Journal: Eur Heart J

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Abstract

Prognostic value of comprehensive intracoronary physiology assessment early after heart transplantation.

Ahn JM, Zimmermann FM, Arora S, Solberg OG, ... Gullestad L, Fearon WF
Aims
We evaluated the long-term prognostic value of invasively assessing coronary physiology after heart transplantation in a large multicentre registry.
Methods and results
Comprehensive intracoronary physiology assessment measuring fractional flow reserve (FFR), the index of microcirculatory resistance (IMR), and coronary flow reserve (CFR) was performed in 254 patients at baseline (a median of 7.2 weeks) and in 240 patients at 1 year after transplantation (199 patients had both baseline and 1-year measurement). Patients were classified into those with normal physiology, reduced FFR (FFR ≤ 0.80), and microvascular dysfunction (either IMR ≥ 25 or CFR ≤ 2.0 with FFR > 0.80). The primary outcome was the composite of death or re-transplantation at 10 years. At baseline, 5.5% had reduced FFR; 36.6% had microvascular dysfunction. Baseline reduced FFR [adjusted hazard ratio (aHR) 2.33, 95% confidence interval (CI) 0.88-6.15; P = 0.088] and microvascular dysfunction (aHR 0.88, 95% CI 0.44-1.79; P = 0.73) were not predictors of death and re-transplantation at 10 years. At 1 year, 5.0% had reduced FFR; 23.8% had microvascular dysfunction. One-year reduced FFR (aHR 2.98, 95% CI 1.13-7.87; P = 0.028) and microvascular dysfunction (aHR 2.33, 95% CI 1.19-4.59; P = 0.015) were associated with significantly increased risk of death or re-transplantation at 10 years. Invasive measures of coronary physiology improved the prognostic performance of clinical variables (χ2 improvement: 7.41, P = 0.006). However, intravascular ultrasound-derived changes in maximal intimal thickness were not predictive of outcomes.
Conclusion
Abnormal coronary physiology 1 year after heart transplantation was common and was a significant predictor of death or re-transplantation at 10 years.

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 Oct 2021; epub ahead of print
Ahn JM, Zimmermann FM, Arora S, Solberg OG, ... Gullestad L, Fearon WF
Eur Heart J: 18 Oct 2021; epub ahead of print | PMID: 34665224
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Abstract

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HBR.

Escaned J, Cao D, Baber U, Nicolas J, ... Pocock S, Mehran R
Aims
Patients at high bleeding risk (HBR) represent a prevalent subgroup among those undergoing percutaneous coronary intervention (PCI). Early aspirin discontinuation after a short course of dual antiplatelet therapy (DAPT) has emerged as a bleeding avoidance strategy. The aim of this study was to assess the effects of ticagrelor monotherapy after 3-month DAPT in a contemporary HBR population.
Methods and results
This prespecified analysis of the TWILIGHT trial evaluated the treatment effects of early aspirin withdrawal followed by ticagrelor monotherapy in HBR patients undergoing PCI with drug-eluting stents. After 3 months of ticagrelor plus aspirin, event-free patients were randomized to 12 months of aspirin or placebo in addition to ticagrelor. A total of 1064 (17.2%) met the Academic Research Consortium definition for HBR. Ticagrelor monotherapy reduced the incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding compared with ticagrelor plus aspirin in HBR (6.3% vs. 11.4%; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.35-0.82) and non-HBR patients (3.5% vs. 5.9%; HR 0.59, 95% CI 0.46-0.77) with similar relative (Pinteraction = 0.67) but a trend towards greater absolute risk reduction in the former [-5.1% vs. -2.3%; difference in absolute risk differences (ARDs) -2.8%, 95% CI -6.4% to 0.8%, P = 0.130]. A similar pattern was observed for more severe BARC 3 or 5 bleeding with a larger absolute risk reduction in HBR patients (-3.5% vs. -0.5%; difference in ARDs -3.0%, 95% CI -5.2% to -0.8%, P = 0.008). There was no significant difference in the key secondary endpoint of death, myocardial infarction, or stroke between treatment arms, irrespective of HBR status.
Conclusions
Among HBR patients undergoing PCI who completed 3-month DAPT without experiencing major adverse events, aspirin discontinuation followed by ticagrelor monotherapy significantly reduced bleeding without increasing ischaemic events, compared with ticagrelor plus aspirin. The absolute risk reduction in major bleeding was larger in HBR than non-HBR 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: 17 Oct 2021; epub ahead of print
Escaned J, Cao D, Baber U, Nicolas J, ... Pocock S, Mehran R
Eur Heart J: 17 Oct 2021; epub ahead of print | PMID: 34662382
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Abstract

Elevated remnant cholesterol increases the risk of peripheral artery disease, myocardial infarction, and ischaemic stroke: a cohort-based study.

Wadström BN, Wulff AB, Pedersen KM, Jensen GB, Nordestgaard BG
Aims 
The atherogenic potential of cholesterol in triglyceride-rich lipoproteins, also called remnant cholesterol, is being increasingly acknowledged. Elevated remnant cholesterol is associated with increased risk of myocardial infarction and ischaemic stroke. We tested the hypothesis that elevated remnant cholesterol is also associated with increased risk of peripheral artery disease (PAD).
Methods and results 
We studied 106 937 individuals from the Copenhagen General Population Study recruited in 2003-15. During up to 15 years of follow-up, 1586 were diagnosed with PAD, 2570 with myocardial infarction, and 2762 with ischaemic stroke. We also studied 13 974 individuals from the Copenhagen City Heart Study recruited in 1976-78. During up to 43 years of follow-up, 1033 were diagnosed with PAD, 2236 with myocardial infarction, and 1976 with ischaemic stroke. Remnant cholesterol was calculated from a standard lipid profile. Diagnoses were from Danish nationwide health registries. In the Copenhagen General Population Study, elevated remnant cholesterol levels were associated with higher risk of PAD, up to a multivariable adjusted hazard ratio (HR) of 4.8 (95% confidence interval 3.1-7.5) for individuals with levels ≥1.5 mmol/L (58 mg/dL) vs. <0.5 mmol/L (19 mg/dL). Corresponding results were 4.2 (2.9-6.1) for myocardial infarction and 1.8 (1.4-2.5) for ischaemic stroke. In the Copenhagen City Heart Study, corresponding HRs were 4.9 (2.9-8.5) for PAD, 2.6 (1.8-3.8) for myocardial infarction, and 2.1 (1.5-3.1) for ischaemic stroke.
Conclusion 
Elevated remnant cholesterol is associated with a five-fold increased risk of PAD in the general population, higher than for myocardial infarction and ischaemic stroke.

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 Oct 2021; epub ahead of print
Wadström BN, Wulff AB, Pedersen KM, Jensen GB, Nordestgaard BG
Eur Heart J: 17 Oct 2021; epub ahead of print | PMID: 34661640
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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: 13 Oct 2021; 42:4077-4088
Hinterdobler J, Schott S, Jin H, Meesmann A, ... Kessler T, Sager HB
Eur Heart J: 13 Oct 2021; 42:4077-4088 | PMID: 34279021
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Abstract

Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score.

Hwang J, Park SH, Lee SW, Lee SB, ... Shin JI, Smith L
Aims
The clinical manifestation and outcomes of thrombosis with thrombocytopenia syndrome (TTS) after adenoviral COVID-19 vaccine administration are largely unknown due to the rare nature of the disease. We aimed to analyse the clinical presentation, treatment modalities, outcomes, and prognostic factors of adenoviral TTS, as well as identify predictors for mortality.
Methods and results
PubMed, Scopus, Embase, and Web of Science databases were searched and the resulting articles were reviewed. A total of 6 case series and 13 case reports (64 patients) of TTS after ChAdOx1 nCoV-19 vaccination were included. We performed a pooled analysis and developed a novel scoring system to predict mortality. The overall mortality of TTS after ChAdOx1 nCoV-19 vaccination was 35.9% (23/64). In our analysis, age ≤60 years, platelet count <25 × 103/µL, fibrinogen <150 mg/dL, the presence of intracerebral haemorrhage (ICH), and the presence of cerebral venous thrombosis (CVT) were significantly associated with death and were selected as predictors for mortality (1 point each). We named this novel scoring system FAPIC (fibrinogen, age, platelet count, ICH, and CVT), and the C-statistic for the FAPIC score was 0.837 (95% CI 0.732-0.942). Expected mortality increased with each point increase in the FAPIC score, at 2.08, 6.66, 19.31, 44.54, 72.94, and 90.05% with FAPIC scores 0, 1, 2, 3, 4, and 5, respectively. The FAPIC scoring model was internally validated through cross-validation and bootstrapping, then externally validated on a panel of TTS patients after Ad26.COV2.S administration.
Conclusions
Fibrinogen levels, age, platelet count, and the presence of ICH and CVT were significantly associated with mortality in patients with TTS, and the FAPIC score comprising these risk factors could predict mortality. The FAPIC score could be used in the clinical setting to recognize TTS patients at high risk of adverse outcomes and provide early intensive interventions including intravenous immunoglobulins and non-heparin anticoagulants.

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 Oct 2021; 42:4053-4063
Hwang J, Park SH, Lee SW, Lee SB, ... Shin JI, Smith L
Eur Heart J: 13 Oct 2021; 42:4053-4063 | PMID: 34545400
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Abstract

Hypertensive disorders of pregnancy and onset of chronic hypertension in France: the nationwide CONCEPTION study.

Boucheron P, Lailler G, Moutengou E, Regnault N, ... Blacher J, Olié V
Aims 
Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and foetal morbidity and mortality. We aimed to estimate the impact of HDP on the onset of chronic hypertension in primiparous women in the first years following childbirth.
Methods and results 
This nationwide cohort study used data from the French National Health Data System (SNDS). All eligible primiparous women without pre-existing chronic hypertension who delivered between 2010 and 2018 were included. Women were followed up from six weeks post-partum until onset of hypertension, a cardiovascular event, death, or the study end date (31 December 2018). The main outcome was a diagnosis of chronic hypertension. We used Cox models to estimate hazard ratios (HRs) of chronic hypertension for all types of HDP. Overall, 2 663 573 women were included with a mean follow-up time of 3.0 years. Among them, 180 063 (6.73%) had an HDP. Specifically 66 260 (2.16%) had pre-eclampsia (PE) and 113 803 (4.27%) had gestational hypertension (GH). Compared with women who had no HDP, the fully adjusted HRs of chronic hypertension were 6.03 [95% confidence interval (CI) 5.89-6.17] for GH, 8.10 (95% CI 7.88-8.33) for PE (all sorts), 12.95 (95% CI 12.29-13.65) for early PE, 9.90 (95% CI 9.53-10.28) for severe PE, and 13.17 (95% CI 12.74-13.60) for PE following GH. Hypertensive disorders of pregnancy exposure duration was an additional risk factor of chronic hypertension for all PE subgroups. Women with HDP consulted a general practitioner or cardiologist more frequently and earlier.
Conclusion 
Hypertensive disorders of pregnancy exposure greatly increased the risk of chronic hypertension in the first years following delivery.

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: 12 Oct 2021; epub ahead of print
Boucheron P, Lailler G, Moutengou E, Regnault N, ... Blacher J, Olié V
Eur Heart J: 12 Oct 2021; epub ahead of print | PMID: 34643681
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Abstract

Maternal and neonatal complications in women with congenital heart disease: a nationwide analysis.

Lammers AE, Diller GP, Lober R, Möllers M, ... Enders D, Baumgartner H
Aims
The aim of this study was to provide population-based data on maternal and neonatal complications and outcome in the pregnancies of women with congenital heart disease (CHD).
Methods and results
Based on administrative data from one of the largest German Health Insurance Companies (BARMER GEK, ∼9 million members representative for Germany), all pregnancies in women with CHD between 2005 and 2018 were analysed. In addition, an age-matched non-CHD control group was included for comparison and the association between adult CHD (ACHD) and maternal or neonatal outcomes investigated. Overall, 7512 pregnancies occurred in 4015 women with CHD. The matched non-CHD control group included 6502 women with 11 225 pregnancies. Caesarean deliveries were more common in CHD patients (40.5% vs. 31.5% in the control group; P < 0.001). There was no excess mortality. Although the maternal complication rate was low in absolute terms, women with CHD had a significantly higher rate of stroke, heart failure and cardiac arrhythmias during pregnancy (P < 0.001 for all). Neonatal mortality was low but also significantly higher in the ACHD group (0.83% vs. 0.22%; P = 0.001) and neonates to CHD mothers had low/extremely low birth weight or extreme immaturity (<0.001) or required resuscitation and mechanical ventilation more often compared to non-CHD offspring (P < 0.001 for both). On multivariate logistic regression maternal defect complexity, arterial hypertension, heart failure, prior fertility treatment, and anticoagulation with vitamin K antagonists emerged as significant predictors of adverse neonatal outcome (P < 0.05 for all). Recurrence of CHD was 6.1 times higher in infants to ACHD mothers compared to controls (P < 0.0001).
Conclusions
This population-based study illustrates a reassuringly low maternal mortality rate in a highly developed healthcare system. Nevertheless, maternal morbidity and neonatal morbidity/mortality were significantly increased in women with ACHD and their offspring compared to non-ACHD controls highlighting the need of specialized care and pre-pregnancy counselling.

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

Eur Heart J: 11 Oct 2021; epub ahead of print
Lammers AE, Diller GP, Lober R, Möllers M, ... Enders D, Baumgartner H
Eur Heart J: 11 Oct 2021; epub ahead of print | PMID: 34638134
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Abstract

Impact of COVID-19 pandemic restrictions on ST-elevation myocardial infarction: a cardiac magnetic resonance imaging study.

