Topic: Heart Failure

Abstract

Classification of Heart Failure According to Ejection Fraction: JACC Review Topic of the Week.

Lam CSP, Solomon SD
The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to \"preserved\" ejection fraction but referring to \"below normal\" ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the \"mid range\" may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with \"reduced\" (<40%), \"mildly reduced,\" and \"normal\" (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 28 Jun 2021; 77:3217-3225
Lam CSP, Solomon SD
J Am Coll Cardiol: 28 Jun 2021; 77:3217-3225 | PMID: 34167646
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Abstract

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

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

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

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

Pathophysiology of the Lymphatic System in Patients With Heart Failure: JACC State-of-the-Art Review.

Itkin M, Rockson SG, Burkhoff D
The removal of interstitial fluid from the tissues is performed exclusively by the lymphatic system. Tissue edema in congestive heart failure occurs only when the lymphatic system fails or is overrun by fluid leaving the vascular space across the wall of the capillaries into the interstitial space. This process is driven by Starling forces determined by hydrostatic and osmotic pressures and organ-specific capillary permeabilities to proteins of different sizes. In this review, we summarize current knowledge of the generation of lymph in different organs, the mechanics by which lymph is returned to the circulation, and the consequences of the inadequacy of lymph flow. We review recent advances in imaging techniques that have allowed for new research, diagnostic, and therapeutic approaches to the lymphatic system. Finally, we review how efforts to increase lymph flow have demonstrated potential as a viable therapeutic approach for refractory heart failure.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 19 Jul 2021; 78:278-290
Itkin M, Rockson SG, Burkhoff D
J Am Coll Cardiol: 19 Jul 2021; 78:278-290 | PMID: 34266581
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Abstract

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

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

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

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

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

Yu B, Roberts MB, Raffield LM, Zekavat SM, ... Lung, and Blood Institute TOPMed Consortium
Background
Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).
Objectives
This study sought to evaluate whether CHIP is associated with incident HF.
Methods
CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.
Results
Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.
Conclusions
CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 05 Jul 2021; 78:42-52
Yu B, Roberts MB, Raffield LM, Zekavat SM, ... Lung, and Blood Institute TOPMed Consortium
J Am Coll Cardiol: 05 Jul 2021; 78:42-52 | PMID: 34210413
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Abstract

Lymphatic Dysregulation in Patients With Heart Failure: JACC Review Topic of the Week.

Fudim M, Salah HM, Sathananthan J, Bernier M, ... Virani SA, Patel MR
The lymphatic system is an integral part of the circulatory system and plays an important role in the volume homeostasis of the human body. The complex anatomy and physiology paired with a lack of simple diagnostic tools to study the lymphatic system have led to an underappreciation of the contribution of the lymphatic system to acute and chronic heart failure (HF). Herein, we discuss the physiological role of the lymphatic system in volume management and the evidence demonstrating the dysregulation of the lymphatic system in HF. Further, we discuss the opportunity to target the lymphatic system in the management of HF and different potential approaches to accessing the lymphatic system.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 05 Jul 2021; 78:66-76
Fudim M, Salah HM, Sathananthan J, Bernier M, ... Virani SA, Patel MR
J Am Coll Cardiol: 05 Jul 2021; 78:66-76 | PMID: 34210416
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Abstract

Diagnosis and Management of Myocarditis in Children: A Scientific Statement From the American Heart Association.

Law YM, Lal AK, Chen S, Čiháková D, ... Towbin JA, American Heart Association Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young and Stroke Council
Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.



Circulation: 06 Jul 2021:CIR0000000000001001; epub ahead of print
Law YM, Lal AK, Chen S, Čiháková D, ... Towbin JA, American Heart Association Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young and Stroke Council
Circulation: 06 Jul 2021:CIR0000000000001001; epub ahead of print | PMID: 34229446
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Abstract

Appropriate Use of High-Flow Nasal Oxygen in Hospitalized Patients for Initial or Postextubation Management of Acute Respiratory Failure: A Clinical Guideline From the American College of Physicians.

Qaseem A, Etxeandia-Ikobaltzeta I, Fitterman N, Williams JW, Kansagara D, Clinical Guidelines Committee of the American College of Physicians
Description
The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the appropriate use of high-flow nasal oxygen (HFNO) in hospitalized patients for initial or postextubation management of acute respiratory failure. It is based on the best available evidence on the benefits and harms of HFNO, taken in the context of costs and patient values and preferences.
Methods
The ACP Clinical Guidelines Committee based these recommendations on a systematic review on the efficacy and safety of HFNO. The patient-centered health outcomes evaluated included all-cause mortality, hospital length of stay, 30-day hospital readmissions, hospital-acquired pneumonia, days of intubation or reintubation, intensive care unit (ICU) admission and ICU transfers, patient comfort, dyspnea, delirium, barotrauma, compromised nutrition, gastric dysfunction, functional independence at discharge, discharge disposition, and skin breakdown. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method.
Target audience and patient population
The target audience is all clinicians, and the target patient population is adult patients with acute respiratory failure treated in a hospital setting (including emergency departments, hospital wards, intermediate or step-down units, and ICUs).
Recommendation 1a
ACP suggests that clinicians use high-flow nasal oxygen rather than noninvasive ventilation in hospitalized adults for the management of acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence).
Recommendation 1b
ACP suggests that clinicians use high-flow nasal oxygen rather than conventional oxygen therapy for hospitalized adults with postextubation acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence).



Ann Intern Med: 29 Jun 2021; 174:977-984
Qaseem A, Etxeandia-Ikobaltzeta I, Fitterman N, Williams JW, Kansagara D, Clinical Guidelines Committee of the American College of Physicians
Ann Intern Med: 29 Jun 2021; 174:977-984 | PMID: 33900796
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Abstract

Nocturnal Hypertension and Heart Failure: Mechanisms, Evidence, and New Treatments.

Kario K, Williams B
Heart failure (HF) is a common condition with an increasing prevalence. Despite a variety of evidence-based treatments for patients with HF with reduced ejection fraction, morbidity and mortality rates remain high. Furthermore, there are currently no treatments that have yet been shown to reduce complication and death rates in patients who have HF with preserved ejection fraction. Hypertension is a common comorbidity in patients with HF, contributing to disease development and prognosis. For example, hypertension is closely associated with the development of left ventricular hypertrophy, which an important precursor of HF. In particular, nighttime blood pressure (BP) appears to be an important, modifiable risk factor. Both nighttime BP and an abnormal circadian pattern of nighttime BP dipping have been shown to predict development of HF and the occurrence of cardiovascular events, independent of office BP. Key mechanisms for this association include sodium handling/salt sensitivity and increased sympathetic activation. These pathogenic mechanisms are targeted by several new treatment options, including sodium-glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and renal denervation. All of these could form part of antihypertensive strategies designed to control nighttime BP and contribute to the goal of achieving perfect 24-hour BP management. Nevertheless, additional research is needed to determine the effects of reducing nighttime BP and improving the circadian BP profile on the rate of HF, other cardiovascular events, and mortality.



Hypertension: 05 Jul 2021:HYPERTENSIONAHA12117440; epub ahead of print
Kario K, Williams B
Hypertension: 05 Jul 2021:HYPERTENSIONAHA12117440; epub ahead of print | PMID: 34225469
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Abstract

Antiprothrombin antibodies induce platelet activation: A possible explanation for anti-FXa therapy failure in patients with antiphospholipid syndrome?

Chayoua W, Nicolson PLR, Meijers JCM, Kardeby C, ... Watson SP, de Groot PG
Background
Arterial and venous thrombosis are both common in antiphospholipid syndrome (APS). Recent studies have shown that anti-factor Xa (FXa) therapy in APS patients leads to a greater number of patients with arterial thrombosis than with warfarin. We hypothesize that this may be due to the lowering of prothrombin levels by warfarin.
Objectives
To investigate whether antiprothrombin antibodies induce platelet aggregation and to identify the platelet receptors involved. A second aim was to investigate the effect of reduced prothrombin levels on antiprothrombin antibody-induced platelet aggregation.
Methods
Enzyme-linked immunosorbent assays were performed to measure binding of antiprothrombin antibodies to prothrombin fragment 1+2 and prothrombin. Platelet aggregation assays in washed platelets were performed. FcγRIIA was immunoprecipitated and tyrosine-phosphorylated FcγRIIA was measured by western blot.
Results
The antiprothrombin antibodies 28F4 and 3B1 had lupus anticoagulant (LAC) activity and caused platelet aggregation in the presence of Ca2+ and prothrombin. Antiprothrombin antibodies without LAC activity did not activate platelets. Inhibition of Syk and Src kinases and FcγRIIA blocked platelet aggregation. Fab and F(ab\')2 fragments of 28F4 were unable to induce platelet aggregation. Immunoprecipitations showed that whole 28F4 immunoglobulin G induced tyrosine phosphorylation of FcγRIIA. Platelet aggregation was significantly reduced when prothrombin levels were reduced from 1 µM to 0.2 µM.
Conclusions
Antiprothrombin antibodies with LAC activity are able to activate platelets via FcγRIIA. Decreased prothrombin levels resulted in less antiprothrombin antibody-mediated platelet aggregation. This may explain the lower incidence of arterial thrombosis in patients treated with warfarin than with anti-FXa therapy.

© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 29 Jun 2021; 19:1776-1782
Chayoua W, Nicolson PLR, Meijers JCM, Kardeby C, ... Watson SP, de Groot PG
J Thromb Haemost: 29 Jun 2021; 19:1776-1782 | PMID: 33774918
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Abstract

Heart failure medication dosage and survival in women and men seen at outpatient clinics.

Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Objective
Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care.
Methods
Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality.
Results
The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality.
Conclusion
Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 13 Jul 2021; epub ahead of print
Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Heart: 13 Jul 2021; epub ahead of print | PMID: 34261736
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Abstract

Multimarker profiling identifies protective and harmful immune processes in heart failure: findings from BIOSTAT-CHF.

Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, Fereirra JP, ... Voors AA, van der Meer P
Aims
The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF.
Methods and results
We measured 355 biomarkers in 2,022 patients with worsening HF and an independent validation cohort (n = 1,691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the Gene Ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of \"T-cell costimulation\" and \"response to interferon gamma/positive regulation of interferon gamma production\" showed the most consistent positive and negative associations with all-cause mortality respectively, after external validation. Within T-cell costimulation, inducible co-stimulator-ligand (ICOSLG), CD28, CD70, and tumor necrosis factor superfamily member-14 (TNFSF14) were identified as potential therapeutic targets.
Conclusions
We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.

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

Cardiovasc Res: 14 Jul 2021; epub ahead of print
Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, Fereirra JP, ... Voors AA, van der Meer P
Cardiovasc Res: 14 Jul 2021; epub ahead of print | PMID: 34264317
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Abstract

Management of cardiac fibrosis is the largest unmet medical need in heart failure Cardiac fibrosis in heart failure.

Díez J, de Boer RA
Cardiac fibrosis is a major driver associated with the growing burden of heart failure, especially in older people. However, integrating cardiac fibrosis in heart failure management is still an unmet medical need, which may be explained by its high tissue heterogeneity and clinical diversity, and, as a consequence, the very real limitations of its diagnosis and treatment. In this viewpoint article we summarize the challenges and requirements in the clinical management of cardiac fibrosis in heart failure patients.

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

Cardiovasc Res: 08 Jul 2021; epub ahead of print
Díez J, de Boer RA
Cardiovasc Res: 08 Jul 2021; epub ahead of print | PMID: 34244741
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Abstract

CENTRAL AND PERIPHERAL SYMPATHETIC ACTIVATION IN HEART FAILURE.

Grassi G, Mancia G, Esler M
The sympathetic nervous system overdrive occurring in heart failure has been reported since more than half a century. Refinements in the methodological approaches to assess human sympathetic neural function have allowed during recent years to better define various aspects related to the neuroadrenergic alteration. These include 1) the different participation of the individual regional sympathetic cardiovascular districts at the process, 2) the role of the central nervous system in determining the neuroadrenergic overdrive, 3) the involvement of baroreflex, cardiopulmonary reflex and chemoreflex mechanisms in the phoenomenon, which is also closely linked to inflammation and the immune reaction, 4) the relationships with the severity of the disease, its ischaemic or idiopathic nature and the preserved or reduced left ventricular ejection fraction and 5) the adverse functional and structural impact of the sympathetic activation on cardiovascular organs, such as the brain, the heart and the kidneys. Information have been also gained on the active role exerted by the sympathetic activation on the disease outcome and its potential relevance as target of the therapeutic interventions based on non-pharmacological, pharmacological and invasive approaches, including the renal denervation, the splanchnic sympathetic nerve ablation and the carotid baroreflex stimulation. The still undefined aspects of the neurogenic alterations and the unmet goals of the therapeutic approach having the sympathetic activation as a target of the intervention will be finally mentioned.

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

Cardiovasc Res: 06 Jul 2021; epub ahead of print
Grassi G, Mancia G, Esler M
Cardiovasc Res: 06 Jul 2021; epub ahead of print | PMID: 34240147
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Abstract

Natriuretic peptide level at heart failure diagnosis and risk of hospitalisation and death in England 2004-2018.

Taylor CJ, Lay-Flurrie SL, Ordóñez-Mena JM, Goyder CR, ... Roalfe AK, Hobbs FR
Objective
Heart failure (HF) is a malignant condition requiring urgent treatment. Guidelines recommend natriuretic peptide (NP) testing in primary care to prioritise referral for specialist diagnostic assessment. We aimed to assess association of baseline NP with hospitalisation and mortality in people with newly diagnosed HF.
Methods
Population-based cohort study of 40 007 patients in the Clinical Practice Research Datalink in England with a new HF diagnosis (48% men, mean age 78.5 years). We used linked primary and secondary care data between 1 January 2004 and 31 December 2018 to report one-year hospitalisation and 1-year, 5-year and 10-year mortality by NP level.
Results
22 085 (55%) participants were hospitalised in the year following diagnosis. Adjusted odds of HF-related hospitalisation in those with a high NP (NT-proBNP >2000 pg/mL) were twofold greater (OR 2.26 95% CI 1.98 to 2.59) than a moderate NP (NT-proBNP 400-2000 pg/mL). All-cause mortality rates in the high NP group were 27%, 62% and 82% at 1, 5 and 10 years, compared with 19%, 50% and 77%, respectively, in the moderate NP group and, in a competing risks model, risk of HF-related death was 50% higher at each timepoint. Median time between NP test and HF diagnosis was 101 days (IQR 19-581).
Conclusions
High baseline NP is associated with increased HF-related hospitalisation and poor survival. While healthcare systems remain under pressure from the impact of COVID-19, research to test novel strategies to prevent hospitalisation and improve outcomes-such as a mandatory two-week HF diagnosis pathway-is urgently needed.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Heart: 27 Jun 2021; epub ahead of print
Taylor CJ, Lay-Flurrie SL, Ordóñez-Mena JM, Goyder CR, ... Roalfe AK, Hobbs FR
Heart: 27 Jun 2021; epub ahead of print | PMID: 34183432
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Abstract

Association of long-term SBP with clinical outcomes and quality of life in heart failure with preserved ejection fraction: an analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial.

Huang P, Yu Y, Wei F, Zhu W, ... Dong Y, Liu C
Aims
To determine the associations of long-term SBP (LT-SBP) levels with clinical outcomes and health-related quality of life in heart failure with preserved ejection fraction (HFpEF).
Methods and results
We analyzed participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study with available different SBP measurements from different follow-ups (n = 3310). LT-SBP was the mean SBP value from 4-week measurement to the last one. The outcome measures are all-cause mortality and a composite of heart failure readmission or all-cause mortality and the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. To determine the associations of LT-SBP and outcomes, we used adjusted Cox proportional hazards models and restricted cubic spline models. After multivariable adjustment, LT-SBP of 120-129 and 130-139 mmHg were associated with a lower risk of mortality (hazard ratio 0.66, 95% CI 0.51-0.87, P = 0.003; hazard ratio 0.68, 95% CI 0.51-0.90, P = 0.007, respectively); LT-SBP of 100-119 mmHg had similar risk of mortality (hazard ratio 0.96, 95% CI 0.72-1.28, P = 0.778) compared with LT-SBP of at least 140 mmHg. There was U-shaped relationship between LT-SBP and all-cause mortality (P < 0.001) with nadir risk occurring around 123 mmHg. Similar relationships were observed between LT-SBP and composite end point of heart failure readmission or all-cause mortality. The adjusted mean improvement in KCCQ score was significantly higher in the 120-129 mmHg group than in the at least 140 mmHg group beginning from the 12-month follow-up visit without significant differences in other groups.
Conclusion
Among patients with HFpEF, long-term control of SBP level at 120-129 mmHg is independently associated with the highest risk reduction of all-cause mortality and improvement of KCCQ score. Future randomized clinical trials need to specifically evaluate optimal SBP treatment goals in patients with HFpEF.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 30 Jun 2021; 39:1378-1385
Huang P, Yu Y, Wei F, Zhu W, ... Dong Y, Liu C
J Hypertens: 30 Jun 2021; 39:1378-1385 | PMID: 33534342
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Abstract

Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials.

