Journal: Eur Heart J

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Abstract

The heart of the ageing endurance athlete: the role of chronic coronary stress.

Parry-Williams G, Gati S, Sharma S
Moderate physical exercise is associated with an irrefutable reduction in cardiac morbidity and mortality. The current guidelines recommend at least 150 min of moderate exercise or 75 min of vigorous exercise per week. Endurance athletes perform exercise at a level that is 10- to 20-fold greater than these recommendations. These athletes reveal several structural and functional cardiac adaptations including increased cardiac size, enhanced ventricular filling, and augmentation of stroke volume even at the highest heart rates. The long-term effects of endurance exercise on the heart are unknown. Endurance exercise is associated with a transient increase in serum concentrations of biomarkers of cardiac damage and ventricular dysfunction which improves within 72 h. Over the past decade, there have been emerging studies reporting attenuated mortality benefit amongst individuals who perform the highest volume of exercise. Studies in lifelong male athletes aged above 40 years old show a higher prevalence of high coronary artery calcium scores (>300 Agatston units), a higher coronary plaque burden, and myocardial fibrosis compatible with subclinical myocardial infarction compared with relatively sedentary healthy controls, raising speculation that lifelong intense exercise imposes chronic coronary stress on the heart. This review article will provide a critical analysis of the existing data.

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

Eur Heart J: 20 Jul 2021; 42:2737-2744
Parry-Williams G, Gati S, Sharma S
Eur Heart J: 20 Jul 2021; 42:2737-2744 | PMID: 33748860
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Abstract

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Aims
Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE).
Methods and results
We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060).
Conclusion
Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

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

Eur Heart J: 20 Jul 2021; 42:2765-2775
Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Eur Heart J: 20 Jul 2021; 42:2765-2775 | PMID: 33769515
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Abstract

Colchicine and the heart.

Imazio M, Nidorf M
Colchicine is a unique, sophisticated anti-inflammatory agent that has been used for decades for the prevention of acute inflammatory flares in gout and familial Mediterranean fever. In recent years, clinical trials have demonstrated its potential in a range of cardiovascular (CV) conditions. Colchicine is avidly taken up by leucocytes, and its ability to bind to tubulin and interfere with microtubular function affects the expression of cytokines and interleukins, and the ability of neutrophils to marginate, ingress, aggregate, express superoxide, release neutrophil extracellular traps, and interact with platelets. In patients with acute and recurrent pericarditis, clinical trials in >1600 patients have consistently shown that colchicine halves the risk of recurrence [relative risk (RR) 0.50, 95% confidence interval (CI) 0.42-0.60]. In patients with acute and chronic coronary syndromes, multicentre randomized controlled trials in >11 000 patients followed for up to 5 years demonstrated that colchicine may reduce the risk of CV death, myocardial infarction, ischaemic stroke and ischaemia-driven revascularization by >30% (RR 0.63, 95% CI 0.49-0.81). The use of colchicine at doses of 0.5-1.0 mg daily in CV trials has proved safe. Early gastrointestinal intolerance limits its use in ∼10% of patients; however, ∼90% of patients tolerate it well over the long term. Despite isolated case reports, clinically relevant drug interactions with moderate to strong CYP3A4 inhibitors/competitors or P-glycoprotein inhibitors/competitors are rare if this dosage of colchicine is used in the absence of advanced renal or liver disease. The aim of this review is to summarize the contemporary data supporting the efficacy and safety of colchicine in patients with CV disease.

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

Eur Heart J: 20 Jul 2021; 42:2745-2760
Imazio M, Nidorf M
Eur Heart J: 20 Jul 2021; 42:2745-2760 | PMID: 33961006
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Abstract

European Heart Journal quality standards.

Alfonso F, Torp-Pedersen C, Carter RE, Crea F
The aim of the European Heart Journal (EHJ) is to attract innovative, methodologically sound, and clinically relevant research manuscripts able to change clinical practice and/or substantially advance knowledge on cardiovascular diseases. As the reference journal in cardiovascular medicine, the EHJ is committed to publishing only the best cardiovascular science adhering to the highest ethical principles. EHJ uses highly rigorous peer-review, critical statistical review and the highest quality editorial process, to ensure the novelty, accuracy, quality, and relevance of all accepted manuscripts with the aim of inspiring the clinical practice of EHJ readers and reducing the global burden of cardiovascular diseases. This review article summarizes the quality standards pursued by the EHJ to fulfill its mission.

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

Eur Heart J: 20 Jul 2021; 42:2729-2736
Alfonso F, Torp-Pedersen C, Carter RE, Crea F
Eur Heart J: 20 Jul 2021; 42:2729-2736 | PMID: 34289494
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Abstract

Post-stenting fractional flow reserve vs coronary angiography for optimisation of percutaneous coronary intervention: TARGET-FFR trial.

Collison D, Didagelos M, Aetesam-Ur-Rahman M, Copt S, ... Berry C, Oldroyd KG
Aims 
A fractional flow reserve (FFR) value ≥0.90 after percutaneous coronary intervention (PCI) is associated with a reduced risk of adverse cardiovascular events. TARGET-FFR is an investigator-initiated, single-centre, randomized controlled trial to determine the feasibility and efficacy of a post-PCI FFR-guided optimization strategy vs. standard coronary angiography in achieving final post-PCI FFR values ≥0.90.
Methods and results 
After angiographically guided PCI, patients were randomized 1:1 to receive a physiology-guided incremental optimization strategy (PIOS) or a blinded coronary physiology assessment (control group). The primary outcome was the proportion of patients with a final post-PCI FFR ≥0.90. Final FFR ≤0.80 was a prioritized secondary outcome. A total of 260 patients were randomized (131 to PIOS, 129 to control) and 68.1% of patients had an initial post-PCI FFR <0.90. In the PIOS group, 30.5% underwent further intervention (stent post-dilation and/or additional stenting). There was no significant difference in the primary endpoint of the proportion of patients with final post-PCI FFR ≥0.90 between groups (PIOS minus control 10%, 95% confidence interval -1.84 to 21.91, P = 0.099). The proportion of patients with a final FFR ≤0.80 was significantly reduced when compared with the angiography-guided control group (-11.2%, 95% confidence interval -21.87 to -0.35], P = 0.045).
Conclusion 
Over two-thirds of patients had a physiologically suboptimal result after angiography-guided PCI. An FFR-guided optimization strategy did not significantly increase the proportion of patients with a final FFR ≥0.90, but did reduce the proportion of patients with a final FFR ≤0.80.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Collison D, Didagelos M, Aetesam-Ur-Rahman M, Copt S, ... Berry C, Oldroyd KG
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34279606
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Abstract

Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction.

Rhee S, Paik DT, Yang JY, Nagelberg D, ... Wu JC, Red-Horse K
Aims
Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.
Methods and results
We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.
Conclusions
These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Rhee S, Paik DT, Yang JY, Nagelberg D, ... Wu JC, Red-Horse K
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34279605
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Abstract

Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy.

Aboyans V, Bauersachs R, Mazzolai L, Brodmann M, ... Schlager O, De Carlo M
The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial diseases. Antithrombotic therapy is a pillar of optimal medical treatment for these patients at very high cardiovascular risk. While the number of trials on antithrombotic therapies in patients with aortic or peripheral arterial diseases is substantially smaller than for those with coronary artery disease, recent evidence deserves to be incorporated into clinical practice. In the absence of specific indications for chronic oral anticoagulation due to concomitant cardiovascular disease, a single antiplatelet agent is the basis for long-term antithrombotic treatment in patients with aortic or peripheral arterial diseases. Its association with another antiplatelet agent or low-dose anticoagulants will be discussed, based on patient\'s ischaemic and bleeding risk as well therapeutic paths (e.g. endovascular therapy). This consensus document aims to provide a guidance for antithrombotic therapy according to arterial disease localizations and clinical presentation. However, it cannot substitute multidisciplinary team discussions, which are particularly important in patients with uncertain ischaemic/bleeding balance. Importantly, since this balance evolves over time in an individual patient, a regular reassessment of the antithrombotic therapy is of paramount importance.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Aboyans V, Bauersachs R, Mazzolai L, Brodmann M, ... Schlager O, De Carlo M
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34279602
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Abstract

Acute mental stress drives vascular inflammation and promotes plaque destabilization in mouse atherosclerosis.

Hinterdobler J, Schott S, Jin H, Meesmann A, ... Kessler T, Sager HB
Aims
Mental stress substantially contributes to the initiation and progression of human disease, including cardiovascular conditions. We aim to investigate the underlying mechanisms of these contributions since they remain largely unclear.
Methods and results 
Here, we show in humans and mice that leucocytes deplete rapidly from the blood after a single episode of acute mental stress. Using cell-tracking experiments in animal models of acute mental stress, we found that stress exposure leads to prompt uptake of inflammatory leucocytes from the blood to distinct tissues including heart, lung, skin, and, if present, atherosclerotic plaques. Mechanistically, we found that acute stress enhances leucocyte influx into mouse atherosclerotic plaques by modulating endothelial cells. Specifically, acute stress increases adhesion molecule expression and chemokine release through locally derived norepinephrine. Either chemical or surgical disruption of norepinephrine signalling diminished stress-induced leucocyte migration into mouse atherosclerotic plaques.
Conclusion 
Our data show that acute mental stress rapidly amplifies inflammatory leucocyte expansion inside mouse atherosclerotic lesions and promotes plaque vulnerability.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Hinterdobler J, Schott S, Jin H, Meesmann A, ... Kessler T, Sager HB
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34279021
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Abstract

Effects of canagliflozin on human myocardial redox signalling: clinical implications.

Kondo H, Akoumianakis I, Badi I, Akawi N, ... Casadei B, Antoniades C
Aims
Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans.
Methods and results
Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.-) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.- production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM.
Conclusions
We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Kondo H, Akoumianakis I, Badi I, Akawi N, ... Casadei B, Antoniades C
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34293101
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Abstract

Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study.

Quispe R, Martin SS, Michos ED, Lamba I, ... Jones SR, Elshazly MB
Aims
Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD.
Methods and results
We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45-1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08-1.35). Similar results were shown when examining discordance across clinical cutpoints.
Conclusions
In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.