Lechner I, Reindl M, Tiller C, Holzknecht M, ... Metzler B, Reinstadler SJ
Aims
The severity of myocardial tissue damage following ST-elevation myocardial infarction (STEMI) strongly determines short- and long-term prognosis. This study explored the impact of the coronavirus disease 2019 (COVID-19) pandemic and associated public health restrictions on infarct severity.
Methods and results
STEMI patients treated with primary percutaneous coronary intervention (PCI) and included in the prospective Magnetic Resonance Imaging in Acute ST-Elevation Myocardial Infarction (MARINA-STEMI) cohort study from 2015- 2020 (n = 474) were categorized according to (i) timeframes with and without major public health restrictions in 2020, and (ii) timeframes of major public health restrictions during 2020 and during the corresponding timeframes between 2015-2019. Myocardial damage was evaluated by cardiac magnetic resonance imaging. During major public health restrictions in 2020 (n = 48), there was an increase in infarct size (22 [IQR 12-29] vs. 14 [IQR 6-23]%, P < 0.01), a higher frequency (77% vs. 52%, P < 0.01) and larger extent of microvascular obstruction (1.5 [IQR 0.1-11.4] vs. 0.2 [IQR 0.0-2.6]%, P < 0.01) and a higher rate of intramyocardial haemorrhage (56% vs. 34%, P = 0.02) as compared to the phases without major restrictions in 2020 (n = 101). These findings were confirmed in adjusted analysis and were consistent when comparing patients admitted in 2020 versus patients admitted in the \"pre-pandemic\" era (2015-2019). Patient characteristics were comparable between groups, except for a significantly longer total ischemia time (P < 0.01) and higher frequency of pre-PCI Thrombolysis in Myocardial Infarction (TIMI) flow 0 during times of major restrictions (P = 0.03).
Conclusion
This study provides novel mechanistic insights demonstrating a significant increase in myocardial damage in STEMI patients admitted during the COVID-19 pandemic with a temporal relation to major public health restrictions.

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

Eur Heart J: 10 Oct 2021; epub ahead of print
Lechner I, Reindl M, Tiller C, Holzknecht M, ... Metzler B, Reinstadler SJ
Eur Heart J: 10 Oct 2021; epub ahead of print | PMID: 34632491
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Abstract

Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Lüscher TF, Davies A, Beer JH, Valgimigli M, ... Diener HC, Konstantinides SV
Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow\'s triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.

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 Oct 2021; epub ahead of print
Lüscher TF, Davies A, Beer JH, Valgimigli M, ... Diener HC, Konstantinides SV
Eur Heart J: 07 Oct 2021; epub ahead of print | PMID: 34624084
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Abstract

Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study.

Salem JE, Nguyen LS, Moslehi JJ, Ederhy S, ... Funck-Brentano C, Gougis P
Aims
With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA).
Methods and results
We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967-83 to 15 070 in 2014-18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P < 0.0001). Concordance between these VigiBase signals and data concerning diLQT and VA/TdP identified in CredibleMeds or US Food and Drug Administration (FDA) labels was moderate (κ = 0.47 and 0.40, P < 0.0001). Twenty-three drugs represent new signals, while 24 flagged by CredibleMeds or FDA had no signal in VigiBase. A three-level SD risk stratification relying on isolated long QT (low risk), associated with VA without SD (moderate risk), and VA with SD (high risk) is proposed.
Conclusion
This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements.
Clinical trial registration
NCT03530215.

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 Oct 2021; 42:3915-3928
Salem JE, Nguyen LS, Moslehi JJ, Ederhy S, ... Funck-Brentano C, Gougis P
Eur Heart J: 06 Oct 2021; 42:3915-3928 | PMID: 34370839
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Abstract

Artificial intelligence in the diagnosis and management of arrhythmias.

Nagarajan VD, Lee SL, Robertus JL, Nienaber CA, Trayanova NA, Ernst S
The field of cardiac electrophysiology (EP) had adopted simple artificial intelligence (AI) methodologies for decades. Recent renewed interest in deep learning techniques has opened new frontiers in electrocardiography analysis including signature identification of diseased states. Artificial intelligence advances coupled with simultaneous rapid growth in computational power, sensor technology, and availability of web-based platforms have seen the rapid growth of AI-aided applications and big data research. Changing lifestyles with an expansion of the concept of internet of things and advancements in telecommunication technology have opened doors to population-based detection of atrial fibrillation in ways, which were previously unimaginable. Artificial intelligence-aided advances in 3D cardiac imaging heralded the concept of virtual hearts and the simulation of cardiac arrhythmias. Robotics, completely non-invasive ablation therapy, and the concept of extended realities show promise to revolutionize the future of EP. In this review, we discuss the impact of AI and recent technological advances in all aspects of arrhythmia care.

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

Eur Heart J: 06 Oct 2021; 42:3904-3916
Nagarajan VD, Lee SL, Robertus JL, Nienaber CA, Trayanova NA, Ernst S
Eur Heart J: 06 Oct 2021; 42:3904-3916 | PMID: 34392353
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Abstract

Deep learning analysis of electrocardiogram for risk prediction of drug-induced arrhythmias and diagnosis of long QT syndrome.

Prifti E, Fall A, Davogustto G, Pulini A, ... Extramiana F, Salem JE
Aims
Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, QTc has a low positive predictive value.
Methods and results
We used convolutional neural network (CNN) models to quantify ECG alterations induced by sotalol, an IKr blocker associated with TdP, aiming to provide new tools (CNN models) to enhance the prediction of drug-induced TdP (diTdP) and diagnosis of cLQTS. Tested CNN models used single or multiple 10-s recordings/patient using 8 leads or single leads in various cohorts: 1029 healthy subjects before and after sotalol intake (n = 14 135 ECGs); 487 cLQTS patients (n = 1083 ECGs: 560 type 1, 456 type 2, 67 type 3); and 48 patients with diTdP (n = 1105 ECGs, with 147 obtained within 48 h of a diTdP episode). CNN models outperformed models using QTc to identify exposure to sotalol [area under the receiver operating characteristic curve (ROC-AUC) = 0.98 vs. 0.72, P ≤ 0.001]. CNN models had higher ROC-AUC using multiple vs. single 10-s ECG (P ≤ 0.001). Performances were comparable for 8-lead vs. single-lead models. CNN models predicting sotalol exposure also accurately detected the presence and type of cLQTS vs. healthy controls, particularly for cLQT2 (AUC-ROC = 0.9) and were greatest shortly after a diTdP event and declining over time (P ≤ 0.001), after controlling for QTc and intake of culprit drugs. ECG segment analysis identified the J-Tpeak interval as the best discriminator of sotalol intake.
Conclusion
CNN models applied to ECGs outperform QTc measurements to identify exposure to drugs altering the QT interval, congenital LQTS, and are greatest shortly after a diTdP episode.

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 Oct 2021; 42:3948-3961
Prifti E, Fall A, Davogustto G, Pulini A, ... Extramiana F, Salem JE
Eur Heart J: 06 Oct 2021; 42:3948-3961 | PMID: 34468739
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Abstract

Day-to-day measurement of physical activity and risk of atrial fibrillation.

Bonnesen MP, Frodi DM, Haugan KJ, Kronborg C, ... Svendsen JH, Diederichsen SZ
Aims 
The aim of this study was to investigate the association between within-individual changes in physical activity and onset of atrial fibrillation (AF).
Methods and results 
A total of 1410 participants from the general population (46.2% women, mean age 74.7 ± 4.1 years) with risk factors but with no prior AF diagnosis underwent continuous monitoring for AF episodes along with daily accelerometric assessment of physical activity using an implantable loop recorder during ≈3.5 years. The combined duration of monitoring was ≈1.6 million days, where 10 851 AF episodes lasting ≥60 min were detected in 361 participants (25.6%) with a median of 5 episodes (2, 25) each. The median daily physical activity was 112 (66, 168) min/day. A dynamic parameter describing within-individual changes in daily physical activity, i.e. average daily activity in the last week compared to the previous 100 days, was computed and used to model the onset of AF. A 1-h decrease in average daily physical activity was associated with AF onset the next day [odds ratio 1.24 (1.18-1.31)]. This effect was modified by overall level of activity (P < 0.001 for interaction), and the signal was strongest in the tertile of participants with lowest activity overall [low: 1.62 (1.41-1.86), mid: 1.27 (1.16-1.39), and high: 1.10 (1.01-1.19)].
Conclusions 
Within-individual changes in physical activity are associated with the onset of AF episodes as detected by continuous monitoring in a high-risk population. For each person, a 1-h decrease in daily physical activity during the last week increased the odds of AF onset the next day by ≈25%, while the strongest association was seen in the group with the lowest activity overall.
Clinical trial registration
ClinicalTrials.gov, identifier: NCT02036450.

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

Eur Heart J: 06 Oct 2021; 42:3979-3988
Bonnesen MP, Frodi DM, Haugan KJ, Kronborg C, ... Svendsen JH, Diederichsen SZ
Eur Heart J: 06 Oct 2021; 42:3979-3988 | PMID: 34471928
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Abstract

Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy.

Nauffal V, Marstrand P, Han L, Parikh VN, ... Olivotto I, Ho CY
Aims 
Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry.
Methods and results
We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97]).
Conclusion 
Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

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 Oct 2021; 42:3932-3944
Nauffal V, Marstrand P, Han L, Parikh VN, ... Olivotto I, Ho CY
Eur Heart J: 06 Oct 2021; 42:3932-3944 | PMID: 34491319
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Impact:
Abstract

Five-year outcomes after state-of-the-art percutaneous coronary revascularization in patients with de novo three-vessel disease: final results of the SYNTAX II study.

Banning AP, Serruys P, De Maria GL, Ryan N, ... Tijssen J, Escaned J
Aims
The SYNTAX II study evaluated the impact of advances in percutaneous coronary intervention (PCI), integrated into a single revascularization strategy, on outcomes of patients with de novo three-vessel disease. The study employed decision-making utilizing the SYNTAX score II, use of coronary physiology, thin-strut biodegradable polymer drug-eluting stents, intravascular ultrasound, enhanced treatments of chronic total occlusions, and optimized medical therapy. Patients treated with this approach were compared with predefined patients from the SYNTAX I trial.
Methods and results
SYNTAX II was a multicentre, single-arm, open-label study of patients requiring revascularization who demonstrated clinical equipoise for treatment with either coronary artery bypass grafting (CABG) or PCI, predicted by the SYNTAX score II. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which included any revascularization. The comparators were a matched PCI cohort trial and a matched CABG cohort, both from the SYNTAX I trial. At 5 years, MACCE rate in SYNTAX II was significantly lower than in the SYNTAX I PCI cohort (21.5% vs. 36.4%, P < 0.001). This reflected lower rates of revascularization (13.8% vs. 23.8%, P < 0.001), and myocardial infarction (MI) (2.7% vs. 10.4%, P < 0.001), consisting of both procedural MI (0.2% vs. 3.8%, P < 0.001) and spontaneous MI (2.3% vs. 6.9%, P = 0.004). All-cause mortality was lower in SYNTAX II (8.1% vs. 13.8%, P = 0.013) reflecting a lower rate of cardiac death (2.8% vs. 8.4%, P < 0.001). Major adverse cardiac and cerebrovascular events\' outcomes at 5 years among patients in SYNTAX II and predefined patients in the SYNTAX I CABG cohort were similar (21.5% vs. 24.6%, P = 0.35).
Conclusions
Use of the SYNTAX II PCI strategy in patients with de novo three-vessel disease led to improved and durable clinical results when compared to predefined patients treated with PCI in the original SYNTAX I trial. A predefined exploratory analysis found no significant difference in MACCE between SYNTAX II PCI and matched SYNTAX I CABG patients at 5-year follow-up.

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

Eur Heart J: 06 Oct 2021; epub ahead of print
Banning AP, Serruys P, De Maria GL, Ryan N, ... Tijssen J, Escaned J
Eur Heart J: 06 Oct 2021; epub ahead of print | PMID: 34617993
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Impact:
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, ... Douglas P, Hlatky M
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 groups 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: 30 Sep 2021; 42:3844-3852
Curzen N, Nicholas Z, Stuart B, Wilding S, ... Douglas P, Hlatky M
Eur Heart J: 30 Sep 2021; 42:3844-3852 | PMID: 34269376
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Impact:
Abstract

Prognostic value of stress echocardiography assessed by the ABCDE protocol.

Ciampi Q, Zagatina A, Cortigiani L, Wierzbowska-Drabik K, ... Pellikka PA, Picano E
Aim
The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve.
Methods and results
From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13-36), 73 deaths occurred. Global X2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B-E steps (P < 0.001 vs. step A). Annual mortality rate ranged from 0.4% person-year for score 0 up to 2.7% person-year for score 5.
Conclusion
ABCDE-SE allows an effective prediction of survival in patients with chronic coronary syndromes.

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

Eur Heart J: 30 Sep 2021; 42:3869-3878
Ciampi Q, Zagatina A, Cortigiani L, Wierzbowska-Drabik K, ... Pellikka PA, Picano E
Eur Heart J: 30 Sep 2021; 42:3869-3878 | PMID: 34449837
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Impact:
Abstract

Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Aims
Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism.
Methods and results
Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels.
Conclusion
Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

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 Sep 2021; epub ahead of print
Haghikia A, Zimmermann F, Schumann P, Jasina A, ... Haghikia A, Landmesser U
Eur Heart J: 30 Sep 2021; epub ahead of print | PMID: 34597388
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Impact:
Abstract

TRI-SCORE: a new risk score for in-hospital mortality prediction after isolated tricuspid valve surgery.