Fernandes GC, Fernandes A, Cardoso R, Penalver J, ... Myerburg RJ, Goldberger JJ
Background
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce hospitalizations and death from heart failure (HF), but their effect on arrhythmia expression has been poorly investigated.
Objective
The purpose of this study was to evaluate the association of SGLT2is with arrhythmias in patients with type 2 diabetes mellitus (T2DM) or HF.
Methods
We searched PubMed and ClinicalTrials.gov. Two independent investigators identified randomized double-blind trials that compared SGLT2is with placebo or active control for adults with T2DM or HF. Primary outcomes were incident atrial arrhythmias, ventricular arrhythmias (VAs), and sudden cardiac death (SCD).
Results
We included 34 randomized (25 placebo-controlled and 9 active-controlled) trials with 63,166 patients (35,883 SGLT2is vs 27,273 control: mean age 53-67 years; 63% male). Medications included canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin. Except for 1 study of HF, all patients had T2DM. Follow-up ranged from 24 weeks to 5.7 years. The cumulative incidence of events was low: 3.6, 1.4, and 2.5 per 1000 patient-years for atrial arrhythmias, VAs and SCD, respectively. SGLT2i therapy was associated with a significant reduction in the risk of incident atrial arrhythmias (odds ratio 0.81; 95% confidence interval 0.69-0.95; P = .008) and the \"SCD\" component of the SCD outcome (odds ratio 0.72; 95% confidence interval 0.54-0.97; P = .03) compared with control. There was no significant difference in incident VA or the \"cardiac arrest\" SCD component between groups.
Conclusion
SGLT2is are associated with significantly reduced risks of incident atrial arrhythmias and SCD in patients with T2DM. Prospective trials are warranted to confirm the antiarrhythmic effect of SGLT2is and whether this is a class or drug-specific effect.

Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 29 Jun 2021; 18:1098-1105
Fernandes GC, Fernandes A, Cardoso R, Penalver J, ... Myerburg RJ, Goldberger JJ
Heart Rhythm: 29 Jun 2021; 18:1098-1105 | PMID: 33757845
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Abstract

Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.

Ambrosy AP, von Haehling S, Kalra PR, Court E, ... McDonagh T, Cleland JGF
Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2021; 152:138-145
Ambrosy AP, von Haehling S, Kalra PR, Court E, ... McDonagh T, Cleland JGF
Am J Cardiol: 31 Jul 2021; 152:138-145 | PMID: 34162484
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Abstract

Incidence and Predictors of Progression in Asymptomatic Patients With Stable Heart Failure.

Marschall A, Del Castillo Carnevali H, Fernández Pascual C, Lorente Rubio A, ... Álvarez Antón S, Martí Sánchez D
Data from previous heart failure (HF) trials suggest that patients with mild symptoms (NYHA II) actually have a poor clinical outcome. However, these studies did not assess clinical stability and rarely included patients in NYHA I. We sought to determine the incidence of short-term clinical progression in supposedly stable HF patients in NYHA I. In addition, we aimed to investigate the predictive value of widely available electrocardiographic and echocardiographic parameters for short-term disease progression. This is a retrospective study including 153 consecutive patients with HF with reduced and mid-range ejection fraction (HFrEF: LVEF<40%; HFmrEF: LVEF 40-49%) in NYHA I with no history of decompensation within the previous 6 months. All patients underwent comprehensive baseline echocardiographic and electrocardiographic assessment. The primary endpoint was the composite of cardiovascular death, hospitalization and need for intensification of HF treatment within a 12 month follow-up period. The cumulative incidence of HF progression was 17.8%, with a median time to event of 193 days. Death and hospitalization due to HF accounted for three-quarters of the events. QRS duration ≥120ms and mitral regurgitation grade >1 showed to be significant predictors of HF progression (HR: 8.92, p<0.001; and HR: 4.10, p<0.001, respectively). Patients without these risk factors had a low incidence of clinical events (3.8%). In conclusion, almost one in five supposedly stable HF patients in NYHA I experience clinical progression in short-term follow-up. Simple electrocardiographic and echocardiographic predictors may be useful for risk stratification and could help to improve individual HF patient management and outcomes.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2021; 152:88-93
Marschall A, Del Castillo Carnevali H, Fernández Pascual C, Lorente Rubio A, ... Álvarez Antón S, Martí Sánchez D
Am J Cardiol: 31 Jul 2021; 152:88-93 | PMID: 34147209
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Impact:
Abstract

Impact of Oral Soluble Guanylate Cyclase Stimulators in Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Moghaddam N, Malhi N, Toma M
Background
Soluble guanylate cyclase (sGC) stimulators are a novel class of medications with emerging role in heart failure (HF). The aim of this study is to evaluate the efficacy and safety of oral sGC stimulators in patients with HF with reduced and preserved ejection fraction (HFrEF and HFpEF) by pooling data from all available randomized control trials (RCT).
Methods
A comprehensive search of electronic databases from 2000-2020 was performed. Seven RCTs, three HFrEF and four HFpEF studies, were identified. The follow-up duration ranged from 1 month to a median of 10.8 months. A random-effects meta-analysis was conducted to summarize the studies.
Results
The study population included 7190 patients: 5707 HFrEF and 1483 HFpEF patients. In HFrEF, oral sGC stimulators reduced the composite incidence of HF hospitalization and cardiovascular death (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.78-0.97; I2= 0%), primarily driven by lower HF hospitalization (HR 0.88, 95% CI 0.78-0.99; I2= 0%). There was no significant reduction in all-cause death in HFrEF (HR 0.95, 95% CI 0.83-1.09; I2=0%). In HFpEF, there were no improvements in Kansas City Cardiomyopathy Questionnaire clinical summary scores (mean difference 0.81, 95% CI -2.16-3.77; I2=72%) or 6-minute walk distance (mean difference 3.34 meters, 95% CI -7.86-14.54; I2=28%). There was no difference in all-cause mortality in HFpEF (HR 1.94, 95% CI 0.92-4.09; I2=0%). Overall, oral sGC stimulators had low medication-related serious adverse events.
Conclusion
Oral sGC stimulators are well tolerated in HF and reduce the incidence of HF hospitalization but not cardiovascular death among patients with HFrEF. However, there are no apparent benefits in HFpEF.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 16 Jul 2021; epub ahead of print
Moghaddam N, Malhi N, Toma M
Am Heart J: 16 Jul 2021; epub ahead of print | PMID: 34283990
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Abstract

The CHADS-VASc Score for Risk Stratification of Stroke in Heart Failure With-vs-Without Atrial Fibrillation.

Marzouka GR, Rivner H, Mehta V, Lopez J, ... Ishwaran H, Goldberger JJ
A recent study suggested that the CHA2DS2-VASc score can risk stratify heart failure (HF) patients without atrial fibrillation (AF) for stroke. We performed a retrospective analysis using the national Veteran Affairs database to externally validate the findings. Crude incidence rates of end points were calculated. A Cox proportional model was used to study the association between the CHA2DS2-VASc score and outcomes. In HF patients with AF (n = 17,481) and without AF (n = 36,935), the 1 year incidence rate for ischemic stroke, thromboembolism, thromboembolism (without MI), and death were 2.7 and 2.0%; 10.3 and 7.9%; 4.1 and 3.1%; and 19.2 and 26.0%, respectively, with higher rates with increasing CHA2DS2-VASc scores both with and without AF. CHA2DS2-VASc score predicted strokes in HF patients without AF (1-year C-statistic 0.62, 95% CI 0.60-0.64; NPV 85.4%, 95% CI 83.4-87.4%) with similar predictive ability to those with AF (C-statistic 0.59, 95% CI 0.56-0.62; NPV 86.4%, 95% CI 82.6-90.2%). Among patients with HF, there was an increased risk of stroke, thromboembolism, and death with increasing CHA2DS2-VASc scores regardless of AF status. Our findings support the use of the CHA2DS2-VASc score as a prognostic tool in HF.

Published by Elsevier Inc.

Am J Cardiol: 13 Jul 2021; epub ahead of print
Marzouka GR, Rivner H, Mehta V, Lopez J, ... Ishwaran H, Goldberger JJ
Am J Cardiol: 13 Jul 2021; epub ahead of print | PMID: 34274114
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Abstract

Effect of Diabetes Mellitus on 30 and 90-Day Readmissions of Patients With Heart Failure.

