containing vulnerable plaques that may portend a higher risk of future cardiovascular events. However, there are hitherto no studies demonstrating that preventive PCI of vulnerable plaques or more intensive pharmacological treatment is associated with an improved clinical outcome. In this review, we discuss the recent evolving concepts about management of non-culprit plaques in STEMI patients, proposing a diagnostic and therapeutic algorithm to guide physicians in clinical practice. We also underscore the several knowledge gaps to address in future studies.

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

Eur Heart J: 30 Sep 2020; 41:3579-3586
Montone RA, Niccoli G, Crea F, Jang IK
Eur Heart J: 30 Sep 2020; 41:3579-3586 | PMID: 32676644
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Abstract

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

Hopewell JC, Offer A, Haynes R, Bowman L, ... Armitage J, Parish S
Aims
Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.
Methods and results
An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.
Conclusions
The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.

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

Eur Heart J: 13 Sep 2020; 41:3336-3342
Hopewell JC, Offer A, Haynes R, Bowman L, ... Armitage J, Parish S
Eur Heart J: 13 Sep 2020; 41:3336-3342 | PMID: 32702748
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Abstract

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Aims
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.
Methods and results
We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.
Conclusion
Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.
Trial registration
Clinicaltrials.gov identifier: NCT01458405.

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

Eur Heart J: 20 Sep 2020; 41:3451-3458
Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Eur Heart J: 20 Sep 2020; 41:3451-3458 | PMID: 32749459
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Abstract

Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).

Serenelli M, Böhm M, Inzucchi SE, Køber L, ... Jhund PS, McMurray JJV
Aims
Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Methods and results
Key inclusion criteria were: New York Heart Association Class II-IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was -2.54 (-3.33 to -1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome [20.6, 95% confidence interval (95% CI) 17.6-24.2] than those in the highest SBP category (13.8, 11.7-16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60-0.97), 0.76 (0.57-1.02), 0.81 (0.61-1.08), and 0.67 (0.51-0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.
Conclusion
Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF.
Clinical trial registration
ClinicalTrials.gov NCT03036124.

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

Eur Heart J: 20 Sep 2020; 41:3402-3418
Serenelli M, Böhm M, Inzucchi SE, Køber L, ... Jhund PS, McMurray JJV
Eur Heart J: 20 Sep 2020; 41:3402-3418 | PMID: 32820334
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Abstract

Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry.

Sliwa K, Petrie MC, van der Meer P, Mebazaa A, ... McMurray JJV, Bauersachs J
Aims 
We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally.
Methods and results 
In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P < 0.001). Follow-up was available for 598 (81%) women. Six-month mortality was 6% overall, lowest in Europe (4%), and highest in the Middle East (10%). Most deaths were due to heart failure (42%) or sudden (30%). Re-admission for any reason occurred in 10% (with just over half of these for heart failure) and thromboembolic events in 7%. Myocardial recovery (LVEF > 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%).
Conclusion 
Peripartum cardiomyopathy is a global disease, but clinical presentation and outcomes vary by region. Just under half of women experience myocardial recovery. Peripartum cardiomyopathy is a disease with substantial maternal and neonatal morbidity and mortality.

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

Eur Heart J: 13 Oct 2020; 41:3787-3797
Sliwa K, Petrie MC, van der Meer P, Mebazaa A, ... McMurray JJV, Bauersachs J
Eur Heart J: 13 Oct 2020; 41:3787-3797 | PMID: 32840318
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Abstract

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

Mathur A, Fernández-Avilés F, Bartunek J, Belmans A, ... Zeiher A,
Aims 
Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent.
Methods and results 
Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group.
Conclusions 
Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

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

Eur Heart J: 06 Oct 2020; 41:3702-3710
Mathur A, Fernández-Avilés F, Bartunek J, Belmans A, ... Zeiher A,
Eur Heart J: 06 Oct 2020; 41:3702-3710 | PMID: 32860406
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Abstract

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.

Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, ... Tayek J, Nelson JR
Aims
Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients.
Methods and results
A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053).
Conclusions
Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.

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

Eur Heart J: 20 Oct 2020; 41:3925-3932
Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, ... Tayek J, Nelson JR
Eur Heart J: 20 Oct 2020; 41:3925-3932 | PMID: 32860032
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Abstract

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, Hurh E, ... O\'Dea LSL,
Aims 
Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis.
Methods and results 
This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild.
Conclusion 
Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

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

Eur Heart J: 20 Oct 2020; 41:3936-3945
Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, Hurh E, ... O'Dea LSL,
Eur Heart J: 20 Oct 2020; 41:3936-3945 | PMID: 32860031
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Abstract

The win ratio approach for composite endpoints: practical guidance based on previous experience.