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

Eur Heart J: 18 Jul 2021; epub ahead of print
Quispe R, Martin SS, Michos ED, Lamba I, ... Jones SR, Elshazly MB
Eur Heart J: 18 Jul 2021; epub ahead of print | PMID: 34293083
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Abstract

Lack of specialist care is associated with increased morbidity and mortality in adult congenital heart disease: a population-based study.

Diller GP, Orwat S, Lammers AE, Radke RM, ... Kaleschke G, Baumgartner H
Aims
The aim of this study was to provide population-based data on the healthcare provision for adults with congenital heart disease (ACHD) and the impact of cardiology care on morbidity and mortality in this vulnerable population.
Methods and results
Based on administrative data from one of the largest German Health Insurance Companies, all insured ACHD patients (<70 years of age) were included. Patients were stratified into those followed exclusively by primary care physicians (PCPs) and those with additional cardiology follow-up between 2014 and 2016. Associations between level of care and outcome were assessed by multivariable/propensity score Cox analyses. Overall, 24 139 patients (median age 43 years, 54.8% female) were included. Of these, only 49.7% had cardiology follow-up during the 3-year period, with 49.2% of patients only being cared for by PCPs and 1.1% having no contact with either. After comprehensive multivariable and propensity score adjustment, ACHD patients under cardiology follow-up had a significantly lower risk of death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67-0.98; P = 0.03) or major events (HR 0.85, 95% CI 0.78-0.92; P < 0.001) compared to those only followed by PCPs. At 3-year follow-up, the absolute risk difference for mortality was 0.9% higher in ACHD patients with moderate/severe complexity lesions cared by PCPs compared to those under cardiology follow-up.
Conclusion
Cardiology care compared with primary care is associated with superior survival and lower rates of major complications in ACHD. It is alarming that even in a high resource setting with well-established specialist ACHD care approximately 50% of contemporary ACHD patients are still not linked to regular cardiac care. Almost all patients had at least one contact with a PCP during the study period, suggesting that opportunities to refer patients to cardiac specialists were missed at PCP level. More efforts are required to alert PCPs and patients to appropriate ACHD care.

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

Eur Heart J: 15 Jul 2021; epub ahead of print
Diller GP, Orwat S, Lammers AE, Radke RM, ... Kaleschke G, Baumgartner H
Eur Heart J: 15 Jul 2021; epub ahead of print | PMID: 34269382
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Abstract

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial.

Curzen N, Nicholas Z, Stuart B, Wilding S, ... Hlatky MA, FORECAST Investigators
Aims 
Fractional flow reserve (FFRCT) using computed tomography coronary angiography (CTCA) determines both the presence of coronary artery disease and vessel-specific ischaemia. We tested whether an evaluation strategy based on FFRCT would improve economic and clinical outcomes compared with standard care.
Methods and results 
Overall, 1400 patients with stable chest pain in 11 centres were randomized to initial testing with CTCA with selective FFRCT (experimental group) or standard clinical care pathways (standard group). The primary endpoint was total cardiac costs at 9 months; secondary endpoints were angina status, quality of life, major adverse cardiac and cerebrovascular events, and use of invasive coronary angiography. Randomized patients were similar at baseline. Most patients had an initial CTCA: 439 (63%) in the standard group vs. 674 (96%) in the experimental group, 254 of whom (38%) underwent FFRCT. Mean total cardiac costs were higher by £114 (+8%) in the experimental group, with a 95% confidence interval from -£112 (-8%) to +£337 (+23%), though the difference was not significant (P = 0.10). Major adverse cardiac and cerebrovascular events did not differ significantly (10.2% in the experimental group vs. 10.6% in the standard group) and angina and quality of life improved to a similar degree over follow-up in both randomized groups. Invasive angiography was reduced significantly in the experimental group (19% vs. 25%, P = 0.01).
Conclusion 
A strategy of CTCA with selective FFRCT in patients with stable angina did not differ significantly from standard clinical care pathways in cost or clinical outcomes, but did reduce the use of invasive coronary angiography.

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

Eur Heart J: 15 Jul 2021; epub ahead of print
Curzen N, Nicholas Z, Stuart B, Wilding S, ... Hlatky MA, FORECAST Investigators
Eur Heart J: 15 Jul 2021; epub ahead of print | PMID: 34269376
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Abstract

Predictors, time course, and outcomes of persistence patterns in oral anticoagulation for non-valvular atrial fibrillation: a Dutch Nationwide Cohort Study.

Toorop MMA, Chen Q, Tichelaar VYIG, Cannegieter SC, Lijfering WM
Aims 
Persistence with direct oral anticoagulants (DOACs) has become a concern in non-valvular atrial fibrillation (NVAF) patients, but whether this affects prognosis is rarely studied. We investigated the persistence with oral anticoagulants (OACs) and its association with prognosis among a nationwide cohort of NVAF patients.
Methods and results 
DOAC-naive NVAF patients who started to use DOACs for ischaemic stroke prevention between 2013 and 2018 were included using Dutch national statistics. Persistence with OACs was determined based on the presence of a 100-day gap between the last prescription and the end of study period. In 93 048 patients, 75.7% had a baseline CHA2DS2-VASc score of ≥2. The cumulative incidence of persistence with OACs was 88.1% [95% confidence interval (CI) 87.9-88.3%], 82.6% (95% CI 82.3-82.9%), 77.7% (95% CI 77.3-78.1%), and 72.0% (95% CI 71.5-72.5%) at 1, 2, 3, and 4 years after receiving DOACs, respectively. Baseline characteristics associated with better persistence with OACs included female sex, age range 65-74 years, permanent atrial fibrillation, previous exposure to vitamin K antagonists, stroke history (including transient ischaemic attack), and a CHA2DS2-VASc score ≥2. Non-persistence with OACs was associated with an increased risk of the composite outcome of ischaemic stroke and ischaemic stroke-related death [adjusted hazard ratio (aHR) 1.79, 95% CI 1.49-2.15] and ischaemic stroke (aHR 1.58, 95% CI 1.29-1.93) compared with being persistent with OACs.
Conclusion 
At least a quarter of NVAF patients were non-persistent with OACs within 4 years, which was associated with poor efficacy of ischaemic stroke prevention. The identified baseline characteristics may help identify patients at risk of non-persistence.

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

Eur Heart J: 15 Jul 2021; epub ahead of print
Toorop MMA, Chen Q, Tichelaar VYIG, Cannegieter SC, Lijfering WM
Eur Heart J: 15 Jul 2021; epub ahead of print | PMID: 34269375
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Abstract

Immediate post-procedural functional assessment of percutaneous coronary intervention: current evidence and future directions.

Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Percutaneous coronary intervention (PCI) guided by coronary physiology provides symptomatic benefit and improves patient outcomes. Nevertheless, over one-fourth of patients still experience recurrent angina or major adverse cardiac events following the index procedure. Coronary angiography, the current workhorse for evaluating PCI efficacy, has limited ability to identify suboptimal PCI results. Accumulating evidence supports the usefulness of immediate post-procedural functional assessment. This review discusses the incidence and possible mechanisms behind a suboptimal physiology immediately after PCI. Furthermore, we summarize the current evidence base supporting the usefulness of immediate post-PCI functional assessment for evaluating PCI effectiveness, guiding PCI optimization, and predicting clinical outcomes. Multiple observational studies and post hoc analyses of datasets from randomized trials demonstrated that higher post-PCI functional results are associated with better clinical outcomes as well as a reduced rate of residual angina and repeat revascularization. As such, post-PCI functional assessment is anticipated to impact patient management, secondary prevention, and resource utilization. Pre-PCI physiological guidance has been shown to improve clinical outcomes and reduce health care costs. Whether similar benefits can be achieved using post-PCI physiological assessment requires evaluation in randomized clinical outcome trials.

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

Eur Heart J: 14 Jul 2021; 42:2695-2707
Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Eur Heart J: 14 Jul 2021; 42:2695-2707 | PMID: 33822922
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Impact:
Abstract

Long-term follow-up after ultrathin vs. conventional 2nd-generation drug-eluting stents: a systematic review and meta-analysis of randomized controlled trials.

Madhavan MV, Howard JP, Naqvi A, Ben-Yehuda O, ... Stone GW, Ahmad Y
Aims 
Contemporary 2nd-generation thin-strut drug-eluting stents (DES) are considered standard of care for revascularization of patients undergoing percutaneous coronary intervention. A previous meta-analysis of 10 randomized controlled trials (RCTs) with 11 658 patients demonstrated a 16% reduction in the 1-year risk of target lesion failure (TLF) with ultrathin-strut DES compared with conventional 2nd-generation thin-strut DES. Whether this benefit is sustained longer term is not known, and newer trial data may inform these relative outcomes. We therefore sought to perform an updated systematic review and meta-analysis of RCTs comparing clinical outcomes with ultrathin-strut DES (≤70 µm strut thickness) with conventional 2nd-generation thin-strut DES.
Methods and results 
We performed a random-effects meta-analysis of all RCTs comparing ultrathin-strut DES to conventional 2nd-generation thin-strut DES. The pre-specified primary endpoint was long-term TLF, a composite of cardiac death, myocardial infarction (MI), or clinically driven target lesion revascularization (CD-TLR). Secondary endpoints included the components of TLF, stent thrombosis (ST), and all-cause death. There were 16 eligible trials in which 20 701 patients were randomized. The weighted mean follow-up duration was 2.5 years. Ultrathin-strut DES were associated with a 15% reduction in long-term TLF compared with conventional 2nd-generation thin-strut DES [relative risk (RR) 0.85, 95% confidence interval (CI) 0.76-0.96, P = 0.008] driven by a 25% reduction in CD-TLR (RR 0.75, 95% CI 0.62-0.92, P = 0.005). There were no significant differences between stent types in the risks of MI, ST, cardiac death, or all-cause mortality.
Conclusions 
At a mean follow-up of 2.5 years, ultrathin-strut DES reduced the risk of TLF, driven by less CD-TLR compared with conventional 2nd-generation thin-strut DES, with similar risks of MI, ST, cardiac death, and all-cause mortality.