Thyagaturu HS, Bolton AR, Li S, Kumar A, Shah KR, Katz D
The prevalence of diabetes mellitus (DM) in hospitalized heart failure (HF) patients is increasing over time. However, the effect of DM on short-term readmissions for HF is not well established. We investigated the effects of DM on readmissions of HF patients. All adult hospitalizations with a primary diagnosis of HF were identified in the National Readmission Database (NRD) for 2018 and were categorized into those with and without a secondary diagnosis of DM. The primary outcome was to assess risk difference in 30 and 90-day all-cause readmissions. Multivariate Cox survival analysis and multivariate Cox regression were performed to estimate the readmission risk difference in HF patients with and without DM. Of 925,637 HF hospitalizations that met the inclusion criteria, 441,295 (47.6%) had concomitant DM. Diabetics hospitalized for HF had higher prevalence of obesity (37.3% vs 19.5%), kidney disease (58.4% vs 29.2%) and coronary disease (61.1% vs 51.0%), compared to HF hospitalizations without DM. In adjusted analyses, DM was associated with higher hazards for all-cause [hazards ratio (HR), 30 days: 1.04 (1.02-1.06); 90 days: 1.07 (1.05-1.09)], HF [HR, 30 days: 1.05 (1.02-1.07); 90 days: 1.08 (1.05-1.10)] and myocardial infarction (MI) [HR, 30 days: 1.26 (1.12-1.41); 90 days: 1.38 (1.25-1.52)] readmissions. In conclusion, in patients with HF-related hospitalizations, the presence of DM was associated with a higher risk of 30 and 90-day all-cause, HF and MI readmissions.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jul 2021; epub ahead of print
Thyagaturu HS, Bolton AR, Li S, Kumar A, Shah KR, Katz D
Am J Cardiol: 14 Jul 2021; epub ahead of print | PMID: 34275590
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Impact:
Abstract

Prediction Model Using Machine Learning for Mortality in Patients with Heart Failure.

Negassa A, Ahmed S, Zolty R, Patel SR
Heart Failure (HF) is a major cause of morbidity and mortality in the US. With aging of the US population, the public health burden of HF is enormous. We aimed to develop an ensemble prediction model for 30-day mortality after discharge using machine learning. Using an electronic medical records (EMR) database, all patients with a non-elective HF admission over 10 years (January 2001 - December 2010) within the Montefiore Medical Center (MMC) health system, in the Bronx, New York, were included. We developed an ensemble model for 30-day mortality after discharge and employed discrimination, range of prediction, Brier index and explained variance as metrics in assessing model performance. A total of 7,516 patients were included. The discrimination achieved by the ensemble model was higher 0.83 (95% CI: 0.80 to 0.87) compared to the benchmark model 0.79 (95% CI: 0.75 to 0.84). The ensemble model also exhibited a better range of prediction as well as a favorable profile with respect to the other metrics employed. In conclusion, an ensemble machine learning approach exhibited an improvement in performance compared to the benchmark logistic model in predicting all-cause mortality among HF patients within 30-days of discharge. Machine learning is a promising alternative approach for risk profiling of HF patients, and it enhances individualized patient management.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Aug 2021; 153:86-93
Negassa A, Ahmed S, Zolty R, Patel SR
Am J Cardiol: 14 Aug 2021; 153:86-93 | PMID: 34246419
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Impact:
Abstract

Relation of Intravascular Volume Profiles to Heart Failure Progression and Clinical Outcomes.

Kelly KL, Wentz RJ, Johnson BD, Miller WL
Heart failure (HF) commonly progresses over time and identifying differences in volume profiles may help stratify risk and guide therapy. The aim of this study was to assess the pathophysiologic and prognostic roles of volume profiles for HF progression in stable ambulatory and hospitalized patients. HF patients who had undergone quantitative intravascular volume analysis (185 outpatients and 139 inpatients) were retrospectively assessed for the combined end point of HF-related hospital admissions (outpatients), HF-readmissions (inpatients), and overall all-cause mortality. After multivariate Cox regression analysis, greater total blood volume expansion was associated with higher risk of HF-admission in previously stable outpatients (HR: 1.023, CI 1.005 to 1.043; p = 0.013) while in more advanced HF (inpatients) total blood volume expansion was associated with lower risk for HF-readmission and mortality (HR: 0.982, CI 0.967 to 0.997; p = 0.017). Secondary analysis suggests that subclinical plasma volume expansion was a driving factor for the detrimental association in outpatients (HR: 1.018, CI 0.997 to 1.036; p = 0.054), while an increase in red blood cell mass was central to the beneficial association in advanced HF (HR: 0.979, CI 0.968 to 0.991; p <0.001). In conclusion, understanding differences in plasma volume and red blood cell mass profiles can provide insight into the pathophysiology and progression of HF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 28 Jun 2021; epub ahead of print
Kelly KL, Wentz RJ, Johnson BD, Miller WL
Am J Cardiol: 28 Jun 2021; epub ahead of print | PMID: 34215355
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Abstract

Role of Guideline Directed Medical Therapy Doses and Optimization in Patients Hospitalized With Decompensated Systolic Heart Failure.

Grewal D, Partow-Navid R, Garcia D, Coney J, ... Parwani P, Abramov D
Despite significant advances in evidence-based treatments for heart failure with reduced ejection fraction (HFrEF), the use of guideline directed medical therapy (GDMT) at recommended doses remains suboptimal. We examine the usage and modification of inpatient GDMT and its effect on outcomes in patients hospitalized with a diagnosis of acute on chronic HFrEF between 2013 and 2018. Overall use and modification of GDMT, which included heart failure appropriate beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and aldosterone blockers (MRA) during the hospitalization were collected. Target dosages were based on guideline recommendations. Primary endpoints included 30-day hospitalization-free survival and 1-year survival. Among 1,655 patients, discharge use of BB, RASi, and MRA was 73.4%, 55.9% and 13.8%, respectively. Upon discharge, ≥50% target dose of BB, RASi, and MRA was used in 25.3%, 15.6%, and 13.7%, respectively. In multivariable analyses, there was a statistically significant improvement in 1-year survival and 30-day hospitalization-free survival in patients discharged on increasing number of medication classes optimized at ≥50% target dose (per extra medication, HR 0.74, 0.64-0.86, p <0.001, and HR 0.73, 0.62-0.86, p = 0.0002), respectively. Initiation and/or uptitration of BB and RASi was associated with improved 30-day hospitalization-free survival and 1-year survival, (HR 0.73 (0.57-0.92), p = 0.0087; HR 0.62 (0.46-0.82), p <0.001) for BB and (HR 0.77 (0.62-0.95), p <0.001; HR 0.62 (0.48-0.80), p <0.001) for RASi, respectively. In conclusion, inpatient optimization of GDMT in acute HFrEF is feasible and associated with improved 30-day hospitalization-free survival and 1-year survival.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jul 2021; 151:64-69
Grewal D, Partow-Navid R, Garcia D, Coney J, ... Parwani P, Abramov D
Am J Cardiol: 14 Jul 2021; 151:64-69 | PMID: 34167690
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Abstract

Usefulness of Global Longitudinal Strain to Predict Heart Failure Progression in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

Rowin EJ, Maron BJ, Wells S, Burrows A, ... Patel AR, Maron MS
While predicting prognosis to anticipate adverse disease course has long been an aspiration in hypertrophic cardiomyopathy (HC), reliable markers of progressive and unrelenting heart failure symptoms in the absence of obstruction are not well characterized. We sought to evaluate markers of systolic function, including the role of global longitudinal strain (GLS), to identify nonobstructive HC patients at risk for future heart failure. A cohort of 296 consecutive nonobstructive HC patients (42 ± 18years; 75% male) with NYHA class I/II symptoms and preserved systolic function at study entry (EF: 65 ± 6%), were followed for progressive heart failure symptoms (increase in ≥ 1 NYHA functional class) and/or development of systolic dysfunction (EF < 50%). Over median follow-up of 4 ± 3 years, 35 study patients (10%) experienced new heart failure events, including 31 with progressive symptoms and 4 who developed systolic dysfunction. Abnormal GLS < 16% was associated with a 5-fold increase in risk for heart failure compared to GLS > 18% (p < 0.001). GLS remained an independent predictor of heart failure even after adjustment for other relevant disease variables including EF (OR 1.23, p = 0.005). However, notably, when GLS and EF were combined, the prediction of heart failure for individual patients was enhanced (net reclassification improvement 0.55; p = 0.002). Together, GLS < 16% and EF 50% to 59% were associated with a 12.5-fold greater risk for heart failure versus patients with GLS > 18% and EF ≥ 60%, who were at the lowest risk. In conclusion, in nonobstructive HC with no or mild symptoms and preserved EF, abnormal GLS is a strong independent predictor for subsequent development of progressive heart failure symptoms and/or systolic dysfunction. Furthermore, the greatest power in predicting outcome in nonobstructive HC is achieved by combining GLS with EF to identify HC patients at the highest risk for heart failure progression and systolic dysfunction.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jul 2021; 151:86-92
Rowin EJ, Maron BJ, Wells S, Burrows A, ... Patel AR, Maron MS
Am J Cardiol: 14 Jul 2021; 151:86-92 | PMID: 34167691
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Abstract

Advanced heart failure patients supported with ambulatory inotropic therapy: What defines success of therapy?