Dreyfus J, Audureau E, Bohbot Y, Coisne A, ... Obadia JF, Messika-Zeitoun D
Aims 
Isolated tricuspid valve surgery (ITVS) is considered to be a high-risk procedure, but in-hospital mortality is markedly variable. This study sought to develop a dedicated risk score model to predict the outcome of patients after ITVS for severe tricuspid regurgitation (TR).
Methods and results 
All consecutive adult patients who underwent ITVS for severe non-congenital TR at 12 French centres between 2007 and 2017 were included. We identified 466 patients (60 ± 16 years, 49% female, functional TR in 49%). In-hospital mortality rate was 10%. We derived and internally validated a scoring system to predict in-hospital mortality using multivariable logistic regression and bootstrapping with 1000 re-samples. The final risk score ranged from 0 to 12 points and included eight parameters: age ≥70 years, New York Heart Association Class III-IV, right-sided heart failure signs, daily dose of furosemide ≥125 mg, glomerular filtration rate <30 mL/min, elevated bilirubin, left ventricular ejection fraction <60%, and moderate/severe right ventricular dysfunction. Tricuspid regurgitation mechanism was not an independent predictor of outcome. Observed and predicted in-hospital mortality rates increased from 0% to 60% and from 1% to 65%, respectively, as the score increased from 0 up to ≥9 points. Apparent and bias-corrected areas under the receiver operating characteristic curves were 0.81 and 0.75, respectively, much higher than the logistic EuroSCORE (0.67) or EuroSCORE II (0.63).
Conclusion 
We propose TRI-SCORE as a dedicated risk score model based on eight easy to ascertain parameters to inform patients and physicians regarding the risk of ITVS and guide the clinical decision-making process of patients with severe TR, especially as transcatheter therapies are emerging (www.tri-score.com).

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

Eur Heart J: 28 Sep 2021; epub ahead of print
Dreyfus J, Audureau E, Bohbot Y, Coisne A, ... Obadia JF, Messika-Zeitoun D
Eur Heart J: 28 Sep 2021; epub ahead of print | PMID: 34586392
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Impact:
Abstract

Glycosylated apolipoprotein J in cardiac ischaemia: molecular processing and circulating levels in patients with acute ischaemic events.

Cubedo J, Padró T, Vilahur G, Crea F, ... Gallinat A, Badimon L
Aim
Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI.
Methods and results
Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008).
Conclusions
These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.

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

Eur Heart J: 27 Sep 2021; epub ahead of print
Cubedo J, Padró T, Vilahur G, Crea F, ... Gallinat A, Badimon L
Eur Heart J: 27 Sep 2021; epub ahead of print | PMID: 34580705
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Impact:
Abstract

Macrophage NFATc3 prevents foam cell formation and atherosclerosis: evidence and mechanisms.

Liu X, Guo JW, Lin XC, Tuo YH, ... Zhou JG, Liang SJ
Aims
Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis.
Methods and results
Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages.
Conclusion
Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against 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: 26 Sep 2021; epub ahead of print
Liu X, Guo JW, Lin XC, Tuo YH, ... Zhou JG, Liang SJ
Eur Heart J: 26 Sep 2021; epub ahead of print | PMID: 34570211
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Impact:
Abstract

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

Walsh R, Adler A, Amin AS, Abiusi E, ... Wilde AAM, Gollob MH
Aims
Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.
Methods and results
Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).
Conclusions
Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

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

Eur Heart J: 23 Sep 2021; epub ahead of print
Walsh R, Adler A, Amin AS, Abiusi E, ... Wilde AAM, Gollob MH
Eur Heart J: 23 Sep 2021; epub ahead of print | PMID: 34557911
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Impact:
Abstract

Early invasive coronary angiography and acute ischaemic heart failure outcomes.

Kosyakovsky LB, Austin PC, Ross HJ, Wang X, ... Spertus JA, Lee DS
Aims 
While myocardial ischaemia plays a major role in the pathogenesis of heart failure (HF), the indications for coronary angiography during acute HF are not established. We determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization.
Methods and results 
In a two-stage sampling process, we identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined whether they underwent early coronary angiography within 14 days after presentation using administrative databases. After clinical record review, we defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. We oversampled patients undergoing angiography. We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met inclusion criteria [median age 75 (interquartile range 65-83) years; 40.9% women]. Early angiography was performed in 1567 patients (52.3%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.61-0.90, P = 0.002], cardiovascular death (HR 0.72, 95% CI 0.56-0.93, P = 0.012), and HF readmissions (HR 0.84, 95% CI 0.71-0.99, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, 95% CI 1.73-3.86, P < 0.001) and coronary artery bypass grafting (HR 2.94, 95% CI 1.75-4.93, P < 0.001) within 2 years.
Conclusions 
Early coronary angiography was associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia.

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

Eur Heart J: 20 Sep 2021; 42:3756-3766
Kosyakovsky LB, Austin PC, Ross HJ, Wang X, ... Spertus JA, Lee DS
Eur Heart J: 20 Sep 2021; 42:3756-3766 | PMID: 34331056
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Impact:
Abstract

3\' untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein.

Zhao Y, Ling S, Li J, Zhong G, ... Chang YZ, Li Y
Aims
3\' untranslated region (3\' UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of 3\' UTR in cardiovascular disease was largely unknown.
Methods and results
Using bioinformatics, RNA fluorescent in situ hybridization and quantitative real-time polymerase chain reaction, we found that 3\' UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. We generated cardiac-specific Ckip-1 3\' UTR overexpression mice under wild type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiography, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that cardiac Ckip-1 3\' UTR significantly inhibited TAC-induced cardiac hypertrophy independent of CKIP-1 protein. To determine the mechanism of Ckip-1 3\' UTR in cardiac hypertrophy, we performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. We found that Ckip-1 3\' UTR promoted fatty acid metabolism through AMPK-PPARα-CPT1b axis, leading to its protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3\' UTR RNA therapy using adeno-associated virus obviously alleviates cardiac hypertrophy and improves heart function.
Conclusions
These findings disclose that Ckip-1 3\' UTR inhibits cardiac hypertrophy independently of its cognate protein. Ckip-1 3\' UTR is an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure.

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 Sep 2021; 42:3786-3799
Zhao Y, Ling S, Li J, Zhong G, ... Chang YZ, Li Y
Eur Heart J: 20 Sep 2021; 42:3786-3799 | PMID: 34347073
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Impact:
Abstract

Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction.

Jackson AM, Jhund PS, Anand IS, Düngen HD, ... Solomon SD, McMurray JJV
Aims
Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on \'apparent resistant hypertension\' in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril-valsartan with valsartan.
Methods and results
In this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). \'Apparent resistant hypertension\' was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. \'Apparent mineralocorticoid receptor antagonist (MRA)-resistant\' hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril-valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6-19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7-14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05-1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril-valsartan vs. valsartan in patients with apparent resistant hypertension [-4.8 (-7.0 to -2.5) and 3.9 (-6.6 to -1.3) mmHg] and apparent MRA-resistant hypertension [-8.8 (-14.0 to -3.5) and -6.3 (-12.5 to -0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril-valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30-2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18-5.89).
Conclusion
Sacubitril-valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.
Clinical trial registration
PARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.

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

Eur Heart J: 20 Sep 2021; 42:3741-3752
Jackson AM, Jhund PS, Anand IS, Düngen HD, ... Solomon SD, McMurray JJV
Eur Heart J: 20 Sep 2021; 42:3741-3752 | PMID: 34392331
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Impact:
Abstract

Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF.

Curtain JP, Docherty KF, Jhund PS, Petrie MC, ... Solomon SD, McMurray JJV
Aims
The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF).
Methods and results
In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, \'other\' ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group [hazard ratio 0.79 (95% confidence interval 0.63-0.99), P = 0.037], and the effect was consistent across each of the components of the composite outcome.
Conclusions
Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.
Clinical trial registration
 ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).

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

Eur Heart J: 20 Sep 2021; 42:3727-3738
Curtain JP, Docherty KF, Jhund PS, Petrie MC, ... Solomon SD, McMurray JJV
Eur Heart J: 20 Sep 2021; 42:3727-3738 | PMID: 34448003
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Impact:
Abstract

Cardiovascular magnetic resonance imaging in suspected cardiac tumour: a multicentre outcomes study.

Shenoy C, Grizzard JD, Shah DJ, Kassi M, ... Parker MA, Kim RJ
Aims
Cardiovascular magnetic resonance (CMR) imaging is a key diagnostic tool for the evaluation of patients with suspected cardiac tumours. Patient management is guided by the CMR diagnosis, including no further testing if a mass is excluded or if only a pseudomass is found. However, there are no outcomes studies validating this approach.
Methods and results
In this multicentre study of patients undergoing clinical CMR for suspected cardiac tumour, CMR diagnoses were assigned as no mass, pseudomass, thrombus, benign tumour, or malignant tumour. A final diagnosis was determined after follow-up using all available data. The primary endpoint was all-cause mortality. Among 903 patients, the CMR diagnosis was no mass in 25%, pseudomass in 16%, thrombus in 16%, benign tumour in 17%, and malignant tumour in 23%. Over a median of 4.9 years, 376 patients died. Compared with the final diagnosis, the CMR diagnosis was accurate in 98.4% of patients. Patients with CMR diagnoses of pseudomass and benign tumour had similar mortality to those with no mass, whereas those with malignant tumour [hazard ratio (HR) 3.31 (2.40-4.57)] and thrombus [HR 1.46 (1.00-2.11)] had greater mortality. The CMR diagnosis provided incremental prognostic value over clinical factors including left ventricular ejection fraction, coronary artery disease, and history of extracardiac malignancy (P < 0.001).
Conclusion
In patients with suspected cardiac tumour, CMR has high diagnostic accuracy. Patients with CMR diagnoses of no mass, pseudomass, and benign tumour have similar long-term mortality. The CMR diagnosis is a powerful independent predictor of mortality incremental to clinical risk factors.

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 Sep 2021; epub ahead of print
Shenoy C, Grizzard JD, Shah DJ, Kassi M, ... Parker MA, Kim RJ
Eur Heart J: 20 Sep 2021; epub ahead of print | PMID: 34545397
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Abstract

Obesity modifies the energetic phenotype of dilated cardiomyopathy.

Rayner JJ, Peterzan MA, Clarke WT, Rodgers CT, Neubauer S, Rider OJ
Aims
We sought to determine if myocardial energetics could distinguish obesity cardiomyopathy as a distinct entity from dilated cardiomyopathy.
Methods and results
Sixteen normal weight participants with dilated cardiomyopathy (DCMNW), and 27 with DCM and obesity (DCMOB), were compared to 26 normal weight controls (CTLNW). All underwent cardiac magnetic resonance imaging and 31P spectroscopy to assess function and energetics. Nineteen DCMOB underwent repeat assessment after a dietary weight loss intervention. Adenosine triphosphate (ATP) delivery through creatine kinase (CK flux) was 55% lower in DCMNW than in CTLNW (P = 0.004), correlating with left ventricular ejection fraction (LVEF, r = 0.4, P = 0.015). In contrast, despite similar LVEF (DCMOB 41 ± 7%, DCMNW 38 ± 6%, P = 0.14), CK flux was two-fold higher in DCMOB (P < 0.001), due to higher rate through CK [median kf 0.21 (0.14) vs. 0.11 (0.12) s-1, P = 0.002]. During increased workload, the CTLNW heart increased CK flux by 97% (P < 0.001). In contrast, CK flux was unchanged in DCMNW and fell in DCMOB (by >50%, P < 0.001). Intentional weight loss was associated with positive left ventricular remodelling, with reduced left ventricular end-diastolic volume (by 8%, P < 0.001) and a change in LVEF (40 ± 9% vs. 45 ± 10%, P = 0.002). This occurred alongside a fall in ATP delivery rate with weight loss (by 7%, P = 0.049).
Conclusions
In normal weight, DCM is associated with reduced resting ATP delivery. In obese DCM, ATP demand through CK is greater, suggesting reduced efficiency of energy utilization. Dietary weight loss is associated with significant improvement in myocardial contractility, and a fall in ATP delivery, suggesting improved metabolic efficiency. This highlights distinct energetic pathways in obesity cardiomyopathy, which are both different from dilated cardiomyopathy, and may be reversible with weight loss.

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

Eur Heart J: 19 Sep 2021; epub ahead of print
Rayner JJ, Peterzan MA, Clarke WT, Rodgers CT, Neubauer S, Rider OJ
Eur Heart J: 19 Sep 2021; epub ahead of print | PMID: 34542592
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Abstract

Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial.

Oyama K, Giugliano RP, Tang M, Bonaca MP, ... Sabatine MS, Bergmark BA
Aims
We assessed the impact of the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD).
Methods and results
In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74-0.88]; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75-0.91]), cerebrovascular (HR 0.77 [0.65-0.92]), and peripheral vascular (HR 0.58 [0.38-0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69-0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75-0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67-0.85]) thereafter.
Conclusion
The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

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 Sep 2021; epub ahead of print
Oyama K, Giugliano RP, Tang M, Bonaca MP, ... Sabatine MS, Bergmark BA
Eur Heart J: 18 Sep 2021; epub ahead of print | PMID: 34537830
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Abstract

Atrial septal defect in adulthood: a new paradigm for congenital heart disease.

Brida M, Chessa M, Celermajer D, Li W, ... Baumgartner H, Gatzoulis MA
Atrial septal defects (ASDs) represent the most common congenital heart defect diagnosed in adulthood. Although considered a simple defect, challenges in optimal diagnostic and treatment options still exist due to great heterogeneity in terms of anatomy and time-related complications primarily arrhythmias, thromboembolism, right heart failure and, in a subset of patients, pulmonary arterial hypertension (PAH). Atrial septal defects call for tertiary expertise where all options may be considered, namely catheter vs. surgical closure, consideration of pre-closure ablation for patients with atrial tachycardia and suitability for closure or/and targeted therapy for patients with PAH. This review serves to update the clinician on the latest evidence, the nuances of optimal diagnostics, treatment options, and long-term follow-up care for patients with an ASD.

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 Sep 2021; epub ahead of print
Brida M, Chessa M, Celermajer D, Li W, ... Baumgartner H, Gatzoulis MA
Eur Heart J: 17 Sep 2021; epub ahead of print | PMID: 34535989
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Abstract

Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

Cui H, Chen Y, Li K, Zhan R, ... Wang D, Zheng L
Aims
Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.
Methods and results
We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD.
Conclusion
Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.

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

Eur Heart J: 16 Sep 2021; epub ahead of print
Cui H, Chen Y, Li K, Zhan R, ... Wang D, Zheng L
Eur Heart J: 16 Sep 2021; epub ahead of print | PMID: 34534287
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Abstract

Application of artificial intelligence to the electrocardiogram.