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

Eur Heart J: 14 Jul 2021; 42:2643-2654
Madhavan MV, Howard JP, Naqvi A, Ben-Yehuda O, ... Stone GW, Ahmad Y
Eur Heart J: 14 Jul 2021; 42:2643-2654 | PMID: 34002202
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Impact:
Abstract

A randomized evaluation of the TriGuard™ HDH cerebral embolic protection device to Reduce the Impact of Cerebral Embolic LEsions after TransCatheter Aortic Valve ImplanTation: the REFLECT I trial.

Lansky AJ, Makkar R, Nazif T, Messé S, ... Baumbach A, Moses J
Aims 
The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR).
Methods and results 
This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2-5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2-5 days. Cumulative scores were compared between treatment groups using the Finkelstein-Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: -5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P = 0.0698) and at 5 days (61.7 vs. 76.2%, P = 0.054) compared with controls.
Conclusion 
REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls.

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

Eur Heart J: 14 Jul 2021; 42:2670-2679
Lansky AJ, Makkar R, Nazif T, Messé S, ... Baumbach A, Moses J
Eur Heart J: 14 Jul 2021; 42:2670-2679 | PMID: 34000004
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Impact:
Abstract

Long-term mortality in patients with ischaemic heart failure revascularized with coronary artery bypass grafting or percutaneous coronary intervention: insights from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

Völz S, Redfors B, Angerås O, Ioanes D, ... Jeppsson A, Omerovic E
Aims 
To compare coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for treatment of patients with heart failure due to ischaemic heart disease.
Methods and results 
We analysed all-cause mortality following CABG or PCI in patients with heart failure with reduced ejection fraction and multivessel disease (coronary artery stenosis >50% in ≥2 vessels or left main) who underwent coronary angiography between 2000 and 2018 in Sweden. We used a propensity score-adjusted logistic and Cox proportional-hazards regressions and instrumental variable model to adjust for known and unknown confounders. Multilevel modelling was used to adjust for the clustering of observations in a hierarchical database. In total, 2509 patients (82.9% men) were included; 35.8% had diabetes and 34.7% had a previous myocardial infarction. The mean age was 68.1 ± 9.4 years (47.8% were >70 years old), and 64.9% had three-vessel or left main disease. Primary designated therapy was PCI in 56.2% and CABG in 43.8%. Median follow-up time was 3.9 years (range 1 day to 10 years). There were 1010 deaths. Risk of death was lower after CABG than after PCI [odds ratio (OR) 0.62; 95% confidence interval (CI) 0.41-0.96; P = 0.031]. The risk of death increased linearly with quintiles of hospitals in which PCI was the preferred method for revascularization (OR 1.27, 95% CI 1.17-1.38, Ptrend < 0.001).
Conclusion 
In patients with ischaemic heart failure, long-term survival was greater after CABG than after PCI.

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

Eur Heart J: 14 Jul 2021; 42:2657-2664
Völz S, Redfors B, Angerås O, Ioanes D, ... Jeppsson A, Omerovic E
Eur Heart J: 14 Jul 2021; 42:2657-2664 | PMID: 34023903
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Impact:
Abstract

Impact of sex on the management and outcome of aortic stenosis patients.

Bienjonetti-Boudreau D, Fleury MA, Voisine M, Paquin A, ... Salaun E, Clavel MA
Objective
The aim of this study was to assess the impact of sex on the management and outcome of patients according to aortic stenosis (AS) severity.
Introduction
Sex differences in the management and outcome of AS are poorly understood.
Methods
Doppler echocardiography data of patients with at least mild-to-moderate AS [aortic valve area (AVA) ≤1.5 cm2 and peak jet velocity (VPeak) ≥2.5 m/s or mean gradient (MG) ≥25 mmHg] were prospectively collected between 2005 and 2015 and retrospectively analysed. Patients with reduced left ventricular ejection fraction (<50%), or mitral or aortic regurgitation >mild were excluded.
Results
Among 3632 patients, 42% were women. The mean indexed AVA (0.48 ± 0.17 cm2/m2), VPeak (3.74 ± 0.88 m/s), and MG (35.1 ± 18.2 mmHg) did not differ between sexes (all P ≥ 0.18). Women were older (72.9 ± 13.0 vs. 70.1 ± 11.8 years) and had more hypertension (75% vs. 70%; P = 0.0005) and less coronary artery disease (38% vs. 55%, P < 0.0001) compared to men. After inverse-propensity weighting (IPW), female sex was associated with higher mortality (IPW-HR: 1.91 [1.14-3.22]; P = 0.01) and less referral to valve intervention (competitive model IPW-HR: 0.88 [0.82-0.96]; P = 0.007) in the whole cohort. This excess mortality in women was blunted in concordant non-severe AS initially treated conservatively (IPW-HR = 1.03 [0.63-1.68]; P = 0.88) or in concordant severe AS initially treated by valve intervention (IPW-HR = 1.25 [0.71-2.21]; P = 0.43). Interestingly, the excess mortality in women was observed in discordant low-gradient AS patients (IPW-HR = 2.17 [1.19-3.95]; P = 0.01) where women were less referred to valve intervention (IPW-Sub-HR: 0.83 [0.73-0.95]; P = 0.009).
Conclusion
In this large series of patients, despite similar baseline hemodynamic AS severity, women were less referred to AVR and had higher mortality. This seemed mostly to occur in the patient subset with discordant markers of AS severity (i.e. low-gradient AS) where women were less referred to AVR.

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

Eur Heart J: 14 Jul 2021; 42:2683-2691
Bienjonetti-Boudreau D, Fleury MA, Voisine M, Paquin A, ... Salaun E, Clavel MA
Eur Heart J: 14 Jul 2021; 42:2683-2691 | PMID: 34023890
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Impact:
Abstract

Prognostically relevant periprocedural myocardial injury and infarction associated with percutaneous coronary interventions: a Consensus Document of the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI).

Bulluck H, Paradies V, Barbato E, Baumbach A, ... Thygesen K, Hausenloy DJ
A substantial number of chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) experience periprocedural myocardial injury or infarction. Accurate diagnosis of these PCI-related complications is required to guide further management given that their occurrence may be associated with increased risk of major adverse cardiac events (MACE). Due to lack of scientific data, the cut-off thresholds of post-PCI cardiac troponin (cTn) elevation used for defining periprocedural myocardial injury and infarction, have been selected based on expert consensus opinions, and their prognostic relevance remains unclear. In this Consensus Document from the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI), we recommend, whenever possible, the measurement of baseline (pre-PCI) cTn and post-PCI cTn values in all CCS patients undergoing PCI. We confirm the prognostic relevance of the post-PCI cTn elevation >5× 99th percentile URL threshold used to define type 4a myocardial infarction (MI). In the absence of periprocedural angiographic flow-limiting complications or electrocardiogram (ECG) and imaging evidence of new myocardial ischaemia, we propose the same post-PCI cTn cut-off threshold (>5× 99th percentile URL) be used to define prognostically relevant \'major\' periprocedural myocardial injury. As both type 4a MI and major periprocedural myocardial injury are strong independent predictors of all-cause mortality at 1 year post-PCI, they may be used as quality metrics and surrogate endpoints for clinical trials. Further research is needed to evaluate treatment strategies for reducing the risk of major periprocedural myocardial injury, type 4a MI, and MACE in CCS patients undergoing PCI.

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

Eur Heart J: 14 Jul 2021; 42:2630-2642
Bulluck H, Paradies V, Barbato E, Baumbach A, ... Thygesen K, Hausenloy DJ
Eur Heart J: 14 Jul 2021; 42:2630-2642 | PMID: 34059914
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Impact:
Abstract

Alpha-protein kinase 3 (ALPK3)-truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

Lopes LR, Garcia-Hernández S, Lorenzini M, Futema M, ... Monserrat L, Elliott PM
Aims
The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.
Methods and results 
In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.01, 95% confidence interval (CI) 7.89-29.74, P < 8.36e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.
Conclusions 
Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

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

Eur Heart J: 14 Jul 2021; epub ahead of print
Lopes LR, Garcia-Hernández S, Lorenzini M, Futema M, ... Monserrat L, Elliott PM
Eur Heart J: 14 Jul 2021; epub ahead of print | PMID: 34263907
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Impact:
Abstract

Persisting burden and challenges of rheumatic heart disease.

Marijon E, Mocumbi A, Narayanan K, Jouven X, Celermajer DS
Rheumatic heart disease (RHD) is the result of episodes of acute rheumatic fever with valvular (and other cardiac) damage caused by an abnormal immune response to group A streptococcal infections, usually during childhood and adolescence. As a result of improved living conditions and the introduction of penicillin, RHD was almost eradicated in the developed world by the 1980s. However, being a disease of poverty, its burden remains disproportionately high in the developing world, despite being a fundamentally preventable disease. Rheumatic heart disease generates relatively little attention from the medical and science communities, in contrast to other common infectious problems (such as malaria, HIV, tuberculosis), despite the major cardiovascular morbidity/mortality burden imposed by RHD. This relative neglect and paucity of funding have probably contributed to limited fundamental medical advances in this field for over 50 years. Given the importance of prevention before the onset of major valvular damage, the main challenges for RHD prevention are improving social circumstances, early diagnosis, and effective delivery of antibiotic prophylaxis. Early identification through ultrasound of silent, subclinical rheumatic valve lesions could provide an opportunity for early intervention. Simple echocardiographic diagnostic criteria and appropriately trained personnel can be valuable aids in large-scale public health efforts. In addition, a better understanding of the immunogenic determinants of the disease may provide potential routes to vaccine development and other novel therapies.

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

Eur Heart J: 14 Jul 2021; epub ahead of print
Marijon E, Mocumbi A, Narayanan K, Jouven X, Celermajer DS
Eur Heart J: 14 Jul 2021; epub ahead of print | PMID: 34263296
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Impact:
Abstract

PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction.

Da Dalt L, Castiglioni L, Baragetti A, Audano M, ... Catapano AL, Norata GD
Aims
PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function.
Methods and results
Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects.
Conclusion
PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF.

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

Eur Heart J: 11 Jul 2021; epub ahead of print
Da Dalt L, Castiglioni L, Baragetti A, Audano M, ... Catapano AL, Norata GD
Eur Heart J: 11 Jul 2021; epub ahead of print | PMID: 34252181
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Impact:
Abstract

Oral fluoroquinolones and risk of aortic or mitral regurgitation: a nationwide nested case-control study.