Grubb CS, Truby LK, Topkara VK, Bohnen MS, ... Naka Y, Farr M
Objective
The objective of this study was to describe the profiles and outcomes of a cohort of advanced heart failure patients on ambulatory inotropic therapy (AIT).
Background
With the growing burden of patients with end-stage heart failure, AIT is an increasingly common short or long-term option, for use as bridge to heart transplant (BTT), bridge to ventricular assist device (BTVAD), bridge to decision regarding advanced therapies (BTD) or as palliative care. AIT may be preferred by some patients and physicians to facilitate hospital discharge. However, counseling patients on risks and benefits is critically important in the modern era of defibrillators, durable mechanical support and palliative care.
Methods
We retrospectively studied a cohort of 241 patients on AIT. End points included transplant, VAD implantation, weaning of inotropes, or death. The primary outcomes were survival on AIT and ability to reach intended goal if planned as BTT or BTVAD. We also evaluated recurrent heart failure hospitalizations, incidence of ventricular arrhythmias (VT/VF) and indwelling line infections. Unintended consequences of AIT, such reaching unintended end point (e.g. VAD implantation in BTT patient) or worse than expected outcome after LVAD or HT, were recorded.
Results
Mean age of the cohort was 60.7 ± 13.2 years, 71% male, with Class III-IV heart failure (56% non-ischemic). Average ejection fraction was 19.4 ± 10.2%, pre-AIT cardiac index was 1.5 ± 0.4 L/min/m2 and 24% had prior ventricular arrhythmias. Overall on-AIT 1-year survival was 83%. Hospitalizations occurred in 51.9% (125) of patients a total of 174 times for worsening heart failure, line complication or ventricular arrhythmia. In the BTT cohort, only 42% were transplanted by the end of follow-up, with a 14.8% risk of death or delisting for clinical deterioration. For the patients who were transplanted, 1-year post HT survival was 96.7%. In the BTVAD cohort, 1-year survival after LVAD was 90%, but with 61.7% of patients undergoing LVAD as INTERMACS 1-2. In the palliative care cohort, only 24.5% of patients had a formal palliative care consult prior to AIT.
Conclusions
AIT is a strategy to discharge advanced heart failure patients from the hospital. It may be useful as bridge to transplant or ventricular assist device, but may be limited by complications such as hospitalizations, infections, and ventricular arrhythmias. Of particular note, it appears more challenging to bridge to transplant on AIT in the new allocation system. It is important to clarify the goals of AIT therapy upfront and continue to counsel patients on risks and benefits of the therapy itself and potential unintended consequences. Formalized, multi-disciplinary care planning is essential to clearly define individualized patient, as well as programmatic goals of AIT.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 30 Aug 2021; 239:11-18
Grubb CS, Truby LK, Topkara VK, Bohnen MS, ... Naka Y, Farr M
Am Heart J: 30 Aug 2021; 239:11-18 | PMID: 33984317
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Abstract

Sacubitril/valsartan versus enalapril on exercise capacity in patients with heart failure with reduced ejection fraction: A randomized, double-blind, active-controlled study.

Dos Santos MR, Alves MNN, Jordão CP, Pinto CEN, ... Negrão CE, Barretto ACP
Sacubitril/valsartan reduces mortality in patients with heart failure with reduced ejection fraction (HFrEF) when compared with enalapril. However, it is unknown the effect of both treatments on exercise capacity. We compared sacubitril/valsartan versus enalapril in patients with HFrEF based on peak oxygen consumption (VO2) and 6-minute walk test (6-MWT).
Methods
We included 52 participants with HFrEF with a left ventricular ejection fraction <40% to receive either sacubitril/valsartan (target dose of 400 mg daily) or enalapril (target dose of 40 mg daily). Peak VO2 was measured by using cardiopulmonary exercise testing. Six-minute walk test was also performed.
Results
At 12 weeks, the sacubitril/valsartan (mean dose 382.6 ± 57.6 mg daily) group had increased peak VO2 of 13.1% (19.35 ± 0.99 to 21.89 ± 1.04 mL/kg/min) and enalapril (mean dose 34.4 ± 9.2 mg daily) 5.6% (18.58 ± 1.19 to 19.62 ± 1.25 mL/kg/min). However, no difference was found between groups (P = .332 interaction). At 24 weeks, peak VO2 increased 13.5% (19.35 ± 0.99 to 21.96 ± 0.98 mL/kg/min) and 12.0% (18.58 ± 1.19 to 20.82 ± 1.18 mL/kg/min) in sacubitril/valsartan (mean dose 400 ± 0 mg daily) and enalapril (mean dose 32.7 ± 11.0 mg daily), respectively. However, no differences were found between groups (P= .332 interaction). At 12 weeks, 6-MWT increased in both groups (sacubitril/valsartan: 459 ± 18 to 488 ± 17 meters [6.3%] and enalapril: 443 ± 22 to 477 ± 21 meters [7.7%]). At 24 weeks, sacubitril/valsartan increased 18.3% from baseline (543 ± 26 meters) and enalapril decreased slightly to 6.8% (473 ± 31 meters), but no differences existed between groups (P= .257 interaction).
Conclusions
Compared to enalapril, sacubitril/valsartan did not substantially improve peak VO2 or 6-MWT after 12 or 24 weeks in participants with HFrEF. (NEPRIExTol-HF Trial, ClinicalTrials.gov number, NCT03190304).

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 30 Aug 2021; 239:1-10
Dos Santos MR, Alves MNN, Jordão CP, Pinto CEN, ... Negrão CE, Barretto ACP
Am Heart J: 30 Aug 2021; 239:1-10 | PMID: 33992607
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Abstract

Usefulness of Left Atrial Strain to Predict End Stage Renal Failure in Patients With Chronic Kidney Disease.

Gan GCH, Bhat A, Kadappu KK, Fernandez F, ... Nankivell B, Thomas L
Left atrial (LA) enlargement predicts adverse cardiovascular events in patients with chronic kidney disease (CKD). The aim of our study was to evaluate the value of LA reservoir strain, a novel measure of LA function, as a prognostic marker for adverse renal outcomes. A total of 280 patients (65.8 ± 12.2years, 63% male) with stable Stage 3 and 4 CKD without prior cardiac history were evaluated with transthoracic echocardiography and prospectively followed for up to 5 years. The primary end point was progressive renal failure, which was the composite of death from renal cause, end-stage renal failure and/or doubling of serum creatinine. Over a mean follow up of 3.9 ± 2.7years, 56 patients reached the composite endpoint. By log rank test, older age, lower baseline eGFR, anemia, diabetes mellitus, higher urinary albumin/creatinine ratio, number of antihypertensive medications, higher indexed left ventricular mass, larger LA volumes, and impaired LA reservoir strain were significant predictors of the composite outcome (p <0.01 for all). Multi-variable Cox regression analysis found LA reservoir strain, eGFR, number of antihypertensive medications and urinary albumin/creatinine ratio were independent predictors for progressive renal failure (p <0.01 for all). Impaired LA reservoir strain was associated with a 2.5-fold higher risk of the composite outcome (HR 2.51, 95% CI 1.19 to 5.30, p = 0.02) and was the only echocardiographic parameter that predicted progressive renal failure independent of established clinical risk factors for end-stage renal failure. Its utility requires validation in high risk CKD patients with cardiac disease.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jul 2021; 151:105-113
Gan GCH, Bhat A, Kadappu KK, Fernandez F, ... Nankivell B, Thomas L
Am J Cardiol: 14 Jul 2021; 151:105-113 | PMID: 34049674
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Impact:
Abstract

Early diuretic strategies and the association with In-hospital and Post-discharge outcomes in acute heart failure.