Redfors B, Gregson J, Crowley A, McAndrew T, ... Stone GW, Pocock SJ

The win ratio was introduced in 2012 as a new method for examining composite endpoints and has since been widely adopted in cardiovascular (CV) trials. Improving upon conventional methods for analysing composite endpoints, the win ratio accounts for relative priorities of the components and allows the components to be different types of outcomes. For example, the win ratio can combine the time to death with the number of occurrences of a non-fatal outcome such as CV-related hospitalizations (CVHs) in a single hierarchical composite endpoint. The win ratio can provide greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes. The win ratio can also incorporate quantitative outcomes such as exercise tests or quality-of-life scores. There is a need for more practical guidance on how best to design trials using the win ratio approach. This manuscript provides an overview of the principles behind the win ratio and provides insights into how to implement the win ratio in CV trial design and reporting, including how to determine trial size.

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

Eur Heart J: 08 Sep 2020; epub ahead of print
Redfors B, Gregson J, Crowley A, McAndrew T, ... Stone GW, Pocock SJ
Eur Heart J: 08 Sep 2020; epub ahead of print | PMID: 32901285
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Abstract

Timing of intervention in asymptomatic patients with valvular heart disease.

Baumgartner H, Iung B, Otto CM

Current management of valvular heart disease (VHD) seeks to optimize long-term outcome by timely intervention. Recommendations for treatment of patients with symptoms due to severe valvular disease are based on a foundation of solid evidence. However, when to intervene in asymptomatic patients remains controversial and decision requires careful individual weighing of the potential benefits against the risk of intervention and its long-term consequences. The primary rationale for earlier intervention is prevention of irreversible left ventricular (LV) myocardial changes that might result in later clinical symptoms and adverse cardiac events. A number of outcome predictors have been identified that facilitate decision-making. This review summarizes current recommendations and discusses recently published data that challenge them suggesting even earlier intervention. In adults with asymptomatic aortic stenosis (AS), emerging risk markers include very severe valve obstruction, elevated serum natriuretic peptide levels, and imaging evidence of myocardial fibrosis or increased extracellular myocardial volume. Currently, transcatheter aortic valve implantation (TAVI) is not recommended for treatment of asymptomatic severe AS although this may change in the future. In patients with aortic regurgitation (AR), the potential benefit of early intervention in preventing LV dilation and dysfunction must be balanced against the long-term risk of a prosthetic valve, a particular concern because severe AR often occurs in younger patients with a congenital bicuspid valve. In patients with mitral stenosis, the option of transcatheter mitral balloon valvotomy tilts the balance towards earlier intervention to prevent atrial fibrillation, embolic events, and pulmonary hypertension. When chronic severe mitral regurgitation is due to mitral valve prolapse, anatomic features consistent with a high likelihood of a successful and durable valve repair favour early intervention. The optimal timing of intervention in adults with VHD is a constantly changing threshold that depends not only on the severity of valve disease but also on the safety, efficacy, and long-term durability of our treatment options.

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

Eur Heart J: 08 Sep 2020; epub ahead of print
Baumgartner H, Iung B, Otto CM
Eur Heart J: 08 Sep 2020; epub ahead of print | PMID: 32901279
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Abstract

Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4.

Hess A, Derlin T, Koenig T, Diekmann J, ... Bengel FM, Thackeray JT
Aims 
Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction.
Methods and results 
Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = -0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up.
Conclusion 
Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

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

Eur Heart J: 30 Sep 2020; 41:3564-3575
Hess A, Derlin T, Koenig T, Diekmann J, ... Bengel FM, Thackeray JT
Eur Heart J: 30 Sep 2020; 41:3564-3575 | PMID: 32901270
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Impact:
Abstract

Imaging predictors of response to cardiac resynchronization therapy: left ventricular work asymmetry by echocardiography and septal viability by cardiac magnetic resonance.