Strange JE, Holt A, Blanche P, Gislason G, ... Køber L, Rasmussen PV
Aims
Reports have suggested an increased risk of aortic and mitral regurgitation associated with oral fluoroquinolones (FQs) resulting in a safety warning published by the European Medicines Agency (EMA). However, these findings have not yet been replicated.
Methods and results
Using Danish administrative registers, we conducted a nested case-control study in a nationwide cohort of individuals between 2005 and 2018. Cases were defined as the first occurrence of aortic or mitral regurgitation. Exposure of interest was the use of oral FQs. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were obtained by fitting time-dependent Cox regression models, with penicillin V as comparator, to assess the association between FQ use and incident valvular regurgitation. We identified 38 370 cases of valvular regurgitation with 1 115 100 matched controls. FQ exposure was not significantly associated with increased rates of aortic or mitral regurgitation (HR 1.02, 95% CI 0.95-1.09) compared with penicillin V users. Investigating the cumulative defined daily doses (cDDD) of FQs yielded similar results with no significant association between increasing FQ use and valvular regurgitation (e.g. HR 1.08, 95% CI 0.95-1.23 for cDDD >10 compared with cDDD 1-5). These results were consistent across several analyses including a cohort of patients with hypertension and using a case definition based on valvular surgical interventions.
Conclusions
In a nationwide nested case-control study, FQs were not significantly associated with increased rates of valvular regurgitation. Our findings do not support a possible causal connection between FQ exposure and incident valvular regurgitation.

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

Eur Heart J: 09 Jul 2021; epub ahead of print
Strange JE, Holt A, Blanche P, Gislason G, ... Køber L, Rasmussen PV
Eur Heart J: 09 Jul 2021; epub ahead of print | PMID: 34245252
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Impact:
Abstract

A phenomapping-derived tool to personalize the selection of anatomical vs. functional testing in evaluating chest pain (ASSIST).

Oikonomou EK, Van Dijk D, Parise H, Suchard MA, ... Miller EJ, Khera R
Aims 
Coronary artery disease is frequently diagnosed following evaluation of stable chest pain with anatomical or functional testing. A more granular understanding of patient phenotypes that benefit from either strategy may enable personalized testing.
Methods and results 
Using participant-level data from 9572 patients undergoing anatomical (n = 4734) vs. functional (n = 4838) testing in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial, we created a topological representation of the study population based on 57 pre-randomization variables. Within each patient\'s 5% topological neighbourhood, Cox regression models provided individual patient-centred hazard ratios for major adverse cardiovascular events and revealed marked heterogeneity across the phenomap [median 1.11 (10th to 90th percentile: 0.52-2.61]), suggestive of distinct phenotypic neighbourhoods favouring anatomical or functional testing. Based on this risk phenomap, we employed an extreme gradient boosting algorithm in 80% of the PROMISE population to predict the personalized benefit of anatomical vs. functional testing using 12 model-derived, routinely collected variables and created a decision support tool named ASSIST (Anatomical vs. Stress teSting decIsion Support Tool). In both the remaining 20% of PROMISE and an external validation set consisting of patients from SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) undergoing anatomical-first vs. functional-first assessment, the testing strategy recommended by ASSIST was associated with a significantly lower incidence of each study\'s primary endpoint (P = 0.0024 and P = 0.0321 for interaction, respectively), as well as a harmonized endpoint of all-cause mortality or non-fatal myocardial infarction (P = 0.0309 and P < 0.0001 for interaction, respectively).
Conclusion 
We propose a novel phenomapping-derived decision support tool to standardize the selection of anatomical vs. functional testing in the evaluation of stable chest pain, validated in two large and geographically diverse clinical trial populations.

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

Eur Heart J: 07 Jul 2021; 42:2536-2548
Oikonomou EK, Van Dijk D, Parise H, Suchard MA, ... Miller EJ, Khera R
Eur Heart J: 07 Jul 2021; 42:2536-2548 | PMID: 33881513
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Impact:
Abstract

Emergency department management of patients with adult congenital heart disease: a consensus paper from the ESC Working Group on Adult Congenital Heart Disease, the European Society for Emergency Medicine (EUSEM), the European Association for Cardio-Thoracic Surgery (EACTS), and the Association for Acute Cardiovascular Care (ACVC).

Chessa M, Brida M, Gatzoulis MA, Diller GP, ... Gallego P, Tutarel O
Adult congenital heart disease (ACHD) patients represent a growing population with increasing use of acute emergency department (ED) care. Providing comprehensive ED care necessitates an understanding of the most common clinical scenarios to improve morbidity and mortality in this population. The aim of this position document is to provide a consensus regarding the management of the most common clinical scenarios of ACHD patients presenting to the ED.

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Eur Heart J: 07 Jul 2021; 42:2527-2535
Chessa M, Brida M, Gatzoulis MA, Diller GP, ... Gallego P, Tutarel O
Eur Heart J: 07 Jul 2021; 42:2527-2535 | PMID: 34021343
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Impact:
Abstract

HIV infection is associated with thoracic and abdominal aortic aneurysms: a prospective matched cohort study.

Høgh J, Pham MHC, Knudsen AD, Thudium RF, ... Kofoed KF, Nielsen SD
Aims
Little is known about the prevalence of aortic aneurysms among people living with HIV (PLWH). We investigated whether HIV status is independently associated with having aortic aneurysms. Furthermore, we determined risk factors associated with aortic aneurysms in PLWH.
Methods and results
PLWH aged ≥40 years (n = 594) were recruited from the Copenhagen Comorbidity in HIV Infection study and matched for age and sex with uninfected controls (n = 1188) from the Copenhagen General Population Study. Aortic dimensions were assessed using contrast enhanced computed tomography. Aortic aneurysms were defined according to the European Society of Cardiology guidelines, i.e. an aortic dilation of ≥50% or an infrarenal aortic diameter of ≥30 mm. Among PLWH and uninfected controls, the median (interquartile range) age was 52 (47-60) and 52 (48-61) and 88% and 90% were male, respectively. We found 46 aneurysms in 42 (7.1%) PLWH and 31 aneurysms in 29 (2.4%) uninfected controls (P < 0.001). PLWH had a significantly higher prevalence of ascending aortic aneurysms and infrarenal aortic aneurysms. In an adjusted model, HIV was independently associated with aortic aneurysms (adjusted odds ratio; 4.51 [95% confidence interval 2.56-8.08], P < 0.001). Within PLWH, obesity and hepatitis B co-infection were associated with aortic aneurysms.
Conclusion
PLWH had four-fold higher odds of aortic aneurysms compared to uninfected controls, and HIV status was independently associated with aortic aneurysms. Among PLWH, age, obesity and hepatitis B co-infection were associated with higher odds of aortic aneurysms. Our findings suggest that increased attention to aortic aneurysms in PLWH may be beneficial.

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

Eur Heart J: 07 Jul 2021; epub ahead of print
Høgh J, Pham MHC, Knudsen AD, Thudium RF, ... Kofoed KF, Nielsen SD
Eur Heart J: 07 Jul 2021; epub ahead of print | PMID: 34240121
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Impact:
Abstract

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

Pham PT, Fukuda D, Nishimoto S, Kim-Kaneyama JR, ... Barber GN, Sata M
Aims 
Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis.
Methods and results 
Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP.
Conclusion 
Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

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

Eur Heart J: 05 Jul 2021; epub ahead of print
Pham PT, Fukuda D, Nishimoto S, Kim-Kaneyama JR, ... Barber GN, Sata M
Eur Heart J: 05 Jul 2021; epub ahead of print | PMID: 34226923
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Impact:
Abstract

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

Ishikawa T, Kimoto H, Mishima H, Yamagata K, ... Kusano K, Makita N
Aims
The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability.
Methods and results
Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16 985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves.
Conclusion
In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

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

Eur Heart J: 04 Jul 2021; epub ahead of print
Ishikawa T, Kimoto H, Mishima H, Yamagata K, ... Kusano K, Makita N
Eur Heart J: 04 Jul 2021; epub ahead of print | PMID: 34219138
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Impact:
Abstract

Association of the combined effects of air pollution and changes in physical activity with cardiovascular disease in young adults.

Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Aims
Little is known about the trade-off between the health benefits of physical activity (PA) and the potential harmful effects of increased exposure to air pollution during outdoor PA. We examined the association of the combined effects of air pollution and changes in PA with cardiovascular disease (CVD) in young adults.
Methods and results
This nationwide cohort study included 1 469 972 young adults aged 20-39 years. Air pollution exposure was estimated by the annual average cumulative level of particulate matter (PM). PA was calculated as minutes of metabolic equivalent tasks per week (MET-min/week) based on two consecutive health examinations from 2009 to 2012. Compared with the participants exposed to low-to-moderate levels of PM2.5 or PM10 who continuously engaged in ≥1000 MET-min/week of PA, those who decreased their PA from ≥1000 MET-min/week to 1-499 MET-min/week [PM10 adjusted hazard ratio (aHR) 1.22; 95% confidence interval (CI) 1.00-1.48] and to 0 MET-min/week (physically inactive; PM10 aHR 1.38; 95% CI 1.07-1.78) had an increased risk of CVD (P for trend <0.01). Among participants exposed to high levels of PM2.5 or PM10, the risk of CVD was elevated with an increase in PA above 1000 MET-min/week.
Conclusion
Reducing PA may lead to subsequent elevation of CVD risk in young adults exposed to low-to-moderate levels of PM2.5 or PM10, whereas a large increase in PA in a high-pollution environment may adversely affect cardiovascular health.

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

Eur Heart J: 30 Jun 2021; 42:2487-2497
Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Eur Heart J: 30 Jun 2021; 42:2487-2497 | PMID: 33780974
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Impact:
Abstract

Heart healthy cities: genetics loads the gun but the environment pulls the trigger.