Fudim M, Spates T, Sun JL, Kittipibul V, ... O\'Connor CM, Mentz RJ
Background
Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies.
Methods
This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment.
Results
Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P <0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P <0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P >0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832).
Conclusion
In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 30 Aug 2021; 239:110-119
Fudim M, Spates T, Sun JL, Kittipibul V, ... O'Connor CM, Mentz RJ
Am Heart J: 30 Aug 2021; 239:110-119 | PMID: 34052212
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Impact:
Abstract

New Heart Failure After Myocardial Infarction (From the National Cardiovascular Data Registries [NCDR] Linked With All-Payer Claims).

Faridi KF, Bhalla N, Atreja N, Venditto J, ... Yeh RW, Secemsky EA
Heart failure (HF) is common in patients presenting with acute myocardial infarction (MI), but incidence and predictors of new onset HF after hospitalization for MI are less well characterized. We evaluated patients hospitalized for acute MI without preceding or concurrent HF in the National Cardiovascular Data Registry (NCDR) CathPCI and Chest Pain-MI registries linked with claims data between April 2010 and March 2017. Cumulative incidence and independent predictors of HF after discharge were determined, and a simplified risk score was developed to predict incident HF following MI. In 337,274 patients with acute MI and no history of HF, 8.0% developed incident HF within 1 year after discharge and 18.8% developed HF within 5 years. Significant predictors of HF after MI included advanced chronic kidney disease (CKD) (HR 2.34, 95% confidence interval [CI] 2.23-2.46 for Stage IV vs Stage I, and HR 2.18, 95% CI 2.07-2.29 for Stage V vs. Stage I), recurrent MI following index MI (HR 2.24, 95% CI 2.19-2.28), African-American race (HR 1.44, 95% CI 1.40-1.48), and diabetes (HR 1.39, 95% CI 1.37-1.42). A risk score of 8 variables predicted HF with modest discrimination (optimism-corrected c-statistic 0.64) and good calibration. In conclusion, nearly 1 in 5 patients in a large nationally representative cohort without preceding or concurrent heart failure at time of MI developed incident HF within 5 years after discharge. Advanced CKD and recurrent MI were the strongest predictors of future HF. Increased recognition of specific risk factors for HF may help inform care strategies following MI.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jul 2021; 151:70-77
Faridi KF, Bhalla N, Atreja N, Venditto J, ... Yeh RW, Secemsky EA
Am J Cardiol: 14 Jul 2021; 151:70-77 | PMID: 34053629
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Abstract

The Additive Prognostic Value of Serial Plasma Interleukin-6 Levels over Changes in Brain Natriuretic Peptide in Patients with Acute Heart Failure.

Markousis-Mavrogenis G, Tromp J, Mentz RJ, O\'Connor CM, ... Voors AA, van der Meer P
Background
Elevated plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure (AHF). However, the predictive value of serial IL-6 measurements beyond brain natriuretic peptide (BNP) remains poorly characterized.
Methods and results
This was a retrospective analysis of the PROTECT cohort (2033 patients with AHF). Plasma IL-6 and BNP levels were determined on days 1, 2, 7 and 14 after admission for AHF in 1591 (78.3%), 1462 (71.9%), 1445 (71.1%) and 1451 (71.4%) patients, respectively. The primary endpoint was 180-day all-cause mortality. The median day-1 IL-6 concentration was 11.1 pg/mL (IQR: 6.6, 20.9) and decreased to 10.1 pg/mL (IQR: 5.6-18.5) at day-7. Higher cross-sectional IL-6 concentrations at all time-points predicted the primary endpoint, independent of a risk model for this cohort and changes in BNP. Each doubling of IL-6 between day-1 and day-7 predicted the primary endpoint independent of baseline IL-6 concentrations, the risk model, baseline BNP and changes in BNP [HR (95% CI): 1.18 (1.07-1.30), p=0.0013]. Collectively, 214 (17%) patients experienced at least a doubling of their IL-6 concentrations between day-1 and day-7.
Conclusions
We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:808-811
Markousis-Mavrogenis G, Tromp J, Mentz RJ, O'Connor CM, ... Voors AA, van der Meer P
J Card Fail: 29 Jun 2021; 27:808-811 | PMID: 33497808
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Abstract

Generalizability of HFA-PEFF and HFPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF.

Faxen UL, Venkateshvaran A, Shah SJ, Lam CSP, ... Hage C, Lund LH
Background
Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers.
Methods and results
Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis.
Conclusions
Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:756-765
Faxen UL, Venkateshvaran A, Shah SJ, Lam CSP, ... Hage C, Lund LH
J Card Fail: 29 Jun 2021; 27:756-765 | PMID: 33647474
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Abstract

Dynamic Assessment of Pulmonary Artery Pulsatility Index Provides Incremental Risk Assessment for Early Right Ventricular Failure After Left Ventricular Assist Device.

Gonzalez MH, Wang Q, Yaranov DM, Albert C, ... Starling RC, Joyce E
Background
The pulmonary artery pulsatility index (PAPi) has been studied to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation, but only as a single time point before LVAD implantation. Multiple clinical factors and therapies impact RV function in pre-LVAD patients. Thus, we hypothesized that serial PAPi measurements during cardiac intensive care unit (CICU) optimization before LVAD implantation would provide incremental risk stratification for early RVF after LVAD implantation.
Methods and results
Consecutive patients who underwent sequential pulmonary artery catherization with cardiac intensive care optimization before durable LVAD implantation were included. Serial hemodynamics were reviewed retrospectively across the optimization period. The optimal PAPi was defined by the initial PAPi + the PAPi at optimized hemodynamics. RVF was defined as need for a right ventricular assist device or prolonged inotrope use (>14 days postoperatively). Patients with early RVF had significantly lower mean optimal PAPi (3.5 vs 7.5, P < .001) compared with those who did not develop RVF. After adjusting for established risk factors of early RVF after LVAD implantation, the optimal PAPi was independently and incrementally associated with early RVF after LVAD implantation (odds ratio 0.64, 95% confidence interval 0.532-0.765, P < .0001).
Conclusions
Optimal PAPi achieved during medical optimization before LVAD implantation provides independent and incremental risk stratification for early RVF, likely identifying dynamic RV reserve.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:777-785
Gonzalez MH, Wang Q, Yaranov DM, Albert C, ... Starling RC, Joyce E
J Card Fail: 29 Jun 2021; 27:777-785 | PMID: 33640481
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Abstract

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates.

Sammour Y, Dezorzi C, Austin BA, Borkon AM, ... Kao AC, Sperry BW
Background
Statins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation.
Methods and results
We identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8-9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8-3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102-148 mg/dL) to 55 mg/dL (IQR, 35-74 mg/dL) after starting PCSK9i (P < .001), with 72% of patients achieving a low-density lipoprotein cholesterol of <70 mg/dL after treatment. There were also significant reductions of total cholesterol, non-high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area.
Conclusions
Among heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:812-815
Sammour Y, Dezorzi C, Austin BA, Borkon AM, ... Kao AC, Sperry BW
J Card Fail: 29 Jun 2021; 27:812-815 | PMID: 33753241
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Abstract

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea.

Martens P, Claessen G, Van De Bruaene A, Verbrugge FH, ... Dendale P, Verwerft J
Background
Iron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.
Methods and results
Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s\' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV-pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm2 vs 2.58 ± 1.14 mm Hg/cm2; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e\' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.
Conclusions
In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:766-776
Martens P, Claessen G, Van De Bruaene A, Verbrugge FH, ... Dendale P, Verwerft J
J Card Fail: 29 Jun 2021; 27:766-776 | PMID: 33838251
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Abstract

Associations of Angiopoietins With Heart Failure Incidence and Severity.

Peplinski BS, Houston BA, Bluemke DA, Kawut SM, ... Tedford RJ, Leary PJ
Background
Angiopoietin-1 and 2 (Ang1, Ang2) are important mediators of angiogenesis. Angiopoietin levels are perturbed in cardiovascular disease, but it is unclear whether angiopoietin signaling is causative, an adaptive response, or merely epiphenomenon of disease activity.
Methods and results
In a cohort free of cardiovascular disease at baseline (Multi-Ethnic Study of Atherosclerosis [MESA]), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension or left heart disease, associations between angiopoietins, invasive hemodynamics, and adverse clinical outcomes were evaluated. In MESA, Ang2 was associated with a higher incidence of heart failure or cardiovascular death (hazard ratio 1.21 per standard deviation, P < .001). Ang2 was associated with increased right atrial pressure (pulmonary arterial hypertension cohort) and increased wedge pressure and right atrial pressure (left heart disease cohort). Elevated Ang2 was associated with mortality in the pulmonary arterial hypertension cohort.
Conclusions
Ang2 was associated with incident heart failure or death among adults without cardiovascular disease at baseline and with disease severity in individuals with existing heart failure. Our finding that Ang2 is increased before disease onset and that elevations reflect disease severity, suggests Ang2 may contribute to heart failure pathogenesis.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:786-795
Peplinski BS, Houston BA, Bluemke DA, Kawut SM, ... Tedford RJ, Leary PJ
J Card Fail: 29 Jun 2021; 27:786-795 | PMID: 33872759
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Abstract

Profile of Patients Hospitalized for Heart Failure Who Leave Against Medical Advice.