Attia ZI, Harmon DM, Behr ER, Friedman PA
Artificial intelligence (AI) has given the electrocardiogram (ECG) and clinicians reading them super-human diagnostic abilities. Trained without hard-coded rules by finding often subclinical patterns in huge datasets, AI transforms the ECG, a ubiquitous, non-invasive cardiac test that is integrated into practice workflows, into a screening tool and predictor of cardiac and non-cardiac diseases, often in asymptomatic individuals. This review describes the mathematical background behind supervised AI algorithms, and discusses selected AI ECG cardiac screening algorithms including those for the detection of left ventricular dysfunction, episodic atrial fibrillation from a tracing recorded during normal sinus rhythm, and other structural and valvular diseases. The ability to learn from big data sets, without the need to understand the biological mechanism, has created opportunities for detecting non-cardiac diseases as COVID-19 and introduced challenges with regards to data privacy. Like all medical tests, the AI ECG must be carefully vetted and validated in real-world clinical environments. Finally, with mobile form factors that allow acquisition of medical-grade ECGs from smartphones and wearables, the use of AI may enable massive scalability to democratize healthcare.

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

Eur Heart J: 16 Sep 2021; epub ahead of print
Attia ZI, Harmon DM, Behr ER, Friedman PA
Eur Heart J: 16 Sep 2021; epub ahead of print | PMID: 34534279
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Abstract

Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects.

Ansell J, Bakhru S, Laulicht BE, Tracey G, Villano S, Freedman D
Aims 
Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults.
Methods and results 
Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50-75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing.
Conclusions 
Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

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

Eur Heart J: 16 Sep 2021; epub ahead of print
Ansell J, Bakhru S, Laulicht BE, Tracey G, Villano S, Freedman D
Eur Heart J: 16 Sep 2021; epub ahead of print | PMID: 34534272
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Abstract

Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction.

Sinha A, Rahman H, Webb A, Shah AM, Perera D
Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD-HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD-HFpEF, as well as the clinical and research implications of the CMD-HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

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

Eur Heart J: 15 Sep 2021; epub ahead of print
Sinha A, Rahman H, Webb A, Shah AM, Perera D
Eur Heart J: 15 Sep 2021; epub ahead of print | PMID: 34529791
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Abstract

Matrix metalloproteinase-2 on activated platelets triggers endothelial PAR-1 initiating atherosclerosis.

Momi S, Falcinelli E, Petito E, Ciarrocca Taranta G, Ossoli A, Gresele P
Aims 
Platelets participate in atherogenesis with mechanisms not yet fully clarified. Vascular wall MMP-2 is involved in the arterial remodelling accompanying atherosclerosis. Platelets contain and release MMP-2 but no informations are available on its role in atherosclerotic lesion formation.
Methods and results 
We generated double knockout mice lacking the LDL receptor and MMP-2 only in circulating blood cells showing that they develop significantly lesser femoral intima thickening after photochemical-induced arterial damage and atherosclerotic lesions in the aorta, measured by the en face method, after 4 months of atherogenic diet. Moreover, repeated transfusions of autologous-activated platelets in LDLR-/- mice on atherogenic diet significantly enhanced the extension of aortic atherosclerotic lesions while transfusion of activated platelets from MMP-2-/- mice did not. In vitro coincubation studies showed that platelet-derived MMP-2 plays a pivotal role in the development and progression of atherosclerosis through a complex cross-talk between activated platelets, monocyte/macrophages, and endothelial cells. Translational studies in patients with CAD and chronic HIV infection showed that platelet surface expression of MMP-2 highly significantly correlated with the degree of carotid artery stenosis.
Conclusion 
We show a previously unknown mechanism of the pathway through which platelets expressing MMP-2 trigger the initial phases of atherosclerosis and provide a mechanism showing that they activate endothelial PAR-1 triggering endothelial p38MAPK signalling and the expression of adhesion molecules. The development of drugs blocking selectively platelet MMP-2 or its expression may represent a new approach to the prevention of 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: 15 Sep 2021; epub ahead of print
Momi S, Falcinelli E, Petito E, Ciarrocca Taranta G, Ossoli A, Gresele P
Eur Heart J: 15 Sep 2021; epub ahead of print | PMID: 34529782
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Abstract

Compensatory post-diuretic renal sodium reabsorption is not a dominant mechanism of diuretic resistance in acute heart failure.

Cox ZL, Rao VS, Ivey-Miranda JB, Moreno-Villagomez J, ... Wilcox CS, Testani JM
Aims
In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown.
Methods and results
Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47).
Conclusion
On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.

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 Sep 2021; epub ahead of print
Cox ZL, Rao VS, Ivey-Miranda JB, Moreno-Villagomez J, ... Wilcox CS, Testani JM
Eur Heart J: 15 Sep 2021; epub ahead of print | PMID: 34529781
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Abstract

Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis.

Dolladille C, Akroun J, Morice PM, Dompmartin A, ... L\'Orphelin JM, Alexandre J
Aims 
The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown.
Methods and results
We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56-12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89-7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0-5.1) to 19.3 (6.7-54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months.
Conclusion
In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis.

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 Sep 2021; epub ahead of print
Dolladille C, Akroun J, Morice PM, Dompmartin A, ... L'Orphelin JM, Alexandre J
Eur Heart J: 15 Sep 2021; epub ahead of print | PMID: 34529770
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Abstract

Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.

Imazio M, Lazaros G, Gattorno M, LeWinter M, ... Brucato A, Klein A
Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor \'trap\', binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.

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

Eur Heart J: 15 Sep 2021; epub ahead of print
Imazio M, Lazaros G, Gattorno M, LeWinter M, ... Brucato A, Klein A
Eur Heart J: 15 Sep 2021; epub ahead of print | PMID: 34528670
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Abstract

Does gut microbiota affect atrial rhythm? Causalities and speculations.

Linz D, Gawałko M, Sanders P, Penders J, ... Nattel S, Dobrev D
Dietary intake has been shown to change the composition of gut microbiota and some changes in microbiota (dysbiosis) have been linked to diabetes, hypertension, and obesity, which are established risk factors for atrial fibrillation (AF). In addition, intestinal dysbiosis generates microbiota-derived bioactive metabolites that might exert proarrhythmic actions. Although emerging preclinical investigations and clinical observational cohort studies suggest a possible role of gut dysbiosis in AF promotion, the exact mechanisms through which dysbiosis contributes to AF remain unclear. This Viewpoint article briefly reviews evidence suggesting that abnormalities in the intestinal microbiota play an important and little-recognized role in the pathophysiology of AF and that an improved understanding of this role may open up new possibilities in the management of AF.

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

Eur Heart J: 13 Sep 2021; 42:3521-3525
Linz D, Gawałko M, Sanders P, Penders J, ... Nattel S, Dobrev D
Eur Heart J: 13 Sep 2021; 42:3521-3525 | PMID: 34338744
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Abstract

Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients.

Romiti GF, Corica B, Pipitone E, Vitolo M, ... Proietti M, AF-COMET International Collaborative Group
Aim
Prevalence of chronic obstructive pulmonary disease (COPD) in atrial fibrillation (AF) patients is unclear, and its association with adverse outcomes is often overlooked. Our aim was to estimate the prevalence of COPD, its impact on clinical management and outcomes in patients with AF, and the impact of beta-blockers (BBs) on outcomes in patients with COPD.
Methods and results
A systematic review and meta-analysis was conducted according to international guidelines. All studies reporting the prevalence of COPD in AF patients were included. Data on comorbidities, BBs and oral anticoagulant prescription, and outcomes (all-cause death, cardiovascular (CV) death, ischaemic stroke, major bleeding) were compared according to COPD and BB status. Among 46 studies, pooled prevalence of COPD was 13% [95% confidence intervals (CI) 10-16%, 95% prediction interval 2-47%]. COPD was associated with higher prevalence of comorbidities, higher CHA2DS2-VASc score and lower BB prescription [odds ratio (OR) 0.77, 95% CI 0.61-0.98]. COPD was associated with higher risk of all-cause death (OR 2.22, 95% CI 1.93-2.55), CV death (OR 1.84, 95% CI 1.39-2.43), and major bleeding (OR 1.45, 95% CI 1.17-1.80); no significant differences in outcomes were observed according to BB use in AF patients with COPD.
Conclusion
COPD is common in AF, being found in 13% of patients, and is associated with increased burden of comorbidities, differential management, and worse outcomes, with more than a two-fold higher risk of all-cause death and increased risk of CV death and major bleeding. Therapy with BBs does not increase the risk of adverse outcomes in patients with AF and COPD.

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 Sep 2021; 42:3541-3554
Romiti GF, Corica B, Pipitone E, Vitolo M, ... Proietti M, AF-COMET International Collaborative Group
Eur Heart J: 13 Sep 2021; 42:3541-3554 | PMID: 34333599
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Abstract

Extracellular vesicles from immortalized cardiosphere-derived cells attenuate arrhythmogenic cardiomyopathy in desmoglein-2 mutant mice.

Lin YN, Mesquita T, Sanchez L, Chen YH, ... Marbán E, Cingolani E
Aims
Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of β-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model.
Methods and results
Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2mt/mt mice receiving EVs. DSG2mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs.
Conclusions
Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease.

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 Sep 2021; 42:3558-3571
Lin YN, Mesquita T, Sanchez L, Chen YH, ... Marbán E, Cingolani E
Eur Heart J: 13 Sep 2021; 42:3558-3571 | PMID: 34345905
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Abstract

Invasive and non-invasive assessment of ischaemia in chronic coronary syndromes: translating pathophysiology to clinical practice.

Demir OM, Rahman H, van de Hoef TP, Escaned J, ... Plein S, Perera D
Intracoronary physiology testing has emerged as a valuable diagnostic approach in the management of patients with chronic coronary syndrome, circumventing limitations like inferring coronary function from anatomical assessment and low spatial resolution associated with angiography or non-invasive tests. The value of hyperaemic translesional pressure ratios to estimate the functional relevance of coronary stenoses is supported by a wealth of prognostic data. The continuing drive to further simplify this approach led to the development of non-hyperaemic pressure-based indices. Recent attention has focussed on estimating physiology without even measuring coronary pressure. However, the reduction in procedural time and ease of accessibility afforded by these simplifications needs to be counterbalanced against the increasing burden of physiological assumptions, which may impact on the ability to reliably identify an ischaemic substrate, the ultimate goal during catheter laboratory assessment. In that regard, measurement of both coronary pressure and flow enables comprehensive physiological evaluation of both epicardial and microcirculatory components of the vasculature, although widespread adoption has been hampered by perceived technical complexity and, in general, an underappreciation of the role of the microvasculature. In parallel, entirely non-invasive tools have matured, with the utilization of various techniques including computational fluid dynamic and quantitative perfusion analysis. This review article appraises the strengths and limitations for each test in investigating myocardial ischaemia and discusses a comprehensive algorithm that could be used to obtain a diagnosis in all patients with angina scheduled for coronary angiography, including those who are not found to have obstructive epicardial coronary disease.

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

Eur Heart J: 12 Sep 2021; epub ahead of print
Demir OM, Rahman H, van de Hoef TP, Escaned J, ... Plein S, Perera D
Eur Heart J: 12 Sep 2021; epub ahead of print | PMID: 34516621
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Abstract

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

Lopez-Sendon JL, Cyr DD, Mark DB, Bangalore S, ... Maron DJ, O\'Brien SM
Aims
The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects.
Methods and results
Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event.
Conclusions
In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy.
Clinical trial registration
ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

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: 12 Sep 2021; epub ahead of print
Lopez-Sendon JL, Cyr DD, Mark DB, Bangalore S, ... Maron DJ, O'Brien SM
Eur Heart J: 12 Sep 2021; epub ahead of print | PMID: 34514494
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Abstract

Primary care heart failure service identifies a missed cohort of heart failure patients with reduced ejection fraction.

Kahn M, Grayson AD, Chaggar PS, Ng Kam Chuen MJ, ... Hughes C, Campbell NG
Aims
We explored whether a missed cohort of patients in the community with heart failure (HF) and left ventricular systolic dysfunction (LVSD) could be identified and receive treatment optimization through a primary care heart failure (PCHF) service.
Methods and results
PCHF is a partnership between Inspira Health, National Health Service Cardiologists and Medtronic. The PCHF service uses retrospective clinical audit to identify patients requiring a prospective face-to-face consultation with a consultant cardiologist for clinical review of their HF management within primary care. The service is delivered via five phases: (i) system interrogation of general practitioner (GP) systems; (ii) clinical audit of medical records; (iii) patient invitation; (iv) consultant reviews; and (v) follow-up. A total of 78 GP practices (864 194 population) have participated. In total, 19 393 patients\' records were audited. HF register was 9668 (prevalence 1.1%) with 6162 patients coded with LVSD (prevalence 0.7%). HF case finder identified 9725 additional patients to be audited of whom 2916 patients required LVSD codes adding to the patient medical record (47% increase in LVSD). Prevalence of HF with LVSD increased from 0.7% to 1.05%. A total of 662 patients were invited for consultant cardiologist review at their local GP practice. The service found that within primary care, 27% of HF patients identified for a cardiologist consultation were eligible for complex device therapy, 45% required medicines optimization, and 47% of patients audited required diagnosis codes adding to their GP record.
Conclusion
A PCHF service can identify a missed cohort of patients with HF and LVSD, enabling the optimization of prognostic medication and an increase in device prescription.

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

Eur Heart J: 10 Sep 2021; epub ahead of print
Kahn M, Grayson AD, Chaggar PS, Ng Kam Chuen MJ, ... Hughes C, Campbell NG
Eur Heart J: 10 Sep 2021; epub ahead of print | PMID: 34508630
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Abstract

Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis.

DeFilippis AP, Trainor PJ, Thanassoulis G, Brumback LC, ... Tsai MY, Tsimikas S
Aims
Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events.
Methods and results
The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2.
Conclusion
Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.