Münzel T, Sørensen M, Lelieveld J, Hahad O, ... Daiber A, Rajagopalan S
The world\'s population is estimated to reach 10 billion by 2050 and 75% of this population will live in cities. Two-third of the European population already live in urban areas and this proportion continues to grow. Between 60% and 80% of the global energy use is consumed by urban areas, with 70% of the greenhouse gas emissions produced within urban areas. The World Health Organization states that city planning is now recognized as a critical part of a comprehensive solution to tackle adverse health outcomes. In the present review, we address non-communicable diseases with a focus on cardiovascular disease and the urbanization process in relation to environmental risk exposures including noise, air pollution, temperature, and outdoor light. The present review reports why heat islands develop in urban areas, and how greening of cities can improve public health, and address climate concerns, sustainability, and liveability. In addition, we discuss urban planning, transport interventions, and novel technologies to assess external environmental exposures, e.g. using digital technologies, to promote heart healthy cities in the future. Lastly, we highlight new paradigms of integrative thinking such as the exposome and planetary health, challenging the one-exposure-one-health-outcome association and expand our understanding of the totality of human environmental exposures.

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

Eur Heart J: 30 Jun 2021; 42:2422-2438
Münzel T, Sørensen M, Lelieveld J, Hahad O, ... Daiber A, Rajagopalan S
Eur Heart J: 30 Jun 2021; 42:2422-2438 | PMID: 34005032
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Abstract

Accelerometer-derived physical activity and risk of atrial fibrillation.

Khurshid S, Weng LC, Al-Alusi MA, Halford JL, ... McManus DD, Lubitz SA
Aims
Physical activity may be an important modifiable risk factor for atrial fibrillation (AF), but associations have been variable and generally based on self-reported activity.
Methods and results
We analysed 93 669 participants of the UK Biobank prospective cohort study without prevalent AF who wore a wrist-based accelerometer for 1 week. We categorized whether measured activity met the standard recommendations of the European Society of Cardiology, American Heart Association, and World Health Organization [moderate-to-vigorous physical activity (MVPA) ≥150 min/week]. We tested associations between guideline-adherent activity and incident AF (primary) and stroke (secondary) using Cox proportional hazards models adjusted for age, sex, and each component of the Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) risk score. We also assessed correlation between accelerometer-derived and self-reported activity. The mean age was 62 ± 8 years and 57% were women. Over a median of 5.2 years, 2338 incident AF events occurred. In multivariable adjusted models, guideline-adherent activity was associated with lower risks of AF [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75-0.89; incidence 3.5/1000 person-years, 95% CI 3.3-3.8 vs. 6.5/1000 person-years, 95% CI 6.1-6.8] and stroke (HR 0.76, 95% CI 0.64-0.90; incidence 1.0/1000 person-years, 95% CI 0.9-1.1 vs. 1.8/1000 person-years, 95% CI 1.6-2.0). Correlation between accelerometer-derived and self-reported MVPA was weak (Spearman r = 0.16, 95% CI 0.16-0.17). Self-reported activity was not associated with incident AF or stroke.
Conclusions
Greater accelerometer-derived physical activity is associated with lower risks of AF and stroke. Future preventive efforts to reduce AF risk may be most effective when targeting adherence to objective activity thresholds.

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

Eur Heart J: 30 Jun 2021; 42:2472-2483
Khurshid S, Weng LC, Al-Alusi MA, Halford JL, ... McManus DD, Lubitz SA
Eur Heart J: 30 Jun 2021; 42:2472-2483 | PMID: 34037209
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Abstract

Salt reduction to prevent hypertension: the reasons of the controversy.

He FJ, Campbell NRC, Woodward M, MacGregor GA
There is a causal relationship between dietary salt intake and blood pressure. A reduction in salt intake from the current world average of ∼10 g/day to the WHO recommended level of <5 g/day, lowers blood pressure and reduces the risk of cardiovascular disease and all-cause mortality. However, a few cohort studies have claimed that there is a J-shaped relationship between salt intake and cardiovascular risk, i.e. both high and low salt intakes are associated with an increased risk. These cohort studies have several methodological problems, including reverse causality, and inaccurate and biased estimation of salt intake, e.g. from a single spot urine sample with formulas. Recent studies have shown that the formulas used to estimate salt intake from spot urine cause a spurious J-curve. Research with inappropriate methodology should not be used to refute the robust evidence on the enormous benefits of population-wide reduction in salt intake. Several countries, e.g. Finland, the UK, have successfully reduced salt intake, which has resulted in falls in population blood pressure and deaths from stroke and ischaemic heart disease. Every country should develop and implement a coherent, workable strategy to reduce salt intake. Even a modest reduction in salt intake across the whole population will lead to a major improvement in public health, along with huge cost-savings to the healthcare service.

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

Eur Heart J: 30 Jun 2021; 42:2501-2505
He FJ, Campbell NRC, Woodward M, MacGregor GA
Eur Heart J: 30 Jun 2021; 42:2501-2505 | PMID: 34117487
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Abstract

SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions.

SCORE2-OP working group and ESC Cardiovascular risk collaboration
Aims 
The aim of this study was to derive and validate the SCORE2-Older Persons (SCORE2-OP) risk model to estimate 5- and 10-year risk of cardiovascular disease (CVD) in individuals aged over 70 years in four geographical risk regions.
Methods and results 
Sex-specific competing risk-adjusted models for estimating CVD risk (CVD mortality, myocardial infarction, or stroke) were derived in individuals aged over 65 without pre-existing atherosclerotic CVD from the Cohort of Norway (28 503 individuals, 10 089 CVD events). Models included age, smoking status, diabetes, systolic blood pressure, and total- and high-density lipoprotein cholesterol. Four geographical risk regions were defined based on country-specific CVD mortality rates. Models were recalibrated to each region using region-specific estimated CVD incidence rates and risk factor distributions. For external validation, we analysed data from 6 additional study populations {338 615 individuals, 33 219 CVD validation cohorts, C-indices ranged between 0.63 [95% confidence interval (CI) 0.61-0.65] and 0.67 (0.64-0.69)}. Regional calibration of expected-vs.-observed risks was satisfactory. For given risk factor profiles, there was substantial variation across the four risk regions in the estimated 10-year CVD event risk.
Conclusions 
The competing risk-adjusted SCORE2-OP model was derived, recalibrated, and externally validated to estimate 5- and 10-year CVD risk in older adults (aged 70 years or older) in four geographical risk regions. These models can be used for communicating the risk of CVD and potential benefit from risk factor treatment and may facilitate shared decision-making between clinicians and patients in CVD risk management in older persons.

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

Eur Heart J: 30 Jun 2021; 42:2455-2467
SCORE2-OP working group and ESC Cardiovascular risk collaboration
Eur Heart J: 30 Jun 2021; 42:2455-2467 | PMID: 34120185
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Abstract

SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe.

SCORE2 working group and ESC Cardiovascular risk collaboration
Aims
The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.
Methods and results 
We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low-risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.
Conclusion 
SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe.

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

Eur Heart J: 30 Jun 2021; 42:2439-2454
SCORE2 working group and ESC Cardiovascular risk collaboration
Eur Heart J: 30 Jun 2021; 42:2439-2454 | PMID: 34120177
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Abstract

Transition to adulthood and transfer to adult care of adolescents with congenital heart disease: a global consensus statement of the ESC Association of Cardiovascular Nursing and Allied Professions (ACNAP), the ESC Working Group on Adult Congenital Heart Disease (WG ACHD), the Association for European Paediatric and Congenital Cardiology (AEPC), the Pan-African Society of Cardiology (PASCAR), the Asia-Pacific Pediatric Cardiac Society (APPCS), the Inter-American Society of Cardiology (IASC), the Cardiac Society of Australia and New Zealand (CSANZ), the International Society for Adult Congenital Heart Disease (ISACHD), the World Heart Federation (WHF), the European Congenital Heart Disease Organisation (ECHDO), and the Global Alliance for Rheumatic and Congenital Hearts (Global ARCH).

Moons P, Bratt EL, De Backer J, Goossens E, ... Yang HL, Thomet C
The vast majority of children with congenital heart disease (CHD) in high-income countries survive into adulthood. Further, paediatric cardiac services have expanded in middle-income countries. Both evolutions have resulted in an increasing number of CHD survivors. Expert care across the life span is necessitated. In adolescence, patients transition from being a dependent child to an independent adult. They are also advised to transfer from paediatrics to adult care. There is no universal consensus regarding how transitional care should be provided and how the transfer should be organized. This is even more challenging in countries with low resources. This consensus document describes issues and practices of transition and transfer of adolescents with CHD, accounting for different possibilities in high-, middle-, and low-income countries. Transitional care ought to be provided to all adolescents with CHD, taking into consideration the available resources. When reaching adulthood, patients ought to be transferred to adult care facilities/providers capable of managing their needs, and systems have to be in place to make sure that continuity of high-quality care is ensured after leaving paediatric cardiology.

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

Eur Heart J: 30 Jun 2021; epub ahead of print
Moons P, Bratt EL, De Backer J, Goossens E, ... Yang HL, Thomet C
Eur Heart J: 30 Jun 2021; epub ahead of print | PMID: 34198319
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Abstract

The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial.

Martens P, Dupont M, Dauw J, Nijst P, ... Tang WHW, Mullens W
Aims
Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF.
Methods and results
Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM.
Conclusions
Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship.

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

Eur Heart J: 28 Jun 2021; epub ahead of print
Martens P, Dupont M, Dauw J, Nijst P, ... Tang WHW, Mullens W
Eur Heart J: 28 Jun 2021; epub ahead of print | PMID: 34185066
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Abstract

Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Lam CSP, Ferreira JP, Pfarr E, Sim D, ... Zannad F, Packer M
Aims
The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.
Methods and results
Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%.
Conclusions
There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.

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

Eur Heart J: 28 Jun 2021; epub ahead of print
Lam CSP, Ferreira JP, Pfarr E, Sim D, ... Zannad F, Packer M
Eur Heart J: 28 Jun 2021; epub ahead of print | PMID: 34184057
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Abstract

Eight-year outcomes for patients with aortic valve stenosis at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement.