Mitchell JE, Chesler R, Zhang S, Matsouaka RA, ... Chang NL, Fonarow GC
Background
There is a paucity of information on patients hospitalized with heart failure (HF) who leave against medical advice (AMA). We sought to identify patient and hospital characteristics and outcomes of patients with HF who left AMA compared with those conventionally discharged to home.
Methods and results
Using the Get With The Guidelines-Heart Failure registry, data were analyzed from January 2010 to June 2019. In addition, outcomes were examined from a subset of hospitalizations with Medicare-linked claims between January 2010 and November 2015. The fully eligible population included 561,823 patients and the Medicare-linked subset included 74,502 patients. In total, 8747 patients (1.56%) left AMA. The proportion of patients leaving AMA increased from 1.1% to 2.1% over the years of study. Patients leaving a HF hospitalization AMA, compared with patients conventionally discharged to home, were more likely younger, minorities, Medicaid covered, or uninsured. The Medicare-linked subset of patients who left AMA had substantially higher 30-day and 12-month readmission rates and higher mortality at each assessment point over 12 months compared with patients who were conventionally discharged to home. After risk adjustments, the hazard ratio of mortality in the Medicare-linked subset AMA group compared with the conventionally discharged to home group was 1.25 (95% confidence interval, 1.03-1.51; P = .005).
Conclusions
One in 64 hospitalized patients with HF left AMA. An AMA discharge status was associated with higher risk for adverse 30-day and 12-month outcomes compared with being conventionally discharged home. Strategies that identify patients at risk of leaving AMA and policies to direct interventional strategies are warranted.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:747-755
Mitchell JE, Chesler R, Zhang S, Matsouaka RA, ... Chang NL, Fonarow GC
J Card Fail: 29 Jun 2021; 27:747-755 | PMID: 33864931
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Abstract

Cardiac Thyrotropin-releasing Hormone Inhibition Improves Ventricular Function and Reduces Hypertrophy and Fibrosis After Myocardial Infarction in Rats.

Schuman ML, Peres Diaz LS, Aisicovich M, Ingallina F, ... Landa MS, García SI
Background
Cardiac thyrotropin-releasing hormone (TRH) is a tripeptide with still unknown functions. We demonstrated that the left ventricle (LV) TRH system is hyperactivated in spontaneously hypertensive rats and its inhibition prevented cardiac hypertrophy and fibrosis. Therefore, we evaluated whether in vivo cardiac TRH inhibition could improve myocardial function and attenuate ventricular remodeling in a rat model of myocardial infarction (MI).
Methods and results
In Wistar rats, MI was induced by a permanent left anterior descending coronary artery ligation. A coronary injection of a specific small interfering RNA against TRH was applied simultaneously. The control group received a scrambled small interfering RNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049 ± 0.102 mL vs 1.339 ± 0.102 mL, P < .05), and end-systolic volumes (0.282 ± 0.043 mL vs 0.515 ± 0.037 mL, P < .001), and increased LV ejection fraction (71.89 ± 2.80% vs 65.69 ± 2.85%, P < .05). Although both MI groups presented similar infarct size, small interfering RNA against TRH treatment attenuated the cardiac hypertrophy index and myocardial interstitial collagen deposition in the peri-infarct myocardium. These effects were accompanied by attenuation in the rise of transforming growth factor-β, collagen I, and collagen III, as well as the fetal genes (atrial natriuretic peptide, B-type natriuretic peptide, and beta myosin heavy chain) expression in the peri-infarct region. In addition, the expression of Hif1α and vascular endothelial growth factor significantly increased compared with all groups.
Conclusions
Cardiac TRH inhibition improves LV systolic function and attenuates ventricular remodeling after MI. These novel findings support the idea that TRH inhibition may serve as a new therapeutic strategy against the progression of heart failure.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Jun 2021; 27:796-807
Schuman ML, Peres Diaz LS, Aisicovich M, Ingallina F, ... Landa MS, García SI
J Card Fail: 29 Jun 2021; 27:796-807 | PMID: 33865967
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Impact:
Abstract

Pericardial Adipose Tissue Volume and Left Ventricular Assist Device-Associated Outcomes.

Rao VN, Obeid MJ, Rigiroli F, Russell SD, ... Agarwal R, Fudim M
Background
Pericardial adipose tissue (PAT) is associated with adverse cardiovascular outcomes in those with and without established heart failure (HF). However, it is not known whether PAT is associated with adverse outcomes in patients with end-stage HF undergoing LVAD. This study aimed to evaluate the associations between PAT and LVAD-associated outcomes.
Methods and results
We retrospectively measured computed tomography (CT)-derived PAT volumes in 77 consecutive adults who had available chest CT imaging prior to HeartMate 3 LVAD surgery between October 2015-March 2019 at Duke University Hospital. Study groups were divided into above-median (≥219cm3) and below-median (<219cm3) PAT volume. Above-median PAT had a higher proportion of atrial fibrillation, chronic kidney disease, and ischemic cardiomyopathy. Above-median vs. below-median PAT groups had similar Kaplan-Meier incidence rates over two years for 1) composite all-cause mortality, redo-LVAD surgery, and cardiac transplantation (35.9 vs. 32.2%; log-rank p=0.65) and 2) composite incident hospitalizations for HF, gastrointestinal bleeding, LVAD-related infection, and stroke (61.5 vs. 60.5%; log-rank p=0.67).
Conclusions
In patients with end-stage HF undergoing LVAD therapy, PAT is not associated with worse two-year LVAD-related outcomes. The significance of regional adiposity versus obesity in LVAD patients warrants further investigation.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 14 Jul 2021; epub ahead of print
Rao VN, Obeid MJ, Rigiroli F, Russell SD, ... Agarwal R, Fudim M
J Card Fail: 14 Jul 2021; epub ahead of print | PMID: 34274515
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Abstract

Prognostic Role of Cardiopulmonary Exercise Testing in Wild Type Transthyretin Amyloid Cardiomyopathy Patients Treated with Tafamidis.

Dalia T, Acharya P, Chan WC, Sauer AJ, ... Porter CB, Shah Z
Background
Prognostic value of cardiopulmonary exercise test (CPET) in wild type transthyretin cardiac amyloidosis (wtATTR) patients treated with Tafamidis is unknown.
Methods
This is a retrospective study of wtATTR patients who underwent baseline CPET and were treated with Tafamidis from 8/31/2018 until 3/31/2020. Univariate logistic and multivariate cox-regression models were used to predict occurrence of primary outcome (composite of mortality, heart transplant and palliative inotrope initiation).
Results
A total of 33 patients were included (median age of 82 years (IQR,79-84), 84% were Caucasians and 79% were males). Majority of patients were NYHA class III at baseline (67%). Baseline median peak oxygen consumption (VO2) and peak circulatory power (CP) were 11.35 (IQR, 8.5-14.2) ml/kg/min and 1485.8 (IQR, 988-2184) mmHg/ml/min, respectively, median VE/VCO2 (Ventilatory efficiency) was 35.7 (IQR, 31-41.2). After 1 year follow up, 11 patients experienced a primary endpoint. Upon multivariate analysis; peak VO2 [HR 0.43 (0.23-0.79), p=0.007], peak CP [HR 0.98 (0.98-0.99), p=0.02], peak VO2/HR (Oxygen pulse) [HR 0.62 (0.39-0.97), p=0.03] and exercise duration >5.5 mins [HR 5.82 (1.29-26.2), p=0.02] were significantly associated with the primary outcome.
Conclusion
Tafamidis treated wtATTR patients who had baseline low peak VO2, peak CP, peak VO2/HR and exercise duration <5.5 minutes had worse outcomes.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 15 Jul 2021; epub ahead of print
Dalia T, Acharya P, Chan WC, Sauer AJ, ... Porter CB, Shah Z
J Card Fail: 15 Jul 2021; epub ahead of print | PMID: 34280522
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Abstract

Right Heart Dysfunction and Readmission Risk across Left Ventricular Ejection Fraction Status in Patients with Acute Heart Failure.