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

Eur Heart J: 10 Sep 2021; epub ahead of print
DeFilippis AP, Trainor PJ, Thanassoulis G, Brumback LC, ... Tsai MY, Tsimikas S
Eur Heart J: 10 Sep 2021; epub ahead of print | PMID: 34508626
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Abstract

Cardiovascular risk associated with allopurinol vs. benzbromarone in patients with gout.

Kang EH, Park EH, Shin A, Song JS, Kim SC
Aims 
With the high prevalence of gout and associated cardiovascular (CV) diseases, information on the comparative CV safety of individual urate-lowering drugs becomes increasingly important. However, few studies examined the CV risk of uricosuric agents. We compared CV risk among patients with gout who initiated allopurinol vs. benzbromarone.
Methods and results 
Using the Korean National Health Insurance claims data (2002-17), we conducted a cohort study of 124 434 gout patients who initiated either allopurinol (n = 103 695) or benzbromarone (n = 20 739), matched on propensity score at a 5:1 ratio. The primary outcome was a composite CV endpoint of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. To account for competing risk of death, we used cause-specific hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes comparing allopurinol initiators with benzbromarone. Over a mean follow-up of 1.16 years, 2258 patients developed a composite CV event. The incidence rate of the composite CV event was higher in allopurinol initiators (1.81 per 100 person-years) than benzbromarone (1.61 per 100 person-years) with a HR of 1.22 (95% CI 1.05-1.41). The HR for all-cause mortality was 1.66 (95% CI 1.43-1.93) among allopurinol initiators compared with benzbromarone.
Conclusion 
In this large population-based cohort of gout patients, allopurinol was associated with an increased risk of composite CV events and all-cause mortality compared to benzbromarone. Benzbromarone may reduce CV risk and mortality in patients with gout, although more studies are necessary to confirm our findings and to advance our understanding of the underlying mechanisms.

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

Eur Heart J: 10 Sep 2021; epub ahead of print
Kang EH, Park EH, Shin A, Song JS, Kim SC
Eur Heart J: 10 Sep 2021; epub ahead of print | PMID: 34508567
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Abstract

Clinical features and survival in Takayasu\'s arteritis-associated pulmonary hypertension: a nationwide study.

Jiang X, Zhu YJ, Zhou YP, Peng FH, ... Zhang SY, Jing ZC
Aims 
This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu\'s arteritis-associated pulmonary hypertension (TA-PH).
Methods and results
We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu\'s arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77-16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03-1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01-1.13), P = 0.015].
Conclusion 
Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators\' personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.

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 Sep 2021; epub ahead of print
Jiang X, Zhu YJ, Zhou YP, Peng FH, ... Zhang SY, Jing ZC
Eur Heart J: 09 Sep 2021; epub ahead of print | PMID: 34506618
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Abstract

Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

Schwartz PJ, Moreno C, Kotta MC, Pedrazzini M, ... Spazzolini C, Volders PGA
Aims
Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.
Methods and results
Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.
Conclusion
KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

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 Sep 2021; epub ahead of print
Schwartz PJ, Moreno C, Kotta MC, Pedrazzini M, ... Spazzolini C, Volders PGA
Eur Heart J: 09 Sep 2021; epub ahead of print | PMID: 34505893
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Abstract

Low coronary flow relative to myocardial mass predicts heart failure in symptomatic hypertensive patients with no obstructive coronary artery disease.

Brown JM, Zhou W, Weber B, Divakaran S, ... Blankstein R, Di Carli MF
Aims
The transition from hypertension to heart failure (HF) remains poorly understood. We hypothesized that insufficient perfusion to match global metabolic demand, reflected by a low ratio of myocardial blood flow to global myocardial mass, may be a HF risk marker.
Methods and results
A retrospective cohort (n = 346) of patients with hypertension who underwent clinical positron emission tomography (PET) myocardial perfusion imaging for chest pain and/or dyspnoea at Brigham and Women\'s Hospital (Boston, MA, USA) were studied. Patients without obstructive coronary artery disease by history or PET perfusion (summed stress score <3), HF, cardiomyopathy, or ejection fraction (EF) <40% were followed for HF hospitalization (primary outcome), all-cause death, and their composite. Myocardial blood flow, left ventricular (LV) mass, volumes, and EF were obtained from PET, and a \'flow/mass ratio\' was determined as hyperaemic myocardial blood flow over LV mass indexed to body surface area. A lower flow/mass ratio was independently associated with larger end-diastolic (β = -0.44, P < 0.001) and end-systolic volume (β = -0.48, P < 0.001) and lower EF (β = 0.33, P < 0.001). A flow/mass ratio below the median was associated with an adjusted hazard ratio of 2.47 [95% confidence interval (CI) 1.24-4.93; P = 0.01] for HF hospitalization, 1.95 (95% CI 1.12-3.41; P = 0.02) for death, and 2.20 (95% CI 1.39-3.49; P < 0.001) for the composite.
Conclusion
An integrated physiological measure of insufficient myocardial perfusion to match global metabolic demand identifies subclinical hypertensive heart disease and elevated risk of HF and death in symptomatic patients with hypertension but without flow-limiting coronary artery disease.

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 Sep 2021; epub ahead of print
Brown JM, Zhou W, Weber B, Divakaran S, ... Blankstein R, Di Carli MF
Eur Heart J: 06 Sep 2021; epub ahead of print | PMID: 34491335
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Abstract

Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.

Ginsberg HN, Packard CJ, Chapman MJ, Borén J, ... Stock JK, Catapano AL
Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

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

Eur Heart J: 01 Sep 2021; epub ahead of print
Ginsberg HN, Packard CJ, Chapman MJ, Borén J, ... Stock JK, Catapano AL
Eur Heart J: 01 Sep 2021; epub ahead of print | PMID: 34472586
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Abstract

Longitudinal strain is an independent predictor of survival and response to therapy in patients with systemic AL amyloidosis.

Cohen OC, Ismael A, Pawarova B, Manwani R, ... Whelan CJ, Wechalekar AD
Aims
Cardiac involvement, a major determinant of prognosis in AL (light-chain immunoglobulin) amyloidosis, is characterized by an impairment of longitudinal strain (LS%). We sought to evaluate the utility of LS% in a prospectively observed series of patients.
Methods and results
A total of 915 serial newly diagnosed AL patients with comprehensive baseline assessments, inclusive of echocardiography, were included. A total of 628/915 (68.6%) patients had cardiac involvement. The LS% worsened with advancing cardiac stage with mean -21.1%, -17.1%, -12.9%, and -12.1% for stages I, II, IIIa, and IIIb, respectively (P < 0.0001). There was a highly significant worsening of overall survival (OS) with worsening LS% quartile: LS% ≤-16.2%: 80 months, -16.1% to -12.2%: 36 [95% confidence interval (CI) 20.9-51.1] months, -12.1% to -9.1%: 22 (95% CI 9.1-34.9) months, and ≥-9.0%: 5 (95% CI 3.2-6.8) months (P < 0.0001). Improvement in LS% was seen at 12 months in patients achieving a haematological complete response (CR) (median improvement from -13.8% to -14.9% in those with CR and difference between involved and uninvolved light chain <10 mg/L). Strain improvement was associated with improved OS (median not reached at 53 months vs. 72 months in patients without strain improvement, P = 0.007). Patients achieving an LS% improvement and a standard N-terminal pro-brain natriuretic peptide-based cardiac response survived longer than those achieving a biomarker-based cardiac response alone (P < 0.0001).
Conclusion
Baseline LS% is a functional marker that correlates with worsening cardiac involvement and is predictive of survival. Baseline LS% and an absolute improvement in LS% are useful additional measures of prognosis and response to therapy in cardiac AL amyloidosis, respectively.

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

Eur Heart J: 01 Sep 2021; epub ahead of print
Cohen OC, Ismael A, Pawarova B, Manwani R, ... Whelan CJ, Wechalekar AD
Eur Heart J: 01 Sep 2021; epub ahead of print | PMID: 34472567
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Abstract

Determinants of outcomes following surgery for type A acute aortic dissection: the UK National Adult Cardiac Surgical Audit.

Benedetto U, Dimagli A, Kaura A, Sinha S, ... Akowuah E, on the behalf of UK Aortic group
Aims 
Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK.
Methods and results
We identified 4203 patients undergoing TAAAD surgery in the UK (2009-18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02-1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51-2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14-1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90-4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71-3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00-3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14-9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86-2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes.
Conclusions 
Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.

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

Eur Heart J: 31 Aug 2021; epub ahead of print
Benedetto U, Dimagli A, Kaura A, Sinha S, ... Akowuah E, on the behalf of UK Aortic group
Eur Heart J: 31 Aug 2021; epub ahead of print | PMID: 34468733
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Abstract

Conservative, surgical, and percutaneous treatment for mitral regurgitation shortly after acute myocardial infarction.

Haberman D, Estévez-Loureiro R, Benito-Gonzalez T, Denti P, ... Taramasso M, Shuvy M
Aims 
Severe mitral regurgitation (MR) following acute myocardial infarction (MI) is associated with high mortality rates and has inconclusive recommendations in clinical guidelines. We aimed to report the international experience of patients with secondary MR following acute MI and compare the outcomes of those treated conservatively, surgically, and percutaneously.
Methods and results 
Retrospective international registry of consecutive patients with at least moderate-to-severe MR following MI treated in 21 centres in North America, Europe, and the Middle East. The registry included patients treated conservatively and those having surgical mitral valve repair or replacement (SMVR) or percutaneous mitral valve repair (PMVR) using edge-to-edge repair. The primary endpoint was in-hospital mortality. A total of 471 patients were included (43% female, age 73 ± 11 years): 205 underwent interventions, of whom 106 were SMVR and 99 PMVR. Patients who underwent mitral valve intervention were in a worse clinical state (Killip class ≥3 in 60% vs. 43%, P < 0.01), but yet had lower in-hospital and 1-year mortality compared with those treated conservatively [11% vs. 27%, P < 0.01 and 16% vs. 35%, P < 0.01; adjusted hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.18-0.46, P < 0.01]. Surgical mitral valve repair or replacement was performed earlier than PMVR [median of 12 days from MI date (interquartile range 5-19) vs. 19 days (10-40), P < 0.01]. The immediate procedural success did not differ between SMVR and PMVR (92% vs. 93%, P = 0.53). However, in-hospital and 1-year mortality rates were significantly higher in SMVR than in PMVR (16% vs. 6%, P = 0.03 and 31% vs. 17%, P = 0.04; adjusted HR 3.75, 95% CI 1.55-9.07, P < 0.01).
Conclusions 
Early intervention may mitigate the poor prognosis associated with conservative therapy in patients with post-MI MR. Percutaneous mitral valve repair can serve as an alternative for surgery in reducing MR for high-risk 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: 30 Aug 2021; epub ahead of print
Haberman D, Estévez-Loureiro R, Benito-Gonzalez T, Denti P, ... Taramasso M, Shuvy M
Eur Heart J: 30 Aug 2021; epub ahead of print | PMID: 34463727
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Abstract

Efficacy of a digital therapeutics system in the management of essential hypertension: the HERB-DH1 pivotal trial.

Kario K, Nomura A, Harada N, Okura A, ... Tanigawa T, Hida E
Aims
Digital therapeutics is a new approach to facilitate the non-pharmacological treatment of hypertension using software programmes such as smartphone applications and/or device algorithms. Based on promising findings from a small pilot trial, the HERB Digital Hypertension 1 (HERB-DH1) pivotal trial investigated the efficacy of digital therapeutics in patients with hypertension not receiving antihypertensive medication.
Methods and results
This prospective, open-label, randomized controlled study was performed at 12 sites in Japan. Patients with hypertension [office systolic blood pressure (SBP) 140 to <180 mmHg and 24 h SBP ≥130 mmHg] were randomly assigned 1:1 to the digital therapeutics group (HERB system + standard lifestyle modification) or control group (standard lifestyle modification alone). The primary efficacy endpoint was the mean change in 24 h ambulatory SBP from baseline to 12 weeks; key secondary efficacy endpoints were mean changes in office and home blood pressure (BP) from baseline to 12 weeks. All analyses were conducted in the full analysis set population. Between December 2019 and June 2020, 390 patients were randomly assigned to the digital therapeutics group (n = 199) or control (n = 191) group. Between-group differences in 24-h ambulatory, home, and office SBPs at 12 weeks were -2.4 (95% confidence interval -4.5 to -0.3), -4.3 (-6.7 to -1.9), and -3.6 (-6.2 to -1.0) mmHg, respectively. No major programme-related safety events occurred up to 24 weeks.
Conclusion
The HERB-DH1 pivotal study showed the superiority of digital therapeutics compared with standard lifestyle modification alone to reduce 24-h ambulatory, home, and office BPs in the absence of antihypertensive medications.

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: 28 Aug 2021; epub ahead of print
Kario K, Nomura A, Harada N, Okura A, ... Tanigawa T, Hida E
Eur Heart J: 28 Aug 2021; epub ahead of print | PMID: 34455443
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Impact:
Abstract

A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs.

Doi T, Langsted A, Nordestgaard BG
Aims
We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.
Methods and results
In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93-0.99] mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH.
Conclusion
The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.

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: 28 Aug 2021; epub ahead of print
Doi T, Langsted A, Nordestgaard BG
Eur Heart J: 28 Aug 2021; epub ahead of print | PMID: 34455435
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Impact:
Abstract

AV junction ablation and cardiac resynchronization for patients with permanent atrial fibrillation and narrow QRS: the APAF-CRT mortality trial.

Brignole M, Pentimalli F, Palmisano P, Landolina M, ... Rienstra M, Van Gelder IC
Aims 
In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown.
Methods and results 
In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002].
Conclusions 
Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF.
Study registration
ClinicalTrials.gov Identifier: NCT02137187.

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 Aug 2021; epub ahead of print
Brignole M, Pentimalli F, Palmisano P, Landolina M, ... Rienstra M, Van Gelder IC
Eur Heart J: 27 Aug 2021; epub ahead of print | PMID: 34453840
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Impact:
Abstract

Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial.