Jørgensen TH, Thyregod HGH, Ihlemann N, Nissen H, ... Olsen PS, Søndergaard L
Aims
The aims of the study were to compare clinical outcomes and valve durability after 8 years of follow-up in patients with symptomatic severe aortic valve stenosis at low surgical risk treated with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR).
Methods and results
In the NOTION trial, patients with symptomatic severe aortic valve stenosis were randomized to TAVI or SAVR. Clinical status, echocardiography, structural valve deterioration, and failure were assessed using standardized definitions. In total, 280 patients were randomized to TAVI (n = 145) or SAVR (n = 135). Baseline characteristics were similar, including mean age of 79.1 ± 4.8 years and a mean STS score of 3.0 ± 1.7%. At 8-year follow-up, the estimated risk of the composite outcome of all-cause mortality, stroke, or myocardial infarction was 54.5% after TAVI and 54.8% after SAVR (P = 0.94). The estimated risks for all-cause mortality (51.8% vs. 52.6%; P = 0.90), stroke (8.3% vs. 9.1%; P = 0.90), or myocardial infarction (6.2% vs. 3.8%; P = 0.33) were similar after TAVI and SAVR. The risk of structural valve deterioration was lower after TAVI than after SAVR (13.9% vs. 28.3%; P = 0.0017), whereas the risk of bioprosthetic valve failure was similar (8.7% vs. 10.5%; P = 0.61).
Conclusions
In patients with severe aortic valve stenosis at low surgical risk randomized to TAVI or SAVR, there were no significant differences in the risk for all-cause mortality, stroke, or myocardial infarction, as well as the risk of bioprosthetic valve failure after 8 years of follow-up.
Clinical trial registration
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01057173.

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

Eur Heart J: 27 Jun 2021; epub ahead of print
Jørgensen TH, Thyregod HGH, Ihlemann N, Nissen H, ... Olsen PS, Søndergaard L
Eur Heart J: 27 Jun 2021; epub ahead of print | PMID: 34179981
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Abstract

Neuraminidase 1 is a driver of experimental cardiac hypertrophy.

Chen QQ, Ma G, Liu JF, Cai YY, ... Zhang L, Qi LW
Aims 
Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminate in heart failure. Neuraminidases are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize the role of neuraminidases in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian neuraminidases.
Methods and results 
Neuraminidase 1 (NEU1) was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy (n = 7) compared with healthy controls (n = 7). The increased NEU1 was mainly localized in cardiomyocytes by co-localization with cardiac troponin T. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to Foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified a novel compound C-09 from millions of compounds that showed favourable binding affinity to human NEU1 (KD = 0.38 μM) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications of cardio-protection.
Conclusions 
This work identifies NEU1 as a critical driver of cardiac hypertrophy and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases.

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

Eur Heart J: 27 Jun 2021; epub ahead of print
Chen QQ, Ma G, Liu JF, Cai YY, ... Zhang L, Qi LW
Eur Heart J: 27 Jun 2021; epub ahead of print | PMID: 34179969
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Abstract

Right ventricle assessment in patients with pulmonary embolism at low risk for death based on clinical models: an individual patient data meta-analysis.

Becattini C, Maraziti G, Vinson DR, Ng ACC, ... Agnelli G, Jiménez D
Aims
 Patients with acute pulmonary embolism (PE) at low risk for short-term death are candidates for home treatment or short-hospital stay. We aimed at determining whether the assessment of right ventricle dysfunction (RVD) or elevated troponin improves identification of low-risk patients over clinical models alone.
Methods and results
 Individual patient data meta-analysis of studies assessing the relationship between RVD or elevated troponin and short-term mortality in patients with acute PE at low risk for death based on clinical models (Pulmonary Embolism Severity Index, simplified Pulmonary Embolism Severity Index or Hestia). The primary study outcome was short-term death defined as death occurring in hospital or within 30 days. Individual data of 5010 low-risk patients from 18 studies were pooled. Short-term mortality was 0.7% [95% confidence interval (CI) 0.4-1.3]. RVD at echocardiography, computed tomography or B-type natriuretic peptide (BNP)/N-terminal pro BNP (NT-proBNP) was associated with increased risk for short-term death (1.5 vs. 0.3%; OR 4.81, 95% CI 1.98-11.68), death within 3 months (1.6 vs. 0.4%; OR 4.03, 95% CI 2.01-8.08), and PE-related death (1.1 vs. 0.04%; OR 22.9, 95% CI 2.89-181). Elevated troponin was associated with short-term death (OR 2.78, 95% CI 1.06-7.26) and death within 3 months (OR 3.68, 95% CI 1.75-7.74).
Conclusion
  RVD assessed by echocardiography, computed tomography, or elevated BNP/NT-proBNP levels and increased troponin are associated with short-term death in patients with acute PE at low risk based on clinical models. RVD assessment, mainly by BNP/NT-proBNP or echocardiography, should be considered to improve identification of low-risk patients that may be candidates for outpatient management or short hospital stay.

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

Eur Heart J: 27 Jun 2021; epub ahead of print
Becattini C, Maraziti G, Vinson DR, Ng ACC, ... Agnelli G, Jiménez D
Eur Heart J: 27 Jun 2021; epub ahead of print | PMID: 34179965
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Abstract

DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells.

Wang Y, Han D, Zhou T, Chen C, ... Cao F, Dong N
Aims 
The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Here, we evaluated the role and therapeutic value of dual-specificity phosphatase 26 (DUSP26) in CAVD.
Methods and results 
Microarray profiling of human calcific aortic valves and normal controls demonstrated that DUSP26 was significantly up-regulated in calcific aortic valves. ApoE-/- mice fed a normal diet or a high cholesterol diet (HCD) were infected with adeno-associated virus serotype 2 carrying DUSP26 short-hairpin RNA to examine the effects of DUSP26 silencing on aortic valve calcification. DUSP26 silencing ameliorated aortic valve calcification in HCD-treated ApoE-/- mice, as evidenced by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and decreased levels of osteogenic markers (Runx2, osterix, and osteocalcin) in the aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Immunoprecipitation, liquid chromatography-tandem mass spectrometry, and functional assays revealed that dipeptidyl peptidase-4 (DPP4) interacted with DUSP26 to mediate the procalcific effects of DUSP26. High N6-methyladenosine levels up-regulated DUSP26 in CAVD; in turn, DUSP26 activated DPP4 by antagonizing mouse double minute 2-mediated ubiquitination and degradation of DPP4, thereby promoting CAVD progression.
Conclusion 
DUSP26 promotes aortic valve calcification by inhibiting DPP4 degradation. Our findings identify a previously unrecognized mechanism of DPP4 up-regulation in CAVD, suggesting that DUSP26 silencing or inhibition is a viable therapeutic strategy to impede CAVD progression.

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

Eur Heart J: 27 Jun 2021; epub ahead of print
Wang Y, Han D, Zhou T, Chen C, ... Cao F, Dong N
Eur Heart J: 27 Jun 2021; epub ahead of print | PMID: 34179958
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Abstract

Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics, and outcome.

Miró Ò, Jiménez S, Mebazaa A, Freund Y, ... Ponce MC, González Del Castillo J
Aims
We investigated the incidence, risk factors, clinical characteristics, and outcomes of pulmonary embolism (PE) in patients with COVID-19 attending emergency departments (EDs), before hospitalization.
Methods and results
We retrospectively reviewed all COVID-19 patients diagnosed with PE in 62 Spanish EDs (20% of Spanish EDs, case group) during the first COVID-19 outbreak. COVID-19 patients without PE and non-COVID-19 patients with PE were included as control groups. Adjusted comparisons for baseline characteristics, acute episode characteristics, and outcomes were made between cases and randomly selected controls (1:1 ratio). We identified 368 PE in 74 814 patients with COVID-19 attending EDs (4.92‰). The standardized incidence of PE in the COVID-19 population resulted in 310 per 100 000 person-years, significantly higher than that observed in the non-COVID-19 population [35 per 100 000 person-years; odds ratio (OR) 8.95 for PE in the COVID-19 population, 95% confidence interval (CI) 8.51-9.41]. Several characteristics in COVID-19 patients were independently associated with PE, the strongest being D-dimer >1000 ng/mL, and chest pain (direct association) and chronic heart failure (inverse association). COVID-19 patients with PE differed from non-COVID-19 patients with PE in 16 characteristics, most directly related to COVID-19 infection; remarkably, D-dimer >1000 ng/mL, leg swelling/pain, and PE risk factors were significantly less present. PE in COVID-19 patients affected smaller pulmonary arteries than in non-COVID-19 patients, although right ventricular dysfunction was similar in both groups. In-hospital mortality in cases (16.0%) was similar to COVID-19 patients without PE (16.6%; OR 0.96, 95% CI 0.65-1.42; and 11.4% in a subgroup of COVID-19 patients with PE ruled out by scanner, OR 1.48, 95% CI 0.97-2.27), but higher than in non-COVID-19 patients with PE (6.5%; OR 2.74, 95% CI 1.66-4.51). Adjustment for differences in baseline and acute episode characteristics and sensitivity analysis reported very similar associations.
Conclusions
PE in COVID-19 patients at ED presentation is unusual (about 0.5%), but incidence is approximately ninefold higher than in the general (non-COVID-19) population. Moreover, risk factors and leg symptoms are less frequent, D-dimer increase is lower and emboli involve smaller pulmonary arteries. While PE probably does not increase the mortality of COVID-19 patients, mortality is higher in COVID-19 than in non-COVID-19 patients with PE.

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

Eur Heart J: 23 Jun 2021; epub ahead of print
Miró Ò, Jiménez S, Mebazaa A, Freund Y, ... Ponce MC, González Del Castillo J
Eur Heart J: 23 Jun 2021; epub ahead of print | PMID: 34164664
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Abstract

Statin associated lower cancer risk and related mortality in patients with heart failure.

Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Aims
Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse.
Methods and results
Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81).
Conclusion
Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.

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

Eur Heart J: 21 Jun 2021; epub ahead of print
Ren QW, Yu SY, Teng TK, Li X, ... Lam CSP, Yiu KH
Eur Heart J: 21 Jun 2021; epub ahead of print | PMID: 34157723
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Impact:
Abstract

Tubulin-folding cofactor E deficiency promotes vascular dysfunction by increased endoplasmic reticulum stress.