Aalen JM, Donal E, Larsen CK, Duchenne J, ... Voigt JU, Smiseth OA
Aims 
Left ventricular (LV) failure in left bundle branch block is caused by loss of septal function and compensatory hyperfunction of the LV lateral wall (LW) which stimulates adverse remodelling. This study investigates if septal and LW function measured as myocardial work, alone and combined with assessment of septal viability, identifies responders to cardiac resynchronization therapy (CRT).
Methods and results 
In a prospective multicentre study of 200 CRT recipients, myocardial work was measured by pressure-strain analysis and viability by cardiac magnetic resonance (CMR) imaging (n = 125). CRT response was defined as ≥15% reduction in LV end-systolic volume after 6 months. Before CRT, septal work was markedly lower than LW work (P < 0.0001), and the difference was largest in CRT responders (P < 0.001). Work difference between septum and LW predicted CRT response with area under the curve (AUC) 0.77 (95% CI: 0.70-0.84) and was feasible in 98% of patients. In patients undergoing CMR, combining work difference and septal viability significantly increased AUC to 0.88 (95% CI: 0.81-0.95). This was superior to the predictive power of QRS morphology, QRS duration and the echocardiographic parameters septal flash, apical rocking, and systolic stretch index. Accuracy was similar for the subgroup of patients with QRS 120-150 ms as for the entire study group. Both work difference alone and work difference combined with septal viability predicted long-term survival without heart transplantation with hazard ratio 0.36 (95% CI: 0.18-0.74) and 0.21 (95% CI: 0.072-0.61), respectively.
Conclusion
Assessment of myocardial work and septal viability identified CRT responders with high accuracy.

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

Eur Heart J: 13 Oct 2020; 41:3813-3823
Aalen JM, Donal E, Larsen CK, Duchenne J, ... Voigt JU, Smiseth OA
Eur Heart J: 13 Oct 2020; 41:3813-3823 | PMID: 32918449
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Impact:
Abstract

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.

Basso C, Leone O, Rizzo S, De Gaspari M, ... Maleszewski JJ, Stone JR
Aims
Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described.
Methods and results
In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.
Conclusions
In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

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

Eur Heart J: 13 Oct 2020; 41:3827-3835
Basso C, Leone O, Rizzo S, De Gaspari M, ... Maleszewski JJ, Stone JR
Eur Heart J: 13 Oct 2020; 41:3827-3835 | PMID: 32968776
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Impact:
Abstract

Isolated tricuspid valve surgery: impact of aetiology and clinical presentation on outcomes.

Dreyfus J, Flagiello M, Bazire B, Eggenspieler F, ... Obadia JF, Messika-Zeitoun D
Aims
The aim of this study was to identify determinants of in-hospital and mid-term outcomes after isolated tricuspid valve surgery (ITVS) and more specifically the impact of tricuspid regurgitation (TR) mechanism and clinical presentation.
Methods and results
Among 5661 consecutive adult patients who underwent a tricuspid valve (TV) surgery at 12 French tertiary centres in 2007-2017 collected from a mandatory administrative database, we identified 466 patients (8% of all tricuspid surgeries) who underwent an ITVS. Most patients presented with advanced disease [47% in New York Heart Association (NYHA) III/IV, 57% with right-sided heart failure (HF) signs]. Tricuspid regurgitation was functional in 49% (22% with prior left-sided heart valve surgery and 27% isolated) and organic in 51% (infective endocarditis in 31% and other causes in 20%). In-hospital mortality and major complications rates were 10% and 31%, respectively. Rates of survival and survival free of HF readmission were 75% and 62% at 5 years. Patients with functional TR incurred a worse in-hospital mortality than those with organic TR (14% vs. 6%, P = 0.004), but presentation was more severe. Independent determinants of outcomes were NYHA Class III/IV [odd ratios (OR) = 2.7 (1.2-6.1), P = 0.01], moderate/severe right ventricular dysfunction [OR = 2.6 (1.2-5.8), P = 0.02], lower prothrombin time [OR = 0.98 (0.96-0.99), P = 0.008], and with borderline statistical significance, right-sided HF signs [OR = 2.4 (0.9-6.5), P = 0.06] while TR mechanism was not [OR = 0.7 (0.3-1.8), P = 0.88].
Conclusion
Isolated TV surgery was associated with high mortality and morbidity, both in hospital and during follow-up, predicted by the severity of the presentation but not by TR mechanism. Our results suggest that TV intervention should be performed earlier in the course of the disease.

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

Eur Heart J: 24 Sep 2020; epub ahead of print
Dreyfus J, Flagiello M, Bazire B, Eggenspieler F, ... Obadia JF, Messika-Zeitoun D
Eur Heart J: 24 Sep 2020; epub ahead of print | PMID: 32974668
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Impact:
Abstract

Assessing left ventricular systolic function: from ejection fraction to strain analysis.