Willems S, Borof K, Brandes A, Breithardt G, ... Wegscheider K, Kirchhof P
Aims
Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control.
Methods and results
This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19).
Conclusion
The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).

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

Eur Heart J: 26 Aug 2021; epub ahead of print
Willems S, Borof K, Brandes A, Breithardt G, ... Wegscheider K, Kirchhof P
Eur Heart J: 26 Aug 2021; epub ahead of print | PMID: 34447995
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Impact:
Abstract

Automated external defibrillators delivered by drones to patients with suspected out-of-hospital cardiac arrest.

Schierbeck S, Hollenberg J, Nord A, Svensson L, ... Axelsson C, Claesson A
Aims 
Early defibrillation is critical for the chance of survival in out-of-hospital cardiac arrest (OHCA). Drones, used to deliver automated external defibrillators (AEDs), may shorten time to defibrillation, but this has never been evaluated in real-life emergencies. The aim of this study was to investigate the feasibility of AED delivery by drones in real-life cases of OHCA.
Methods and results 
In this prospective clinical trial, three AED-equipped drones were placed within controlled airspace in Sweden, covering approximately 80 000 inhabitants (125 km2). Drones were integrated in the emergency medical services for automated deployment in beyond-visual-line-of-sight flights: (i) test flights from 1 June to 30 September 2020 and (ii) consecutive real-life suspected OHCAs. Primary outcome was the proportion of successful AED deliveries when drones were dispatched in cases of suspected OHCA. Among secondary outcomes was the proportion of cases where AED drones arrived prior to ambulance and time benefit vs. ambulance. Totally, 14 cases were eligible for dispatch during the study period in which AED drones took off in 12 alerts to suspected OHCA, with a median distance to location of 3.1 km [interquartile range (IQR) 2.8-3.4). AED delivery was feasible within 9 m (IQR 7.5-10.5) from the location and successful in 11 alerts (92%). AED drones arrived prior to ambulances in 64%, with a median time benefit of 01:52 min (IQR 01:35-04:54) when drone arrived first. In an additional 61 test flights, the AED delivery success rate was 90% (55/61).
Conclusion 
In this pilot study, we have shown that AEDs can be carried by drones to real-life cases of OHCA with a successful AED delivery rate of 92%. There was a time benefit as compared to emergency medical services in cases where the drone arrived first. However, further improvements are needed to increase dispatch rate and time benefits.
Trial registration number
ClinicalTrials.gov Identifier: NCT04415398.

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: 25 Aug 2021; epub ahead of print
Schierbeck S, Hollenberg J, Nord A, Svensson L, ... Axelsson C, Claesson A
Eur Heart J: 25 Aug 2021; epub ahead of print | PMID: 34438449
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Impact:
Abstract

Physical activity and fitness in the community: the Framingham Heart Study.

Nayor M, Chernofsky A, Spartano NL, Tanguay M, ... Shah RV, Lewis GD
Aims
While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood.
Methods and results
Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate <5% for all). Findings were largely consistent across categories of age, sex, obesity, and cardiovascular risk. Increases of 17 min of MVPA/day [95% confidence interval (CI) 14-21] or 4312 steps/day (95% CI 3439-5781; ≈54 min at 80 steps/min), or reductions of 249 min of SED per day (95% CI 149-777) between the two exam cycles corresponded to a 5% (1.2 mL/kg/min) higher peak VO2. Individuals with high (above-mean) steps or MVPA demonstrated above average peak VO2 values regardless of whether they had high or low SED.
Conclusions
Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.

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: 25 Aug 2021; epub ahead of print
Nayor M, Chernofsky A, Spartano NL, Tanguay M, ... Shah RV, Lewis GD
Eur Heart J: 25 Aug 2021; epub ahead of print | PMID: 34436560
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Impact:
Abstract

Evidence to support magnetic resonance conditional labelling of all pacemaker and defibrillator leads in patients with cardiac implantable electronic devices.

Bhuva AN, Moralee R, Brunker T, Lascelles K, ... Baksi AJ, Manisty CH
Aims
Many cardiac pacemakers and defibrillators are not approved by regulators for magnetic resonance imaging (MRI). Even following generator exchange to an approved magnetic resonance (MR)-conditional model, many systems remain classified \'non-MR conditional\' due to the leads. This classification makes patient access to MRI challenging, but there is no evidence of increased clinical risk. We compared the effect of MRI on non-MR conditional and MR-conditional pacemaker and defibrillator leads.
Methods and results
Patients undergoing clinical 1.5T MRI with pacemakers and defibrillators in three centres over 5 years were included. Magnetic resonance imaging protocols were similar for MR-conditional and non-MR conditional systems. Devices were interrogated pre- and immediately post-scan, and at follow-up, and adverse clinical events recorded. Lead parameter changes peri-scan were stratified by MR-conditional labelling. A total of 1148 MRI examinations were performed in 970 patients (54% non-MR conditional systems, 39% defibrillators, 15% pacing-dependent) with 2268 leads. There were no lead-related adverse clinical events, and no clinically significant immediate or late lead parameter changes following MRI in either MR-conditional or non-MR conditional leads. Small reductions in atrial and right ventricular sensed amplitudes and impedances were similar between groups, with no difference in the proportion of leads with parameter changes greater than pre-defined thresholds (7.1%, 95% confidence interval: 6.1-8.3).
Conclusions
There was no increased risk of MRI in patients with non-MR conditional pacemaker or defibrillator leads when following recommended protocols. Standardizing MR conditions for all leads would significantly improve access to MRI by enabling patients to be scanned in non-specialist centres, with no discernible incremental risk.

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

Eur Heart J: 25 Aug 2021; epub ahead of print
Bhuva AN, Moralee R, Brunker T, Lascelles K, ... Baksi AJ, Manisty CH
Eur Heart J: 25 Aug 2021; epub ahead of print | PMID: 34435642
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Impact:
Abstract

Smoking cessation, but not reduction, reduces cardiovascular disease incidence.

Jeong SM, Jeon KH, Shin DW, Han K, ... Nam KW, Lee SP
Aims
The aim of this study was to assess the association of smoking cessation and reduction with risk of cardiovascular disease (CVD).
Methods and results
A total of 897 975 current smokers aged ≥40 years who had undergone two consecutive national health examinations (in 2009 and 2011) were included. Participants were classified as quitters (20.6%), reducers I (≥50% reduction, 7.3%), reducers II (20-50% reduction, 11.6%), sustainers (45.7%), and increasers (≥20% increase, 14.5%). During 5 575 556 person-years (PY) of follow-up, 17 748 stroke (3.2/1000 PY) and 11 271 myocardial infarction (MI) (2.0/1000 PY) events were identified. Quitters had significantly decreased risk of stroke [adjusted hazard ratio (aHR) 0.77 95% confidence interval (CI) 0.74-0.81; absolute risk reduction (ARR) -0.37, 95% CI -0.43 to -0.31] and MI (aHR 0.74, 95% CI 0.70-0.78; ARR -0.27, 95% CI -0.31 to -0.22) compared to sustainers after adjustment for demographic factors, comorbidities, and smoking status. The risk of stroke and MI incidence in reducers I (aHR 1.02, 95% CI 0.97-1.08 and aHR 0.99, 95% CI 0.92-1.06, respectively) and reducers II (aHR 1.00, 95% CI 0.95-1.05 and aHR 0.97, 95% CI 0.92-1.04, respectively) was not significantly different from the risk in sustainers. Further analysis with a subgroup who underwent a third examination (in 2013) showed that those who quit at the second examination but had starting smoking again by the third examination had 42-69% increased risk of CVD compared to sustained quitters.
Conclusions
Smoking cessation, but not reduction, was associated with reduced CVD risk. Our study emphasizes the importance of sustained quitting in terms of CVD risk reduction.

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: 24 Aug 2021; epub ahead of print
Jeong SM, Jeon KH, Shin DW, Han K, ... Nam KW, Lee SP
Eur Heart J: 24 Aug 2021; epub ahead of print | PMID: 34431997
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Impact:
Abstract

Risk factors for type 1 and type 2 myocardial infarction.

Wereski R, Kimenai DM, Bularga A, Taggart C, ... Mills NL, Chapman AR
Aims
Whilst the risk factors for type 1 myocardial infarction due to atherosclerotic plaque rupture and thrombosis are established, our understanding of the factors that predispose to type 2 myocardial infarction during acute illness is still emerging. Our aim was to evaluate and compare the risk factors for type 1 and type 2 myocardial infarction.
Methods and results
We conducted a secondary analysis of a multi-centre randomized trial population of 48 282 consecutive patients attending hospital with suspected acute coronary syndrome. The diagnosis of myocardial infarction during the index presentation and all subsequent reattendances was adjudicated according to the Universal Definition of Myocardial Infarction. Cox regression was used to identify predictors of future type 1 and type 2 myocardial infarction during a 1-year follow-up period. Within 1 year, 1331 patients had a subsequent myocardial infarction, with 924 and 407 adjudicated as type 1 and type 2 myocardial infarction, respectively. Risk factors for type 1 and type 2 myocardial infarction were similar, with age, hyperlipidaemia, diabetes, abnormal renal function, and known coronary disease predictors for both (P < 0.05 for all). Whilst women accounted for a greater proportion of patients with type 2 as compared to type 1 myocardial infarction, after adjustment for other risk factors, sex was not a predictor of type 2 myocardial events [adjusted hazard ratio (aHR) 0.82, 95% confidence interval (CI) 0.66-1.01]. The strongest predictor of type 2 myocardial infarction was a prior history of type 2 events (aHR 6.18, 95% CI 4.70-8.12).
Conclusions
Risk factors for coronary disease that are associated with type 1 myocardial infarction are also important predictors of type 2 events during acute illness. Treatment of these risk factors may reduce future risk of both type 1 and type 2 myocardial infarction.

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

Eur Heart J: 24 Aug 2021; epub ahead of print
Wereski R, Kimenai DM, Bularga A, Taggart C, ... Mills NL, Chapman AR
Eur Heart J: 24 Aug 2021; epub ahead of print | PMID: 34431993
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Impact:
Abstract

Low-dose rivaroxaban plus aspirin in older patients with peripheral artery disease undergoing acute limb revascularization: insights from the VOYAGER PAD trial.

Krantz MJ, Debus SE, Hsia J, Patel MR, ... Bauersachs RM, Bonaca MP
Aims
In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described.
Methods and results
The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding).
Conclusion
Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.

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: 24 Aug 2021; epub ahead of print
Krantz MJ, Debus SE, Hsia J, Patel MR, ... Bauersachs RM, Bonaca MP
Eur Heart J: 24 Aug 2021; epub ahead of print | PMID: 34430972
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Impact:
Abstract

Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.

Oyama K, Raz I, Cahn A, Kuder J, ... Sabatine MS, Wiviott SD
Aims 
We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM).
Methods and results 
DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients.
Conclusions 
In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

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 Aug 2021; epub ahead of print
Oyama K, Raz I, Cahn A, Kuder J, ... Sabatine MS, Wiviott SD
Eur Heart J: 23 Aug 2021; epub ahead of print | PMID: 34427295
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Impact:
Abstract

Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHT-CKD.

Stefanini GG, Briguori C, Cao D, Baber U, ... Pocock S, Mehran R
Aims
The aim of this study was to assess the impact of chronic kidney disease (CKD) on the safety and efficacy of ticagrelor monotherapy among patients undergoing percutaneous coronary intervention (PCI).
Methods and results
In this prespecified subanalysis of the TWILIGHT trial, we evaluated the treatment effects of ticagrelor with or without aspirin according to renal function. The trial enrolled patients undergoing drug-eluting stent implantation who fulfilled at least one clinical and one angiographic high-risk criterion. Chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, was a clinical study entry criterion. Following a 3-month period of ticagrelor plus aspirin, event-free patients were randomly assigned to aspirin or placebo on top of ticagrelor for an additional 12 months. Of the 6835 patients randomized and with available eGFR at baseline, 1111 (16.3%) had CKD. Ticagrelor plus placebo reduced the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding as compared with ticagrelor plus aspirin in both patients with [4.6% vs. 9.0%; hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.80] and without (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47-0.75; Pinteraction = 0.508) CKD, but the absolute risk reduction was greater in the former group. Rates of death, myocardial infarction, or stroke were not significantly different between the two randomized groups irrespective of the presence (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88-2.22) or absence of (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68-1.20; Pinteraction = 0.111) CKD.
Conclusion
Among CKD patients undergoing PCI, ticagrelor monotherapy reduced the risk of bleeding without a significant increase in ischaemic events as compared with ticagrelor plus aspirin.

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 Aug 2021; epub ahead of print
Stefanini GG, Briguori C, Cao D, Baber U, ... Pocock S, Mehran R
Eur Heart J: 22 Aug 2021; epub ahead of print | PMID: 34423374
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Impact:
Abstract

Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial.

Neuen BL, Oshima M, Perkovic V, Agarwal R, ... Mahaffey KW, Heerspink HJL
Aims
Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain.
Methods and results
The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo.
Conclusion
Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.

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 Aug 2021; epub ahead of print
Neuen BL, Oshima M, Perkovic V, Agarwal R, ... Mahaffey KW, Heerspink HJL
Eur Heart J: 22 Aug 2021; epub ahead of print | PMID: 34423370
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Impact:
Abstract

Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial.