Efentakis P, Molitor M, Kossmann S, Bochenek ML, ... Münzel T, Wenzel P
Aims
Assessment of endothelial function in humans by measuring flow-mediated dilation (FMD) risk-stratifies individuals with established cardiovascular disease, whereas its predictive value is limited in primary prevention. We therefore aimed to establish and evaluate novel markers of FMD at the population level.
Methods and results
In order to identify novel targets that were negatively correlated with FMD and investigate their contribution to vascular function, we performed a genome-wide association study (GWAS) of 4175 participants of the population based Gutenberg Health Study. Subsequently, conditional knockout mouse models deleting the gene of interest were generated and characterized. GWAS analysis revealed that single-nucleotide polymorphisms (SNPs) in the tubulin-folding cofactor E (TBCE) gene were negatively correlated with endothelial function and TBCE expression. Vascular smooth muscle cell (VSMC)-targeted TBCE deficiency was associated with endothelial dysfunction, aortic wall hypertrophy, and endoplasmic reticulum (ER) stress-mediated VSMC hyperproliferation in mice, paralleled by calnexin up-regulation and exacerbated by the blood pressure hormone angiotensin II. Treating SMMHC-ERT2-Cre+/-TBCEfl/fl mice with the ER stress modulator tauroursodeoxycholic acid amplified Raptor/Beclin-1-dependent autophagy and reversed vascular dysfunction.
Conclusion
TBCE and tubulin homeostasis seem to be novel predictors of vascular function and offer a new drug target to ameliorate ER stress-dependent vascular dysfunction.

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

Eur Heart J: 15 Jun 2021; epub ahead of print
Efentakis P, Molitor M, Kossmann S, Bochenek ML, ... Münzel T, Wenzel P
Eur Heart J: 15 Jun 2021; epub ahead of print | PMID: 34132336
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Impact:
Abstract

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

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

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

Eur Heart J: 13 Jun 2021; 42:2270-2279
Smilowitz NR, Kunichoff D, Garshick M, Shah B, ... Hochman JS, Berger JS
Eur Heart J: 13 Jun 2021; 42:2270-2279 | PMID: 33448289
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Impact:
Abstract

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction.

Verstraelen TE, van Lint FHM, Bosman LP, de Brouwer R, ... van Tintelen JP, Wilde AAM
Aims
This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model.
Methods and results
Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).
Conclusion
This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.

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

Eur Heart J: 10 Jun 2021; epub ahead of print
Verstraelen TE, van Lint FHM, Bosman LP, de Brouwer R, ... van Tintelen JP, Wilde AAM
Eur Heart J: 10 Jun 2021; epub ahead of print | PMID: 34113975
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Impact:
Abstract

Myocardial hypoxic stress mediates functional cardiac extracellular vesicle release.

Anselmo A, Frank D, Papa L, Viviani Anselmi C, ... Kupatt C, Condorelli G
Aims 
Increased shedding of extracellular vesicles (EVs)-small, lipid bilayer-delimited particles with a role in paracrine signalling-has been associated with human pathologies, e.g. atherosclerosis, but whether this is true for cardiac diseases is unknown.
Methods and results 
Here, we used the surface antigen CD172a as a specific marker of cardiomyocyte (CM)-derived EVs; the CM origin of CD172a+ EVs was supported by their content of cardiac-specific proteins and heart-enriched microRNAs. We found that patients with aortic stenosis, ischaemic heart disease, or cardiomyopathy had higher circulating CD172a+ cardiac EV counts than did healthy subjects. Cellular stress was a major determinant of EV release from CMs, with hypoxia increasing shedding in in vitro and in vivo experiments. At the functional level, EVs isolated from the supernatant of CMs derived from human-induced pluripotent stem cells and cultured in a hypoxic atmosphere elicited a positive inotropic response in unstressed CMs, an effect we found to be dependent on an increase in the number of EVs expressing ceramide on their surface. Of potential clinical relevance, aortic stenosis patients with the highest counts of circulating cardiac CD172a+ EVs had a more favourable prognosis for transcatheter aortic valve replacement than those with lower counts.
Conclusion 
We identified circulating CD172a+ EVs as cardiac derived, showing their release and function and providing evidence for their prognostic potential in aortic stenosis patients.

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

Eur Heart J: 08 Jun 2021; epub ahead of print
Anselmo A, Frank D, Papa L, Viviani Anselmi C, ... Kupatt C, Condorelli G
Eur Heart J: 08 Jun 2021; epub ahead of print | PMID: 34104945
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Impact:
Abstract

Lipoproteins in chronic kidney disease: from bench to bedside.

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

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

Eur Heart J: 06 Jun 2021; 42:2170-2185
Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D
Eur Heart J: 06 Jun 2021; 42:2170-2185 | PMID: 33393990
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Impact:
Abstract

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

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

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

Eur Heart J: 06 Jun 2021; 42:2201-2211
Pérez de Isla L, Watts GF, Alonso R, Díaz-Díaz JL, ... López-Miranda J, Mata P
Eur Heart J: 06 Jun 2021; 42:2201-2211 | PMID: 33437997
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Abstract

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

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

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

Eur Heart J: 06 Jun 2021; 42:2154-2169
Karagiannis AD, Mehta A, Dhindsa DS, Virani SS, ... Stone NJ, Sperling LS
Eur Heart J: 06 Jun 2021; 42:2154-2169 | PMID: 33463677
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Impact:
Abstract

Lower risk of stroke after alcohol abstinence in patients with incident atrial fibrillation: a nationwide population-based cohort study.

Lee SR, Choi EK, Jung JH, Han KD, Oh S, Lip GYH
Aims
The aim of this study was to evaluate the association between alcohol consumption status (and its changes) after newly diagnosed atrial fibrillation (AF) and the risk of ischaemic stroke.
Methods and results
Using the Korean nationwide claims and health examination database, we included subjects who were newly diagnosed with AF between 2010 and 2016. Patients were categorized into three groups according to the status of alcohol consumption before and after AF diagnosis: non-drinkers; abstainers from alcohol after AF diagnosis; and current drinkers. The primary outcome was incident ischaemic stroke during follow-up. Non-drinkers, abstainers, and current drinkers were compared using incidence rate differences after the inverse probability of treatment weighting (IPTW). Among a total of 97 869 newly diagnosed AF patients, 51% were non-drinkers, 13% were abstainers, and 36% were current drinkers. During 310 926 person-years of follow-up, 3120 patients were diagnosed with incident ischaemic stroke (10.0 per 1000 person-years). At 5-year follow-up, abstainers and non-drinkers were associated with a lower risk for stroke than current drinkers (incidence rate differences after IPTW, -2.03 [-3.25, -0.82] for abstainers and -2.98 [-3.81, -2.15] for non-drinkers, per 1000 person-years, respectively; and incidence rate ratios after IPTW, 0.75 [0.70, 0.81] for non-drinkers and 0.83 [0.74, 0.93] for abstainers, respectively).
Conclusion 
Current alcohol consumption was associated with an increased risk of ischaemic stroke in patients with newly diagnosed AF, and alcohol abstinence after AF diagnosis could reduce the risk of ischaemic stroke. Lifestyle intervention, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach to AF management to improve clinical outcomes.

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

Eur Heart J: 06 Jun 2021; epub ahead of print
Lee SR, Choi EK, Jung JH, Han KD, Oh S, Lip GYH
Eur Heart J: 06 Jun 2021; epub ahead of print | PMID: 34097040
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Impact:
Abstract

The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.

Jankowska EA, Kirwan BA, Kosiborod M, Butler J, ... Pocock S, Ponikowski P
Aims
Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population.
Methods and results
The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM.
Conclusion
In iron-deficient patients with HF and left ventricular ejection fraction ≤50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.

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

Eur Heart J: 02 Jun 2021; epub ahead of print
Jankowska EA, Kirwan BA, Kosiborod M, Butler J, ... Pocock S, Ponikowski P
Eur Heart J: 02 Jun 2021; epub ahead of print | PMID: 34080008
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Impact:
Abstract

Clinical characteristics and prognosis of patients with microvascular angina: an international and prospective cohort study by the Coronary Vasomotor Disorders International Study (COVADIS) Group.

Shimokawa H, Suda A, Takahashi J, Berry C, ... Beltrame JF, Merz CNB
Aims
To provide multi-national, multi-ethnic data on the clinical characteristics and prognosis of patients with microvascular angina (MVA).
Methods and results
The Coronary Vasomotor Disorders International Study Group proposed the diagnostic criteria for MVA. We prospectively evaluated the clinical characteristics of patients according to these criteria and their prognosis. The primary endpoint was the composite of major cardiovascular events (MACE), verified by institutional investigators, which included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. During the period from 1 July 2015 to 31 December 2018, 686 patients with MVA were registered from 14 institutes in 7 countries from 4 continents. Among them, 64% were female and the main ethnic groups were Caucasians (61%) and Asians (29%). During follow-up of a median of 398 days (IQR 365-744), 78 MACE occurred (6.4% in men vs. 8.6% in women, P = 0.19). Multivariable Cox proportional hazard analysis disclosed that hypertension and previous history of coronary artery disease (CAD), including acute coronary syndrome and stable angina pectoris, were independent predictors of MACE. There was no sex or ethnic difference in prognosis, although women had lower Seattle Angina Questionnaire scores than men (P < 0.05).
Conclusions
This first international study provides novel evidence that MVA is an important health problem regardless of sex or ethnicity that a diagnosis of MVA portends a substantial risk for MACE associated with hypertension and previous history of CAD, and that women have a lower quality of life than men despite the comparable prognosis.

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

Eur Heart J: 25 May 2021; epub ahead of print
Shimokawa H, Suda A, Takahashi J, Berry C, ... Beltrame JF, Merz CNB
Eur Heart J: 25 May 2021; epub ahead of print | PMID: 34038937
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Impact:
Abstract

Directly measured vs. calculated remnant cholesterol identifies additional overlooked individuals in the general population at higher risk of myocardial infarction.