Halliday BP, Senior R, Pennell DJ

The measurement of left ventricular ejection fraction (LVEF) is a ubiquitous component of imaging studies used to evaluate patients with cardiac conditions and acts as an arbiter for many management decisions. This follows early trials investigating heart failure therapies which used a binary LVEF cut-off to select patients with the worst prognosis, who may gain the most benefit. Forty years on, the cardiac disease landscape has changed. Left ventricular ejection fraction is now a poor indicator of prognosis for many heart failure patients; specifically, for the half of patients with heart failure and truly preserved ejection fraction (HF-PEF). It is also recognized that LVEF may remain normal amongst patients with valvular heart disease who have significant myocardial dysfunction. This emphasizes the importance of the interaction between LVEF and left ventricular geometry. Guidelines based on LVEF may therefore miss a proportion of patients who would benefit from early intervention to prevent further myocardial decompensation and future adverse outcomes. The assessment of myocardial strain, or intrinsic deformation, holds promise to improve these issues. The measurement of global longitudinal strain (GLS) has consistently been shown to improve the risk stratification of patients with heart failure and identify patients with valvular heart disease who have myocardial decompensation despite preserved LVEF and an increased risk of adverse outcomes. To complete the integration of GLS into routine clinical practice, further studies are required to confirm that such approaches improve therapy selection and accordingly, the outcome for patients.

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

Eur Heart J: 24 Sep 2020; epub ahead of print
Halliday BP, Senior R, Pennell DJ
Eur Heart J: 24 Sep 2020; epub ahead of print | PMID: 32974648
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Impact:
Abstract

Development and validation of two SCORE-based cardiovascular risk prediction models for Eastern Europe: a multicohort study.

Tillmann T, Läll K, Dukes O, Veronesi G, ... Kivimäki M, Bobak M
Aims
Cardiovascular disease (CVD) risk prediction models are used in Western European countries, but less so in Eastern European countries where rates of CVD can be two to four times higher. We recalibrated the SCORE prediction model for three Eastern European countries and evaluated the impact of adding seven behavioural and psychosocial risk factors to the model.
Methods and results
We developed and validated models using data from the prospective HAPIEE cohort study with 14 598 participants from Russia, Poland, and the Czech Republic (derivation cohort, median follow-up 7.2 years, 338 fatal CVD cases) and Estonian Biobank data with 4632 participants (validation cohort, median follow-up 8.3 years, 91 fatal CVD cases). The first model (recalibrated SCORE) used the same risk factors as in the SCORE model. The second model (HAPIEE SCORE) added education, employment, marital status, depression, body mass index, physical inactivity, and antihypertensive use. Discrimination of the original SCORE model (C-statistic 0.78 in the derivation and 0.83 in the validation cohorts) was improved in recalibrated SCORE (0.82 and 0.85) and HAPIEE SCORE (0.84 and 0.87) models. After dichotomizing risk at the clinically meaningful threshold of 5%, and when comparing the final HAPIEE SCORE model against the original SCORE model, the net reclassification improvement was 0.07 [95% confidence interval (CI) 0.02-0.11] in the derivation cohort and 0.14 (95% CI 0.04-0.25) in the validation cohort.
Conclusion
Our recalibrated SCORE may be more appropriate than the conventional SCORE for some Eastern European populations. The addition of seven quick, non-invasive, and cheap predictors further improved prediction accuracy.

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

Eur Heart J: 13 Sep 2020; 41:3325-3333
Tillmann T, Läll K, Dukes O, Veronesi G, ... Kivimäki M, Bobak M
Eur Heart J: 13 Sep 2020; 41:3325-3333 | PMID: 33011775
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Impact:
Abstract

Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.

O\'Donnell M, Mente A, Alderman MH, Brady AJB, ... Yancy C, Yusuf S

Several blood pressure guidelines recommend low sodium intake (<2.3 g/day, 100 mmol, 5.8 g/day of salt) for the entire population, on the premise that reductions in sodium intake, irrespective of the levels, will lower blood pressure, and, in turn, reduce cardiovascular disease occurrence. These guidelines have been developed without effective interventions to achieve sustained low sodium intake in free-living individuals, without a feasible method to estimate sodium intake reliably in individuals, and without high-quality evidence that low sodium intake reduces cardiovascular events (compared with moderate intake). In this review, we examine whether the recommendation for low sodium intake, reached by current guideline panels, is supported by robust evidence. Our review provides a counterpoint to the current recommendation for low sodium intake and suggests that a specific low sodium intake target (e.g. <2.3 g/day) for individuals may be unfeasible, of uncertain effect on other dietary factors and of unproven effectiveness in reducing cardiovascular disease. We contend that current evidence, despite methodological limitations, suggests that most of the world\'s population consume a moderate range of dietary sodium (2.3-4.6g/day; 1-2 teaspoons of salt) that is not associated with increased cardiovascular risk, and that the risk of cardiovascular disease increases when sodium intakes exceed 5 g/day. While current evidence has limitations, and there are differences of opinion in interpretation of existing evidence, it is reasonable, based upon observational studies, to suggest a population-level mean target of <5 g/day in populations with mean sodium intake of >5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality.