Pocock SJ, Ferreira JP, Gregson J, Anker SD, ... Zannad F, Packer M
Aims
The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials.
Methods and results
In EMPEROR-Reduced, 33 candidate variables were pre-selected. Multivariable Cox regression models were developed using stepwise selection for: (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, and (iii) cardiovascular mortality. A total of 3730 patients were followed up for a median of 16 months, 823 (22%) patients had a primary outcome and 515 (14%) patients died, of whom 389 (10%) died from a cardiovascular cause. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last HF hospitalization, longer time since HF diagnosis, lower systolic blood pressure, New York Heart Association (NYHA) Class III or IV, higher heart rate and peripheral oedema were key predictors (eight variables in total, all P < 0.001). The primary outcome risk score discriminated well (c-statistic = 0.73), with patients in the top 10th of risk having an event rate >9 times higher than those in the bottom 10th. Empagliflozin benefitted patients across risk levels for the primary outcome. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality, followed by NYHA Class III or IV and ischaemic aetiology (four variables in total, all P < 0.001). The mortality risk model presented good event discrimination for all-cause and cardiovascular mortality (c-statistic = 0.69 for both). These simple models were externally validated in the BIOSTAT-CHF study, achieving similar c-statistics.
Conclusions
The combination of NT-proBNP and hs-cTnT with a small number of readily available clinical variables provides prognostic assessment for patients with HFrEF. This predictive tool kit can be easily implemented for routine clinical use.

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

Eur Heart J: 22 Aug 2021; epub ahead of print
Pocock SJ, Ferreira JP, Gregson J, Anker SD, ... Zannad F, Packer M
Eur Heart J: 22 Aug 2021; epub ahead of print | PMID: 34423361
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Abstract

Effects of lignocaine vs. opioids on antiplatelet activity of ticagrelor: the LOCAL trial.

Fernando H, Duong T, Huynh K, Noonan J, ... Peter K, Stub D
Aims
We assessed the impact of intravenous fentanyl and lignocaine on the pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina and non-ST-elevation myocardial infarction and their procedural analgesic efficacy and safety.
Methods and results
Seventy patients undergoing coronary angiography with ticagrelor loading were included in the pharmacokinetic and pharmacodynamic analyses of this randomized trial. Plasma ticagrelor levels 2 h post-loading dose were significantly lower in the fentanyl arm than in the lignocaine treatment arm (598 vs. 1008 ng/mL, P = 0.014). The area under the plasma-time curves for ticagrelor (1228 vs. 2753 ng h/mL, P < 0.001) and its active metabolite (201 vs. 447 ng h/mL, P = 0.001) were both significantly lower in the fentanyl arm. Expression of activated platelet glycoprotein IIb/IIIa receptor (2829 vs. 1426 mean fluorescence intensity, P = 0.006) and P-selectin (439 vs. 211 mean fluorescence intensity, P = 0.001) was significantly higher at 60 min in the fentanyl arm. A higher proportion of patients had high on-treatment platelet reactivity in the fentanyl arm at 60 min using the Multiplate Analyzer (41% vs. 9%, P = 0.002) and 120 min using the VerifyNow (30% vs. 3%, P = 0.003) and VASP (37% vs. 6%, P = 0.002) assays. Both drugs were well tolerated with a high level of patient satisfaction.
Conclusions
Unlike fentanyl, lignocaine does not impair the bioavailability or delay the antiplatelet effect of ticagrelor. Both drugs were well tolerated and effective with a high level of patient satisfaction for procedural analgesia. Routine procedural analgesia during percutaneous coronary intervention should be reconsidered and if performed, lignocaine is a beneficial alternative to fentanyl.

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 Aug 2021; epub ahead of print
Fernando H, Duong T, Huynh K, Noonan J, ... Peter K, Stub D
Eur Heart J: 22 Aug 2021; epub ahead of print | PMID: 34423354
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Abstract

Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models.

Withaar C, Lam CSP, Schiattarella GG, de Boer RA, Meems LMG
Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.

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

Eur Heart J: 19 Aug 2021; epub ahead of print
Withaar C, Lam CSP, Schiattarella GG, de Boer RA, Meems LMG
Eur Heart J: 19 Aug 2021; epub ahead of print | PMID: 34414416
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Abstract

Single or multiple arterial bypass graft surgery vs. percutaneous coronary intervention in patients with three-vessel or left main coronary artery disease.

Davierwala PM, Gao C, Thuijs DJFM, Wang R, ... Serruys PW, SYNTAX Extended Survival Investigators
Aim
The aim of this study was to compare long-term all-cause mortality between patients receiving percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) using multiple (MAG) or single arterial grafting (SAG).
Methods and results
The current study is a post hoc analysis of the SYNTAX Extended Survival Study, which compared PCI with CABG in patients with three-vessel (3VD) and/or left main coronary artery disease (LMCAD) and evaluated survival with ≥10 years of follow-up. The primary endpoint was all-cause mortality at maximum follow-up (median 11.9 years) assessed in the as-treated population. Of the 1743 patients, 901 (51.7%) underwent PCI, 532 (30.5%) received SAG, and 310 (17.8%) had MAG. At maximum follow-up, all-cause death occurred in 305 (33.9%), 175 (32.9%), and 70 (22.6%) patients in the PCI, SAG, and MAG groups, respectively (P < 0.001). Multiple arterial grafting [adjusted hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89], but not SAG (adjusted HR 0.83, 95% CI 0.67-1.03), was associated with significantly lower all-cause mortality compared with PCI. In patients with 3VD, both MAG (adjusted HR 0.55, 95% CI 0.37-0.81) and SAG (adjusted HR 0.68, 95% CI 0.50-0.91) were associated with significantly lower mortality than PCI, whereas in LMCAD patients, no significant differences between PCI and MAG (adjusted HR 0.90, 95% CI 0.56-1.46) or SAG (adjusted HR 1.11, 95% CI 0.81-1.53) were observed. In patients with revascularization of all three major myocardial territories, a positive correlation was observed between the number of myocardial territories receiving arterial grafts and survival (Ptrend = 0.003).
Conclusion
Our findings suggest that MAG might be the more desirable configuration for CABG to achieve lower long-term all-cause mortality than PCI in patients with 3VD and/or LMCAD.
Trial registration
Registered on clinicaltrial.gov. SYNTAXES: NCT03417050 (https://clinicaltrials.gov/ct2/show/NCT03417050); SYNTAX: NCT00114972 (https://www.clinicaltrials.gov/ct2/show/NCT00114972).

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

Eur Heart J: 17 Aug 2021; epub ahead of print
Davierwala PM, Gao C, Thuijs DJFM, Wang R, ... Serruys PW, SYNTAX Extended Survival Investigators
Eur Heart J: 17 Aug 2021; epub ahead of print | PMID: 34405875
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Abstract

Management of acute cardiovascular complications in pregnancy.

Egidy Assenza G, Dimopoulos K, Budts W, Donti A, ... Valente AM, Roos-Hesselink J
The growing population of women with heart disease of reproductive age has been associated with an increasing number of high-risk pregnancies. Pregnant women with heart disease are a very heterogeneous population, with different risks for maternal cardiovascular, obstetric, and foetal complications. Adverse cardiovascular events during pregnancy pose significant clinical challenges, with uncertainties regarding diagnostic and therapeutic approaches potentially compromising maternal and foetal health. This review summarizes best practice for the treatment of common cardiovascular complications during pregnancy, based on expert opinion, current guidelines, and available evidence. Topics covered include heart failure (HF), arrhythmias, coronary artery disease, aortic and thromboembolic events, and the management of mechanical heart valves during pregnancy. Cardiovascular pathology is the leading cause of non-obstetric morbidity and mortality during pregnancy in developed countries. For women with pre-existing cardiac conditions, preconception counselling and structured follow-up during pregnancy are important measures for reducing the risk of acute cardiovascular complications during gestation and at the time of delivery. However, many women do not receive pre-pregnancy counselling often due to gaps in what should be lifelong care, and physicians are increasingly encountering pregnant women who present acutely with cardiac complications, including HF, arrhythmias, aortic events, coronary syndromes, and bleeding or thrombotic events. This review provides a summary of recommendations on the management of acute cardiovascular complication during pregnancy, based on available literature and expert opinion. This article covers the diagnosis, risk stratification, and therapy and is organized according to the clinical presentation and the type of complication, providing a reference for the practicing cardiologist, obstetrician, and acute medicine specialist, while highlighting areas of need and potential future research.

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 Aug 2021; epub ahead of print
Egidy Assenza G, Dimopoulos K, Budts W, Donti A, ... Valente AM, Roos-Hesselink J
Eur Heart J: 17 Aug 2021; epub ahead of print | PMID: 34405872
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Abstract

Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia.

Holm S, Kared H, Michelsen AE, Kong XY, ... Munthe LA, Halvorsen B
Aims
We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7-10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients.
Methods and results
We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase-DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits.
Conclusions
The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.

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

Eur Heart J: 17 Aug 2021; epub ahead of print
Holm S, Kared H, Michelsen AE, Kong XY, ... Munthe LA, Halvorsen B
Eur Heart J: 17 Aug 2021; epub ahead of print | PMID: 34405870
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Abstract

Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease.

Wang R, Serruys PW, Gao C, Hara H, ... Garg S, Onuma Y
Aims
The aim of this article was to compare rates of all-cause death at 10 years following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in patients with or without diabetes.
Methods and results
The SYNTAXES study evaluated up to 10-year survival of 1800 patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to receive either PCI or CABG in the SYNTAX trial. Ten-year all-cause death according to diabetic status and revascularization strategy was examined. In diabetics (n = 452), the risk of mortality was numerically higher with PCI compared with CABG at 5 years [19.6% vs. 13.3%, hazard ratio (HR): 1.53, 95% confidence interval (CI): 0.96, 2.43, P = 0.075], with the opposite seen between 5 and 10 years (PCI vs. CABG: 20.8% vs. 24.4%, HR: 0.82, 95% CI: 0.52, 1.27, P = 0.366). Irrespective of diabetic status, there was no significant difference in all-cause death at 10 years between patients receiving PCI or CABG, the absolute treatment difference was 1.9% in diabetics (PCI vs. CABG: 36.4% vs. 34.5%, difference: 1.9%, 95% CI: -7.6%, 11.1%, P = 0.551). Among insulin-treated patients (n = 182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%, difference: 8.2%, 95% CI: -6.5%, 22.5%, P = 0.227).
Conclusions
The treatment effects of PCI vs. CABG on all-cause death at 10 years in patients with 3VD and/or LMCAD were similar irrespective of the presence of diabetes. There may, however, be a survival benefit with CABG in patients with insulin-treated diabetes. The association between revascularization strategy and very long-term ischaemic and safety outcomes for patients with diabetes needs further investigation in dedicated trials.
Trial registration
SYNTAX: ClinicalTrials.gov reference: NCT00114972 and SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

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

Eur Heart J: 17 Aug 2021; epub ahead of print
Wang R, Serruys PW, Gao C, Hara H, ... Garg S, Onuma Y
Eur Heart J: 17 Aug 2021; epub ahead of print | PMID: 34405232
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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: 16 Aug 2021; 42:2995-3007
Bosch J, Lonn EM, Jung H, Zhu J, ... Leiter LA, Yusuf S
Eur Heart J: 16 Aug 2021; 42:2995-3007 | PMID: 33963372
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Abstract

Insomnia symptoms and incident heart failure: a population-based cohort study.

Mahmood A, Ray M, Dobalian A, Ward KD, Ahn S
Aims
Heart failure (HF) is an ongoing epidemic and a serious clinical and public health issue. Currently, little is known about prospective associations between insomnia symptoms and HF incidence. We investigated the longitudinal associations between time-varying insomnia symptoms (difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, non-restorative sleep) and incident HF.
Methods and results
Data were obtained from the Health and Retirement Study in the US for a population-representative sample of 12,761 middle-aged and older adults (age ≥ 50 years; mean [SD] age, 66.7 [9.4] years; 57.7% females) who were free from HF at baseline in 2002. Respondents were followed for 16 years for incident HF. We employed marginal structural discrete-time survival analyses to adjust for potential time-varying biological, psycho-cognitive, and behavioral factors and to account for bias due to differential loss to follow-up. At baseline, 38.4% of the respondents reported experiencing at least one insomnia symptom. During the 16-year follow-up, 1,730 respondents developed incident HF. Respondents experiencing one (hazard ratio [HR]=1.22; 95% CI: 1.08-1.38), two (HR=1.45; 95% CI: 1.21-1.72), three (HR=1.66; 95% CI: 1.37-2.02), or four (HR=1.80; 95% CI: 1.25-2.59) insomnia symptoms had a higher hazard of incident HF than asymptomatic respondents. Respondents that had trouble initiating sleep (HR=1.17; 95%CI: 1.01-1.36), maintaining sleep (HR=1.14; 95% CI: 1.01-1.28), early-morning awakening (HR=1.20; 95% CI: 1.02-1.43), or non-restorative sleep (HR=1.25; 95% CI: 1.06-1.46) had a higher hazard of incident HF than asymptomatic respondents.
Conclusion
Insomnia symptoms, both cumulatively and individually, are associated with incident HF. Public health awareness and screening for insomnia symptoms in at-risk populations should be encouraged to reduce HF incidence.

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 Aug 2021; epub ahead of print
Mahmood A, Ray M, Dobalian A, Ward KD, Ahn S
Eur Heart J: 14 Aug 2021; epub ahead of print | PMID: 34392357
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Abstract

Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice.

Mojiri A, Walther BK, Jiang C, Matrone G, ... Wang R, Cooke JP
Aims
Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing.
Methods and results
We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice.
Conclusion
Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related 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: 13 Aug 2021; epub ahead of print
Mojiri A, Walther BK, Jiang C, Matrone G, ... Wang R, Cooke JP
Eur Heart J: 13 Aug 2021; epub ahead of print | PMID: 34389865
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Abstract

Reperfusion therapies and in-hospital outcomes for ST-elevation myocardial infarction in Europe: the ACVC-EAPCI EORP STEMI Registry of the European Society of Cardiology.