Varbo A, Nordestgaard BG
Aims 
We tested the hypothesis that high directly measured remnant cholesterol is associated with increased risk of ischaemic heart disease (IHD) and myocardial infarction (MI) in the general population. We also explored whether directly measured vs. calculated remnant cholesterol is superior in identifying individuals at increased risk.
Methods and results 
Overall, 16 207 individuals from the Copenhagen General Population Study with both directly measured and calculated remnant cholesterol, both representing cholesterol content in triglyceride-rich lipoproteins, were followed up for 14 years to analyse the risk for IHD and MI. For directly measured and calculated remnant cholesterol, hazard ratios for individuals with concentrations ≥95th percentile vs. <40th percentile were 1.75 (95% confidence interval 1.42-2.15) and 1.76 (1.42-2.17) for IHD and 2.05 (1.50-2.80) and 1.93 (1.40-2.66) for MI. Compared to individuals with both directly measured and calculated remnant cholesterol <80th percentile (75% of the whole population), those with only directly measured remnant cholesterol ≥80th percentile (5%) had hazard ratios of 1.42 (1.15-1.75) for IHD and 1.83 (1.35-2.47) for MI. Corresponding hazard ratios for individuals with only calculated remnant cholesterol ≥80th percentile (5%) were 1.14 (0.91-1.44) and 1.14 (0.80-1.62), respectively, and corresponding hazard ratios for individuals with both directly measured and calculated remnant cholesterol ≥80th percentiles (15%) were 1.48 (1.30-1.68) and 1.67 (1.38-2.01), respectively. In individuals with high directly measured or high calculated remnant cholesterol, the median directly measured remnant cholesterol was 1.9 and 1.5 mmol/L, the median plasma triglycerides were 2.0 and 2.7 mmol/L, and the median plasma apolipoprotein B was 132 and 142 mg/dL, respectively.
Conclusions 
Directly measured vs. calculated remnant cholesterol identifies 5% overlooked individuals in the general population with cholesterol-rich, triglyceride-poor remnants and 1.8-fold increased risk of MI.

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

Eur Heart J: 22 May 2021; epub ahead of print
Varbo A, Nordestgaard BG
Eur Heart J: 22 May 2021; epub ahead of print | PMID: 34023898
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Impact:
Abstract

Atrial fibrillation and kidney function: a bidirectional Mendelian randomization study.

Park S, Lee S, Kim Y, Lee Y, ... Kim YS, Kim DK
Aims
The aim of this study was to investigate the causal effects between atrial fibrillation (AF) and kidney function.
Methods and results
We performed a bidirectional summary-level Mendelian randomization (MR) analysis implementing the results from a large-scale genome-wide association study for estimated glomerular filtration rate (eGFR) by the CKDGen (N = 765 348) and AF (N = 588 190) to identify genetic instruments. The inverse variance weighted method was the main MR method used. For replication, an allele score-based MR was performed by individual-level data within a UK Biobank cohort of white British ancestry individuals (N = 337 138). A genetic predisposition to AF was significantly associated with decreased eGFR [for log-eGFR, beta -0.003 (standard error, 0.0005), P < 0.001] and increased risk of chronic kidney disease [beta 0.059 (0.0126), P < 0.001]. The significance remained in MR sensitivity analyses and the causal estimates were consistent when we limited the analysis to individuals of European ancestry. Genetically predicted eGFR did not show a significant association with the risk of AF [beta -0.366 (0.275), P = 0.183]. The results were similar in allele score-based MR, as allele score for AF was significantly associated with reduced eGFR [for continuous eGFR, beta -0.079 (0.021), P < 0.001], but allele score for eGFR did not show a significant association with risk of AF [beta -0.005 (0.008), P = 0.530].
Conclusions
Our study supports that AF is a causal risk factor for kidney function impairment. However, an effect of kidney function on AF was not identified in this study.

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

Eur Heart J: 22 May 2021; epub ahead of print
Park S, Lee S, Kim Y, Lee Y, ... Kim YS, Kim DK
Eur Heart J: 22 May 2021; epub ahead of print | PMID: 34023889
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Impact:
Abstract

Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.

Steinberg C, Davies B, Mellor G, Tadros R, ... Simpson CS, Krahn AD
Aims 
The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors.
Methods and results 
We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control.
Conclusion 
Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.

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

Eur Heart J: 18 May 2021; epub ahead of print
Steinberg C, Davies B, Mellor G, Tadros R, ... Simpson CS, Krahn AD
Eur Heart J: 18 May 2021; epub ahead of print | PMID: 34010395
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Impact:
Abstract

The European bifurcation club Left Main Coronary Stent study: a randomized comparison of stepwise provisional vs. systematic dual stenting strategies (EBC MAIN).

Hildick-Smith D, Egred M, Banning A, Brunel P, ... Morice MC, Louvard Y
Background
Patients with non-left-main coronary bifurcation lesions are usually best treated with a stepwise provisional approach. However, patients with true left main stem bifurcation lesions have been shown in one dedicated randomized study to benefit from systematic dual stent implantation.
Methods and results
Four hundred and sixty-seven patients with true left main stem bifurcation lesions requiring intervention were recruited to the EBC MAIN study in 11 European countries. Patients were aged 71 ± 10 years; 77% were male. Patients were randomly allocated to a stepwise layered provisional strategy (n = 230) or a systematic dual stent approach (n = 237). The primary endpoint (a composite of death, myocardial infarction, and target lesion revascularization at 12 months) occurred in 14.7% of the stepwise provisional group vs. 17.7% of the systematic dual stent group (hazard ratio 0.8, 95% confidence interval 0.5-1.3; P = 0.34). Secondary endpoints were death (3.0% vs. 4.2%, P = 0.48), myocardial infarction (10.0% vs. 10.1%, P = 0.91), target lesion revascularization (6.1% vs. 9.3%, P = 0.16), and stent thrombosis (1.7% vs. 1.3%, P = 0.90), respectively. Procedure time, X-ray dose and consumables favoured the stepwise provisional approach. Symptomatic improvement was excellent and equal in each group.
Conclusions
Among patients with true bifurcation left main stem stenosis requiring intervention, fewer major adverse cardiac events occurred with a stepwise layered provisional approach than with planned dual stenting, although the difference was not statistically significant. The stepwise provisional strategy should remain the default for distal left main stem bifurcation intervention.
Study registration
http://clinicaltrials.gov NCT02497014.

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

Eur Heart J: 17 May 2021; epub ahead of print
Hildick-Smith D, Egred M, Banning A, Brunel P, ... Morice MC, Louvard Y
Eur Heart J: 17 May 2021; epub ahead of print | PMID: 34002215
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Abstract

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: a systematic review and meta-analysis.

Navarese EP, Lansky AJ, Kereiakes DJ, Kubica J, ... Wijns W, Andreotti F
Aims
The value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population.
Methods and results
From inception through November 2020, MEDLINE, EMBASE, Google Scholar, and other databases were searched for randomised trials comparing revascularisation against medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RRs) with 95% confidence intervals, using random-effects models. Cardiac mortality was the pre-specified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI, and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19 806 patients (10 023 randomised to revascularisation plus medical therapy and 9783 to medical therapy alone) were included. Compared with medical therapy alone, revascularisation yielded a lower risk of cardiac death [RR 0.79 (0.67-0.93), P < 0.01] and spontaneous MI [RR 0.74 (0.64-0.86), P < 0.01]. By meta-regression, the cardiac death risk reduction after revascularisation, compared with medical therapy alone, was linearly associated with follow-up duration [RR per 4-year follow-up: 0.81 (0.69-0.96), P = 0.008], spontaneous MI absolute difference (P = 0.01) and percentage of multivessel disease at baseline (P = 0.004). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All-cause mortality [0.94 (0.87-1.01), P = 0.11], any MI (P = 0.14), and stroke risk (P = 0.30) did not differ significantly between strategies.
Conclusion
In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared with medical therapy alone. The cardiac survival benefit after revascularisation improved with longer follow-up times and was associated with fewer spontaneous MIs.

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

Eur Heart J: 17 May 2021; epub ahead of print
Navarese EP, Lansky AJ, Kereiakes DJ, Kubica J, ... Wijns W, Andreotti F
Eur Heart J: 17 May 2021; epub ahead of print | PMID: 34002203
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Abstract

Lowering cholesterol, blood pressure, or both to prevent cardiovascular events: results of 8.7 years of follow-up of Heart Outcomes Evaluation Prevention (HOPE)-3 study participants.

Bosch J, Lonn EM, Jung H, Zhu J, ... Leiter LA, Yusuf S
Aims
Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated.
Methods and results
After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years.
Conclusion
The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect.
Trial registration number
NCT00468923.

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

Eur Heart J: 07 May 2021; epub ahead of print
Bosch J, Lonn EM, Jung H, Zhu J, ... Leiter LA, Yusuf S
Eur Heart J: 07 May 2021; epub ahead of print | PMID: 33963372
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Abstract

Driving following defibrillator implantation: a nationwide register-linked survey study.

Bjerre J, Rosenkranz SH, Schou M, Jøns C, ... Gislason G, Ruwald AC
Aims
Patients are restricted from driving following implantable cardioverter defibrillator (ICD) implantation or shock. We sought to investigate how many patients are aware of, and adhere to, the driving restrictions, and what proportion experience an ICD shock or other cardiac symptoms while driving.
Methods and results
We performed a nationwide survey of all living Danish residents 18 years or older who received a first-time ICD between 2013 and 2016 (n = 3913) and linked their responses with nationwide registers. Of 2741 respondents (47% primary prevention, 83% male, median age 67 years), 2513 (92%) held a valid driver\'s license at ICD implantation, 175 (7%) of whom had a license for professional driving. Many drivers were unaware of driving restrictions: primary prevention 58%; secondary prevention 36%; post-appropriate shock 28%; professional drivers 55%. Almost all (94%) resumed non-professional driving after ICD implantation, more than one-third during the restricted period; 35% resumed professional driving. During a median follow-up of 2.3 years, 5 (0.2%) reported receiving an ICD shock while driving, one of which resulted in a traffic accident. The estimated risk of harm was 0.0002% per person-year.
Conclusion
In this nationwide study, many ICD patients were unaware of driving restrictions, and more than one third resumed driving during a driving restriction period. However, the rate of reported ICD shocks while driving was very low.

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

Eur Heart J: 04 May 2021; epub ahead of print
Bjerre J, Rosenkranz SH, Schou M, Jøns C, ... Gislason G, Ruwald AC
Eur Heart J: 04 May 2021; epub ahead of print | PMID: 33954626
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Abstract

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

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

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

Eur Heart J: 30 Apr 2021; 42:1676-1684
Younis A, Goldberger JJ, Kutyifa V, Zareba W, ... Stein K, Goldenberg I
Eur Heart J: 30 Apr 2021; 42:1676-1684 | PMID: 33417692
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This program is still in alpha version.