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

Eur Heart J: 13 Sep 2020; 41:3363-3373
O'Donnell M, Mente A, Alderman MH, Brady AJB, ... Yancy C, Yusuf S
Eur Heart J: 13 Sep 2020; 41:3363-3373 | PMID: 33011774
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Impact:
Abstract

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

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

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

Eur Heart J: 05 Oct 2020; epub ahead of print
Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Eur Heart J: 05 Oct 2020; epub ahead of print | PMID: 33022705
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Impact:
Abstract

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

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

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

Eur Heart J: 06 Oct 2020; epub ahead of print
Clemente-Moragón A, Gómez M, Villena-Gutiérrez R, Lalama DV, ... Oliver E, Ibáñez B
Eur Heart J: 06 Oct 2020; epub ahead of print | PMID: 33026079
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Impact:
Abstract

Validation of high bleeding risk criteria and definition as proposed by the academic research consortium for high bleeding risk.

Corpataux N, Spirito A, Gragnano F, Vaisnora L, ... Windecker S, Valgimigli M
Aims
To validate the set of clinical and biochemical criteria proposed by consensus by the Academic Research Consortium (ARC) for High Bleeding Risk (HBR) for the identification of HBR patients. These criteria were categorized into major and minor, if expected to carry in isolation, respectively, ≥4% and <4% Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding risk within 1-year after percutaneous coronary intervention (PCI). High bleeding risk patients are those meeting at least 1 major or 2 minor criteria.
Methods and results
All patients undergoing PCI at Bern University Hospital, between February 2009 and September 2018 were prospectively entered into the Bern PCI Registry (NCT02241291). Age, haemoglobin, platelet count, creatinine, and use of oral anticoagulation were prospectively collected, while the remaining HBR criteria except for planned surgery were retrospectively adjudicated. A total of 16 580 participants with complete ARC-HBR criteria were included. After assigning 1 point to each major and 0.5 point to each minor criterion, we observed for every 0.5 score increase a step-wise augmentation of BARC 3 or 5 bleeding rates at 1 year ranging from 1.90% among patients fulfilling no criterion, through 4.01%, 5.98%, 7.42%, 8.60%, 12.21%, 12.29%, and 17.64%. All major and five out of six minor criteria, conferred in isolation a risk for BARC 3 or 5 bleeding at 1 year exceeding 4% at the upper limit of the 95% confidence intervals.
Conclusion
All major and the majority of minor ARC-HBR criteria identify in isolation patients at HBR.

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

Eur Heart J: 06 Oct 2020; 41:3743-3749
Corpataux N, Spirito A, Gragnano F, Vaisnora L, ... Windecker S, Valgimigli M
Eur Heart J: 06 Oct 2020; 41:3743-3749 | PMID: 33029615
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Impact:
Abstract

1970-2020: 50 years of research on the long QT syndrome-from almost zero knowledge to precision medicine.

Schwartz PJ

To those of us involved in clinical research it seldom happens to begin working on a rather obscure disease, still largely unexplored, and to follow its ripening into a medical entity of large interest to clinicians and basic scientists alike, and moreover to do so for exactly 50 years. This is what has been my privilege in the relentless pursuit of the intriguing disease known as the long QT syndrome (LQTS). This essay begins with the encounter with my first patient affected by LQTS when just a handful of cardiologists had seen similar cases and continues with the series of efforts, some sound some amateurish, which eventually led-together with many brilliant partners and associates-to describe and understand the natural history of the disease and the most effective therapies. It then touches on how our International Registry for LQTS, with its well-documented family trees, constituted the necessary springboard for the major genetic discoveries of the 1990s. From the explosion of genetic data, my own interest focused first on the intriguing genotype-phenotype correlation and then on \'modifier genes\', in the attempt of understanding why family members with the same disease-causing mutation could have an opposite clinical history. And from there on to iPS-derived cardiomyocytes, used to unravelling the specific mechanisms of action of modifier genes and to exploring novel therapeutic strategies. This long, and highly rewarding, journey continues because the fascination and the attraction of the unknown are irresistible.

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

Eur Heart J: 14 Oct 2020; epub ahead of print
Schwartz PJ
Eur Heart J: 14 Oct 2020; epub ahead of print | PMID: 33057695
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Impact:
Abstract

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.

Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, ... Schwartz GG,
Aims
Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.
Methods and results
Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.
Conclusion
Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

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

Eur Heart J: 13 Oct 2020; epub ahead of print
Szarek M, Bittner VA, Aylward P, Baccara-Dinet M, ... Schwartz GG,
Eur Heart J: 13 Oct 2020; epub ahead of print | PMID: 33051646
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Abstract

Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

Leistner DM, Kränkel N, Meteva D, Abdelwahed YS, ... Libby P, Landmesser U
Aims 
Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping.
Methods and results 
The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS.
Conclusions 
The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC.
Trial registration
The study was registered at clinicalTrials.gov (NCT03129503).

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

Eur Heart J: 30 Sep 2020; 41:3549-3560
Leistner DM, Kränkel N, Meteva D, Abdelwahed YS, ... Libby P, Landmesser U
Eur Heart J: 30 Sep 2020; 41:3549-3560 | PMID: 33080003
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Impact:
Abstract

Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS.

Baber U, Dangas G, Angiolillo DJ, Cohen DJ, ... Gibson CM, Mehran R
Aims 
The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES).
Methods and results 
We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36-0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54-1.06; P = 0.11; nominal Pint = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (Pint = 0.96).
Conclusion 
Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS.
Trial registration
Clinicaltrials.gov identifier: NCT02270242.

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

Eur Heart J: 30 Sep 2020; 41:3533-3545
Baber U, Dangas G, Angiolillo DJ, Cohen DJ, ... Gibson CM, Mehran R
Eur Heart J: 30 Sep 2020; 41:3533-3545 | PMID: 33085967
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Impact:
Abstract

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

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

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

Eur Heart J: 21 Oct 2020; epub ahead of print
Batkai S, Genschel C, Viereck J, Rump S, ... Gyöngyösi M, Thum T
Eur Heart J: 21 Oct 2020; epub ahead of print | PMID: 33089304
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Impact:
Abstract

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

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

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

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

Eur Heart J: 24 Oct 2020; epub ahead of print
Agarwal R, Kolkhof P, Bakris G, Bauersachs J, ... Wada T, Zannad F
Eur Heart J: 24 Oct 2020; epub ahead of print | PMID: 33099609
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Abstract

Prevention and treatment of pulmonary congestion in patients undergoing venoarterial extracorporeal membrane oxygenation for cardiogenic shock.

Lüsebrink E, Orban M, Kupka D, Scherer C, ... Schäfer A, Orban M

Cardiogenic shock is still a major driver of mortality on intensive care units and complicates ∼10% of acute coronary syndromes with contemporary mortality rates up to 50%. In the meantime, percutaneous circulatory support devices, in particular venoarterial extracorporeal membrane oxygenation (VA-ECMO), have emerged as an established salvage intervention for patients in cardiogenic shock. Venoarterial extracorporeal membrane oxygenation provides temporary circulatory support until other treatments are effective and enables recovery or serves as a bridge to ventricular assist devices, heart transplantation, or decision-making. In this critical care perspective, we provide a concise overview of VA-ECMO utilization in cardiogenic shock, considering rationale, critical care management, as well as weaning aspects. We supplement previous literature by focusing on therapeutic issues related to the vicious circle of retrograde aortic VA-ECMO flow, increased left ventricular (LV) afterload, insufficient LV unloading, and severe pulmonary congestion limiting prognosis in a relevant proportion of patients receiving VA-ECMO treatment. We will outline different modifications in percutaneous mechanical circulatory support to meet this challenge. Besides a strategy of running ECMO at lowest possible flow rates, novel therapeutic options including the combination of VA-ECMO with percutaneous microaxial pumps or implementation of a venoarteriovenous-ECMO configuration based on an additional venous cannula supplying towards pulmonary circulation are most promising among LV unloading and venting strategies. The latter may even combine the advantages of venovenous and venoarterial ECMO therapy, providing potent respiratory and circulatory support at the same time. However, whether VA-ECMO can reduce mortality has to be evaluated in the urgently needed, ongoing prospective randomized studies EURO-SHOCK (NCT03813134), ANCHOR (NCT04184635), and ECLS-SHOCK (NCT03637205). These studies will provide the opportunity to investigate indication, mode, and effect of LV unloading in dedicated sub-analyses. In future, the Heart Teams should aim at conducting a dedicated randomized trial comparing VA-ECMO support with vs. without LV unloading strategies in patients with cardiogenic shock.

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

Eur Heart J: 06 Oct 2020; 41:3753-3761
Lüsebrink E, Orban M, Kupka D, Scherer C, ... Schäfer A, Orban M
Eur Heart J: 06 Oct 2020; 41:3753-3761 | PMID: 33099278
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Abstract

Two-year outcome after implantation of a full magnetically levitated left ventricular assist device: results from the ELEVATE Registry.