Zeymer U, Ludman P, Danchin N, Kala P, ... Weidinger F, ACVC EAPCI EORP ACS STEMI investigators group of the ESC
Aims 
The aim of this study was to determine the contemporary use of reperfusion therapy in the European Society of Cardiology (ESC) member and affiliated countries and adherence to ESC clinical practice guidelines in patients with ST-elevation myocardial infarction (STEMI).
Methods and results 
Prospective cohort (EURObservational Research Programme STEMI Registry) of hospitalized STEMI patients with symptom onset <24 h in 196 centres across 29 countries. A total of 11 462 patients were enrolled, for whom primary percutaneous coronary intervention (PCI) (total cohort frequency: 72.2%, country frequency range 0-100%), fibrinolysis (18.8%; 0-100%), and no reperfusion therapy (9.0%; 0-75%) were performed. Corresponding in-hospital mortality rates from any cause were 3.1%, 4.4%, and 14.1% and overall mortality was 4.4% (country range 2.5-5.9%). Achievement of quality indicators for reperfusion was reported for 92.7% (region range 84.8-97.5%) for the performance of reperfusion therapy of all patients with STEMI <12 h and 54.4% (region range 37.1-70.1%) for timely reperfusion.
Conclusions 
The use of reperfusion therapy for STEMI in the ESC member and affiliated countries was high. Primary PCI was the most frequently used treatment and associated total in-hospital mortality was below 5%. However, there was geographic variation in the use of primary PCI, which was associated with differences in in-hospital 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: 13 Aug 2021; epub ahead of print
Zeymer U, Ludman P, Danchin N, Kala P, ... Weidinger F, ACVC EAPCI EORP ACS STEMI investigators group of the ESC
Eur Heart J: 13 Aug 2021; epub ahead of print | PMID: 34389857
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Abstract

Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy.

Michel L, Helfrich I, Hendgen-Cotta UB, Mincu RI, ... Totzeck M, Rassaf T
Aims
Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease.
Methods and results
We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure-volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy.
Conclusions
Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

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 Aug 2021; epub ahead of print
Michel L, Helfrich I, Hendgen-Cotta UB, Mincu RI, ... Totzeck M, Rassaf T
Eur Heart J: 13 Aug 2021; epub ahead of print | PMID: 34389849
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Impact:
Abstract

Chronic venous insufficiency, cardiovascular disease, and mortality: a population study.

Prochaska JH, Arnold N, Falcke A, Kopp S, ... Münzel T, Wild PS
Aims 
Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce.
Methods and results 
Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6-37.4%], 13.3% [12.6-13.9%], and 40.8% [39.9-41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19-1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11-2.05), P = 0.009].
Conclusion 
Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.

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: 12 Aug 2021; epub ahead of print
Prochaska JH, Arnold N, Falcke A, Kopp S, ... Münzel T, Wild PS
Eur Heart J: 12 Aug 2021; epub ahead of print | PMID: 34387673
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Impact:
Abstract

Long-term night shift work is associated with the risk of atrial fibrillation and coronary heart disease.

Wang N, Sun Y, Zhang H, Wang B, ... Qi L, Lu Y
Aims
The aim of this study was to test whether current and past night shift work was associated with incident atrial fibrillation (AF) and whether this association was modified by genetic vulnerability. Its associations with coronary heart disease (CHD), stroke, and heart failure (HF) were measured as a secondary aim.
Methods and results
This cohort study included 283 657 participants in paid employment or self-employed without AF and 276 009 participants free of CHD, stroke, and HF at baseline in the UK Biobank. Current and lifetime night shift work information was obtained. Cox proportional hazard models were used. Weighted genetic risk score for AF was calculated. During a median follow-up of 10.4 years, 5777 incident AF cases were documented. From \'day workers\', \'shift but never/rarely night shifts\', and \'some night shifts\' to \'usual/permanent night shifts\', there was a significant increasing trend in the risk of incident AF (P for trend 0.013). Usual or permanent night shifts were associated with the highest risk [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.02-1.32]. Considering a person\'s lifetime work schedule and compared with shift workers never working nights, participants with a duration over 10 years and an average 3-8 nights/month frequency of night shift work exposure possessed higher AF risk (HR 1.18, 95% CI 0.99-1.40 and HR 1.22, 95% CI 1.02-1.45, respectively). These associations between current and lifetime night shifts and AF were not modified by genetic predisposition to AF. Usual/permanent current night shifts, ≥10 years and 3-8 nights/month of lifetime night shifts were significantly associated with a higher risk of incident CHD (HR 1.22, 95% CI 1.11-1.35, HR 1.37, 95% CI 1.20-1.58 and HR 1.35, 95% CI 1.18-1.55, respectively). These associations in stroke and HF were not significant.
Conclusion
Both current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk. Night shift exposure also increased the risk of CHD but not stroke or HF. Whether decreasing night shift work frequency and duration might represent another avenue to improve heart health during working life and beyond warrants further 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: 09 Aug 2021; epub ahead of print
Wang N, Sun Y, Zhang H, Wang B, ... Qi L, Lu Y
Eur Heart J: 09 Aug 2021; epub ahead of print | PMID: 34374755
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Impact:
Abstract

Electrocardiogram screening for aortic valve stenosis using artificial intelligence.

Cohen-Shelly M, Attia ZI, Friedman PA, Ito S, ... Lopez-Jimenez F, Oh JK
Aims 
Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS.
Methods and results 
Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90-2.50).
Conclusion 
An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.

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 Aug 2021; 42:2885-2896
Cohen-Shelly M, Attia ZI, Friedman PA, Ito S, ... Lopez-Jimenez F, Oh JK
Eur Heart J: 06 Aug 2021; 42:2885-2896 | PMID: 33748852
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Abstract

Management of acute coronary syndromes in older adults.

Morici N, De Servi S, De Luca L, Crimi G, ... Valgimigli M, Savonitto S
Older patients are underrepresented in prospective studies and randomized clinical trials of acute coronary syndromes (ACS). Over the last decade, a few specific trials have been conducted in this population, allowing more evidence-based management. Older adults are a heterogeneous, complex, and high-risk group whose management requires a multidimensional clinical approach beyond coronary anatomic variables. This review focuses on available data informing evidence-based interventional and pharmacological approaches for older adults with ACS, including guideline-directed management. Overall, an invasive approach appears to demonstrate a better benefit-risk ratio compared to a conservative one across the ACS spectrum, even considering patients\' clinical complexity and multiple comorbidities. Conversely, more powerful strategies of antithrombotic therapy for secondary prevention have been associated with increased bleeding events and no benefit in terms of mortality reduction. An interdisciplinary evaluation with geriatric assessment should always be considered to achieve a holistic approach and optimize any treatment on the basis of the underlying biological vulnerability.

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

Eur Heart J: 03 Aug 2021; epub ahead of print
Morici N, De Servi S, De Luca L, Crimi G, ... Valgimigli M, Savonitto S
Eur Heart J: 03 Aug 2021; epub ahead of print | PMID: 34347065
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Abstract

The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms.

Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R
Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-β, tumour necrosis factor-α, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase Cε, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks.

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

Eur Heart J: 02 Aug 2021; epub ahead of print
Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R
Eur Heart J: 02 Aug 2021; epub ahead of print | PMID: 34343257
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Abstract

Impact of cholesterol on proinflammatory monocyte production by the bone marrow.

Stiekema LCA, Willemsen L, Kaiser Y, Prange KHM, ... Stroes ESG, Kroon J
Aim
Preclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects.
Methods and results
A multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (β = 0.131 [95% CI: 0.036-0.225]; P = 0.007), at the expense of granulocytes (β = -0.876 [95% CI: -1.046 to -0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability.
Conclusions
Collectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.

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

Eur Heart J: 02 Aug 2021; epub ahead of print
Stiekema LCA, Willemsen L, Kaiser Y, Prange KHM, ... Stroes ESG, Kroon J
Eur Heart J: 02 Aug 2021; epub ahead of print | PMID: 34343254
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Abstract

Sex differences in outcomes after coronary artery bypass grafting: a pooled analysis of individual patient data.

Gaudino M, Di Franco A, Alexander JH, Bakaeen F, ... Fremes SE, Benedetto U
Aims
Data suggest that women have worse outcomes than men after coronary artery bypass grafting (CABG), but results have been inconsistent across studies. Due to the large differences in baseline characteristics between sexes, suboptimal risk adjustment due to low-quality data may be the reason for the observed differences. To overcome this limitation, we undertook a systematic review and pooled analysis of high-quality individual patient data from large CABG trials to compare the adjusted outcomes of women and men.
Methods and results
The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), stroke, and repeat revascularization (major adverse cardiac and cerebrovascular events, MACCE). The secondary outcome was all-cause mortality. Multivariable mixed-effect Cox regression was used. Four trials involving 13 193 patients (10 479 males; 2714 females) were included. Over 5 years of follow-up, women had a significantly higher risk of MACCE [adjusted hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.21; P = 0.004] but similar mortality (adjusted HR 1.03, 95% CI 0.94-1.14; P = 0.51) compared to men. Women had higher incidence of MI (adjusted HR 1.30, 95% CI 1.11-1.52) and repeat revascularization (adjusted HR 1.22, 95% CI 1.04-1.43) but not stroke (adjusted HR 1.17, 95% CI 0.90-1.52). The difference in MACCE between sexes was not significant in patients 75 years and older. The use of off-pump surgery and multiple arterial grafting did not modify the difference between sexes.
Conclusions
Women have worse outcomes than men in the first 5 years after CABG. This difference is not significant in patients aged over 75 years and is not affected by the surgical technique.

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

Eur Heart J: 01 Aug 2021; epub ahead of print
Gaudino M, Di Franco A, Alexander JH, Bakaeen F, ... Fremes SE, Benedetto U
Eur Heart J: 01 Aug 2021; epub ahead of print | PMID: 34338767
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Abstract

The Stanford experience of heart transplantation over five decades.

Zhu Y, Lingala B, Baiocchi M, Toro Arana V, ... Oyer PE, Woo YJ
Aims 
Since 1968, heart transplantation has become the definitive treatment for patients with end-stage heart failure. We aimed to summarize our experience in heart transplantation at Stanford University since the first transplantation performed over 50 years ago.
Methods and results 
From 6 January 1968 to 30 November 2020, 2671 patients presented to Stanford University for heart transplantation, of which 1958 were adult heart transplantations. Descriptive analyses were performed for patients in 1968-95 (n = 639). Stabilized inverse probability weighting was applied to compare patients in 1996-2006 (n = 356) vs. 2007-19 (n = 515). Follow-up data were updated through 2020. The primary endpoint was all-cause mortality. Prior to weighting, recipients in 2007-19 vs. those in 1996-2006 were older and had heavier burden of chronic diseases. After the application of stabilized inverse probability weighting, the distance organ travelled increased from 84.2 ± 111.1 miles to 159.3 ± 169.9 miles from 1996-2006 to 2007-19. Total allograft ischaemia time also increased over time (199.6 ± 52.7 vs. 225.3 ± 50.0 min). Patients in 2007-19 showed superior survival than those in 1996-2006 with a median survival of 12.1 vs. 11.1 years.
Conclusion 
In this half-century retrospective descriptive study from one of the largest heart transplant programmes in the USA, long-term survival after heart transplantation has improved over time despite increased recipient and donor age, worsening comorbidities, increased technical complexity, and prolonged total allograft ischaemia time. Further investigation is warranted to delineate factors associated with the excellent outcomes observed 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: 31 Jul 2021; epub ahead of print
Zhu Y, Lingala B, Baiocchi M, Toro Arana V, ... Oyer PE, Woo YJ
Eur Heart J: 31 Jul 2021; epub ahead of print | PMID: 34333595
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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: 30 Jul 2021; 42:2827-2838
Steinberg C, Davies B, Mellor G, Tadros R, ... Simpson CS, Krahn AD
Eur Heart J: 30 Jul 2021; 42:2827-2838 | PMID: 34010395
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Abstract

Genome-wide association study identifies 18 novel loci associated with left atrial volume and function.

Ahlberg G, Andreasen L, Ghouse J, Bertelsen L, ... Svendsen JH, Olesen MS
Aims 
Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data.
Methods and results 
We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14].
Conclusion 
We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.

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

Eur Heart J: 28 Jul 2021; epub ahead of print
Ahlberg G, Andreasen L, Ghouse J, Bertelsen L, ... Svendsen JH, Olesen MS
Eur Heart J: 28 Jul 2021; epub ahead of print | PMID: 34338756
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Abstract

Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve: the COMBINE OCT-FFR trial.

Kedhi E, Berta B, Roleder T, Hermanides RS, ... Granada JF, Wojakowski W
Aims
The aim of this study was to understand the impact of optical coherence tomography (OCT)-detected thin-cap fibroatheroma (TCFA) on clinical outcomes of diabetes mellitus (DM) patients with fractional flow reserve (FFR)-negative lesions.
Methods and results
COMBINE OCT-FFR study was a prospective, double-blind, international, natural history study. After FFR assessment, and revascularization of FFR-positive lesions, patients with ≥1 FFR-negative lesions (target lesions) were classified in two groups based on the presence or absence of ≥1 TCFA lesion. The primary endpoint compared FFR-negative TCFA-positive patients with FFR-negative TCFA-negative patients for a composite of cardiac mortality, target vessel myocardial infarction, clinically driven target lesion revascularization or unstable angina requiring hospitalization at 18 months. Among 550 patients enrolled, 390 (81%) patients had ≥1 FFR-negative lesions. Among FFR-negative patients, 98 (25%) were TCFA positive and 292 (75%) were TCFA negative. The incidence of the primary endpoint was 13.3% and 3.1% in TCFA-positive vs. TCFA-negative groups, respectively (hazard ratio 4.65; 95% confidence interval, 1.99-10.89; P < 0.001). The Cox regression multivariable analysis identified TCFA as the strongest predictor of major adverse clinical events (MACE) (hazard ratio 5.12; 95% confidence interval 2.12-12.34; P < 0.001).
Conclusions
Among DM patients with ≥1 FFR-negative lesions, TCFA-positive patients represented 25% of this population and were associated with a five-fold higher rate of MACE despite the absence of ischaemia. This discrepancy between the impact of vulnerable plaque and ischaemia on future adverse events may represent a paradigm shift for coronary artery disease risk stratification in DM 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: 28 Jul 2021; epub ahead of print
Kedhi E, Berta B, Roleder T, Hermanides RS, ... Granada JF, Wojakowski W
Eur Heart J: 28 Jul 2021; epub ahead of print | PMID: 34345911
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This program is still in alpha version.