Zimpfer D, Gustafsson F, Potapov E, Pya Y, ... Gazzola C, Garbade J
Aims
The ELEVATE Registry was designed to study long-term outcomes with the Heartmate 3 (HM3), a fully magnetically levitated centrifugal ventricular assist device, in a real-world population following CE-mark approval.
Methods and results
A total of 540 patients, implanted in Europe and the Middle East were followed in ELEVATE. The registry included 463 patients receiving the HM3 as primary implant (Primary Implant Cohort), 19 patients underwent a pump upgrade from another device (Pump Exchange Cohort) and 58 patients who had experienced an outcome before having the possibility to sign the Informed Consent, for which only outcome data were collected (Anonymized Cohort). Data collection included demographics, survival, adverse events, EQ-5D Visual Analog Score quality of life (EQ-5D VAS QOL) questionnaire, and 6-min walk distance (6MWD). Mean age was 55.6 ± 11.7 years (89% male, 48% ischaemic cardiomyopathy). Seventy per cent of patients were in INTERMACS Profile 1-3 and 12.7% were on temporary mechanical circulatory support. Primary Implant Cohort survival was 83% after 2 years. In the Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Primary Implant Cohort, strokes were observed in 10.2%, gastrointestinal bleedings in 9.7%, pump thrombosis in 1.5%, and outflow graft twists in 3.5%. Heartmate 3 implantation resulted in a significant and sustained improvement of functional capacity and QOL.
Conclusion
In a real-world population, cohort implanted with the HM3 left ventricular assist device we demonstrate good long-term survival, sustained improvement of functional capacity, and low rates of adverse events (including pump thrombosis).
Clinicaltrials.gov identifier
NCT02497950.

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

Eur Heart J: 13 Oct 2020; 41:3801-3809
Zimpfer D, Gustafsson F, Potapov E, Pya Y, ... Gazzola C, Garbade J
Eur Heart J: 13 Oct 2020; 41:3801-3809 | PMID: 33107561
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Abstract

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

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

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

Eur Heart J: 05 Nov 2020; epub ahead of print
Verdonschot JAJ, Merlo M, Dominguez F, Wang P, ... Garcia-Pavia P, Heymans SRB
Eur Heart J: 05 Nov 2020; epub ahead of print | PMID: 33156912
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Abstract

Multimodality imaging in valvular heart disease: how to use state-of-the-art technology in daily practice.

Reid A, Blanke P, Bax JJ, Leipsic J

Our understanding of the complexities of valvular heart disease (VHD) has evolved in recent years, primarily because of the increased use of multimodality imaging (MMI). Whilst echocardiography remains the primary imaging technique, the contemporary evaluation of patients with VHD requires comprehensive analysis of the mechanism of valvular dysfunction, accurate quantification of severity, and active exclusion extravalvular consequences. Furthermore, advances in surgical and percutaneous therapies have driven the need for meticulous multimodality imaging to aid in patient and procedural selection. Fundamental decision-making regarding whom, when, and how to treat patients with VHD has become more complex. There has been rapid technological advancement in MMI; many techniques are now available in routine clinical practice, and their integration into has the potential to truly individualize management strategies. This review provides an overview of the current evidence for the use of MMI in VHD, and how various techniques within each modality can be used practically to answer clinical conundrums.

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

Eur Heart J: 12 Nov 2020; epub ahead of print
Reid A, Blanke P, Bax JJ, Leipsic J
Eur Heart J: 12 Nov 2020; epub ahead of print | PMID: 33186469
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Abstract

Arrhythmias right ventricular cardiomyopathy and sports activity: from molecular pathways in diseased hearts to new insights into the athletic heart mimicry.

Gasperetti A, James CA, Cerrone M, Delmar M, Calkins H, Duru F

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease associated with a high risk of sudden cardiac death. Among other factors, physical exercise has been clearly identified as a strong determinant of phenotypic expression of the disease, arrhythmia risk, and disease progression. Because of this, current guidelines advise that individuals with ARVC should not participate in competitive or frequent high-intensity endurance exercise. Exercise-induced electrical and morphological para-physiological remodelling (the so-called \'athlete\'s heart\') may mimic several of the classic features of ARVC. Therefore, the current International Task Force Criteria for disease diagnosis may not perform as well in athletes. Clear adjudication between the two conditions is often a real challenge, with false positives, that may lead to unnecessary treatments, and false negatives, which may leave patients unprotected, both of which are equally inacceptable. This review aims to summarize the molecular interactions caused by physical activity in inducing cardiac structural alterations, and the impact of sports on arrhythmia occurrence and other clinical consequences in patients with ARVC, and help the physicians in setting the two conditions apart.

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

Eur Heart J: 16 Nov 2020; epub ahead of print
Gasperetti A, James CA, Cerrone M, Delmar M, Calkins H, Duru F
Eur Heart J: 16 Nov 2020; epub ahead of print | PMID: 33200174
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Abstract

Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.

Jiang X, Eales JM, Scannali D, Nazgiewicz A, ... Charchar FJ, Tomaszewski M
Aims
Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.
Methods and results
We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.
Conclusion
Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.

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

Eur Heart J: 26 Oct 2020; epub ahead of print
Jiang X, Eales JM, Scannali D, Nazgiewicz A, ... Charchar FJ, Tomaszewski M
Eur Heart J: 26 Oct 2020; epub ahead of print | PMID: 33206176
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Abstract

Brugada syndrome genetics is associated with phenotype severity.

Ciconte G, Monasky MM, Santinelli V, Micaglio E, ... Petretto E, Pappone C
Aims 
Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.
Methods and results
Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.
Conclusion 
In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

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

Eur Heart J: 20 Nov 2020; epub ahead of print
Ciconte G, Monasky MM, Santinelli V, Micaglio E, ... Petretto E, Pappone C
Eur Heart J: 20 Nov 2020; epub ahead of print | PMID: 33221895
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Abstract

Prognostic importance of the transmitral pressure gradient in mitral annular calcification with associated mitral valve dysfunction.

Bertrand PB, Churchill TW, Yucel E, Namasivayam M, ... Levine RA, Hung J
Aims 
The aim of this study was to define the natural history of patients with mitral annular calcification (MAC)-related mitral valve dysfunction and to assess the prognostic importance of mean transmitral pressure gradient (MG) and impact of concomitant mitral regurgitation (MR).
Methods and results 
The institutional echocardiography database was examined from 2001 to 2019 for all patients with MAC and MG ≥3 mmHg. A total of 5754 patients were stratified by MG in low (3-5 mmHg, n = 3927), mid (5-10 mmHg, n = 1476), and high (≥10 mmHg, n = 351) gradient. The mean age was 78 ± 11 years, and 67% were female. MR was none/trace in 32%, mild in 42%, moderate in 23%, and severe in 3%. Primary outcome was all-cause mortality, and outcome models were adjusted for age, sex, and MAC-related risk factors (hypertension, diabetes, coronary artery disease, chronic kidney disease). Survival at 1, 5, and 10 years was 77%, 42%, and 18% in the low-gradient group; 73%, 38%, and 17% in the mid-gradient group; and 67%, 25%, and 11% in the high-gradient group, respectively (log-rank P < 0.001 between groups). MG was independently associated with mortality (adjusted HR 1.064 per 1 mmHg increase, 95% CI 1.049-1.080). MR severity was associated with mortality at low gradients (P < 0.001) but not at higher gradients (P = 0.166 and 0.372 in the mid- and high-gradient groups, respectively).
Conclusion 
In MAC-related mitral valve dysfunction, mean transmitral gradient is associated with increased mortality after adjustment for age, sex, and MAC-related risk factors. Concomitant MR is associated with excess mortality in low-gradient ranges (3-5 mmHg) but gradually loses prognostic importance at higher gradients, indicating prognostic utility of transmitral gradient in MAC regardless of MR severity.

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

Eur Heart J: 21 Nov 2020; epub ahead of print
Bertrand PB, Churchill TW, Yucel E, Namasivayam M, ... Levine RA, Hung J
Eur Heart J: 21 Nov 2020; epub ahead of print | PMID: 33221855
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Abstract

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

Grünig E, MacKenzie A, Peacock AJ, Eichstaedt CA, ... Bossone E, Johnson M
Aims
This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
Methods and results
For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2  P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group.
Conclusion
This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.

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

Eur Heart J: 23 Nov 2020; epub ahead of print
Grünig E, MacKenzie A, Peacock AJ, Eichstaedt CA, ... Bossone E, Johnson M
Eur Heart J: 23 Nov 2020; epub ahead of print | PMID: 33232470
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Abstract

Assessment and pathophysiology of microvascular disease: recent progress and clinical implications.

Masi S, Rizzoni D, Taddei S, Widmer RJ, ... Lanza GA, Virdis A

The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.

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

Eur Heart J: 29 Nov 2020; epub ahead of print
Masi S, Rizzoni D, Taddei S, Widmer RJ, ... Lanza GA, Virdis A
Eur Heart J: 29 Nov 2020; epub ahead of print | PMID: 33257973
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This program is still in alpha version.