Santas E, Miñana G, Palau P, Espriella R, ... Bayes-Genís A, Núñez J
Background
Right heart dysfunction (RHD) parameters are increasingly important in heart failure (HF). This study aimed to evaluate the association of advanced RHD with the risk of recurrent admissions across the spectrum of left ventricular ejection fraction (LVEF).
Methods and results
We included 3,383 consecutive patients discharged for acute HF (AHF). Of them, in 1,435 (42.4%) pulmonary artery systolic pressure (PASP) could not be accurately measured, leaving a final sample size of 1,948 patients. Advanced RHD was defined as the combination of a ratio of tricuspid annular plane systolic excursion (TAPSE)/PASP<0.36 and significant tricuspid regurgitation (n=196, 10.2%). Negative binomial regression analyses were used to evaluate the risk of recurrent admissions. At a median follow up of 2.2 years (IQR=0.63-4.71), 3,782 readmissions were registered in 1,296 patients (66.5%). Patients with advanced RHD showed higher readmission rates, but only if LVEF≥40% (p<0.001). In multivariable analyses, this differential association persisted for CV and HF recurrent admissions (p-value for interaction=0.015 and p=0.016; respectively). Advanced RHD was independently associated with the risk of recurrent CV and HF admissions if HF with LVEF≥40% (IRR=1.64; 95% CI: 1.18-2.26; p=0.003; and IRR=1.73; 95% CI: 1.25-2.41; p=0.001;respectively). In contrast, it was not associated with readmission risks if LVEF<40%.
Conclusion
Following an admission for AHF, advanced RHD was strongly associated with a higher risk of recurrent CV and HF admissions, but only in patients with LVEF≥40%.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 13 Jul 2021; epub ahead of print
Santas E, Miñana G, Palau P, Espriella R, ... Bayes-Genís A, Núñez J
J Card Fail: 13 Jul 2021; epub ahead of print | PMID: 34273477
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Abstract

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

Seferović PM, Tsutsui H, Mcnamara DM, Ristić AD, ... Coats AJS, Starling RC
Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 29 Jun 2021; 27:727-743
Seferović PM, Tsutsui H, Mcnamara DM, Ristić AD, ... Coats AJS, Starling RC
J Card Fail: 29 Jun 2021; 27:727-743 | PMID: 34022400
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Impact:
Abstract

Representativeness of the VICTORIA Trial Population in Clinical Practice: Analysis of the PINNACLE Registry.

Butler J, Djatche LM, Lautsch D, Yang L, Patel MJ, Mentz RJ
Background
. In the VICTORIA trial, vericiguat reduced the risk of cardiovascular mortality and heart failure (HF) hospitalization among patients with heart failure with reduced ejection fraction (HFrEF) and a recent worsening heart failure event (WHFE). The representativeness of VICTORIA population to patients with WHFE in clinical practice is unknown.
Methods and results
. Patients with HF and ejection fraction <45% were identified in the PINNACLE registry and stratified by the occurrence of WHFE. Characteristics and outcomes of PINNACLE patients with and without a WHFE were compared to the VICTORIA population. Of the 14,180 PINNACLE patients with HFrEF identified, 26.5% had a WHFE. The VICTORIA population was similar to PINNACLE patients with a WHFE in mean age (67.3 vs. 66.7), ejection fraction (28.9% vs. 28.3%), body mass index (26.8 vs. 27.6), and comorbidity burden. The rate of HF hospitalization at 1 year was 29.6% in the placebo group of VICTORIA, compared to 35.8% in PINNACLE patients with a WHFE and 13.3% in patients without a WHFE.
Conclusions
. The PINNACLE patients with a WHFE meeting the VICTORIA definition resembled the VICTORIA population in characteristics and outcomes, suggesting that VICTORIA\'s population may be generalizable to patients with a WHFE in clinical practice.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 12 Jul 2021; epub ahead of print
Butler J, Djatche LM, Lautsch D, Yang L, Patel MJ, Mentz RJ
J Card Fail: 12 Jul 2021; epub ahead of print | PMID: 34271161
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Abstract

Use of Outpatient Intravenous Calcitropes for Heart Failure in the United States.

Gottlieb SS, Psotka MA, Desai N, Lindenfeld J, Russo P, Allen LA
Rationale
Outpatient calcitrope infusions-i.e., cardiac inotropes milrinone and dobutamine-are often used for bridge-to-transplantation and palliation in advanced heart failure, but few data exist about real world use of these agents.
Methods and results
We used the Symphony Integrated DataVerse® of commercial, managed Medicare, and Medicaid insurance claims of approximately 280 million people (2012- 2020) to determine the incidence and characteristics of ambulatory calcitrope use. Demographics were calculated, including geographic densities at the Metropolitan Statistical Area level. A population projection normalized for age, sex, and location was extrapolated to the total US population. Ambulatory dispensing of milrinone was found in 10,533 outpatients, 1867 in 2019. Ambulatory dobutamine use was found in 4967 outpatients, 836 in 2019. The 2019 total U.S. projection was 3411 for milrinone and 1281 for dobutamine. The mean age was 62 years for milrinone and 68 for dobutamine. Males represented 70% of use. There were differences between drugs in geographic distribution, with more milrinone use in the Northeast and South and more dobutamine use in the Midwest. Duration of use was 4.6 ± 7.2 months for milrinone and 1.8 ± 4.0 months for dobutamine. 30.6% of patients receiving milrinone subsequently underwent cardiac transplantation or LVAD placement whereas 10% receiving dobutamine went on to advanced therapies. Less than 0.5% of patients received calcitropes while enrolled in hospice care.
Conclusion
More than 4000 patients receive outpatient infusion of calcitropes annually in the outpatient setting. Men are much more likely to receive these medications. A minority of the use is as a bridge to advanced therapies. Geographic variability in use suggests better evidence and consistent guidelines may be helpful.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 11 Jul 2021; epub ahead of print
Gottlieb SS, Psotka MA, Desai N, Lindenfeld J, Russo P, Allen LA
J Card Fail: 11 Jul 2021; epub ahead of print | PMID: 34265464
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Impact:
Abstract

Additional diagnostic value of cardiac magnetic resonance feature tracking in patients with biopsy-proven arrhythmogenic cardiomyopathy.

Muscogiuri G, Fusini L, Ricci F, Sicuso R, ... Guaricci AI, Pontone G
Background
We aim to evaluate the value of Cardiac magnetic resonance (CMR) feature tracking (CMR-FT) in addition to Task Force Criteria(TFC) in patients with (arrhythmogenic cardiomyopathy) AC biopsy-proved.
Methods
Thirty-five patients with AC histologically proven who performed CMR with late gadolinium enhancement (LGE) acquisition were enrolled. The study population was divided in Group1 (negative CMR TFC and LV ejection fraction≥55%) and Group2 (positive CMR TFC and/or LVEF<55%) and compared to an age and gender-matched control group. CMR datasets of all patients were analyzed to calculate LV indexed end-diastolic (LVEDi) and end-systolic (LVESi) volumes and RV indexed end-diastolic (RVEDi) and end-systolic (RVESi) volumes, both LV ejection fraction (LVEF) and RV ejection fraction (RVEF). Moreover, LV and RV global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain were measured.
Results
The AC patients showed both higher LVEDi (p:0.002) and RVEDi (p:0.017) and lower LVEF (p: 0.016) as compared to control patients. Moreover, AC patients showed impaired LV-GLS (p < 0.001), LV-GRS (p < 0.001), LV-GCS (p < 0.001) and RV-GRS (p:0.026) as compared to control subjects. Group1 patients showed a significant reduction of LV-GRS (p < 0.05) and LV-GCS p < 0.01) as compared to control subjects. At univariate analysis LV-GCS was the most discriminatory parameter between Group1 vs heathy subjects with an optimal cut-off of -15.8 (Sensitivity: 74%; Specificity: 10%).
Conclusions
In patients with AC biopsy-proven, CMR-FT could improve the diagnostic yield in the subset of patients who results negative for imaging TFC criteria resulting as useful gatekeeper for indication of myocardial biopsy in case of equivocal clinical and imaging presentation.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 06 Jul 2021; epub ahead of print
Muscogiuri G, Fusini L, Ricci F, Sicuso R, ... Guaricci AI, Pontone G
Int J Cardiol: 06 Jul 2021; epub ahead of print | PMID: 34242689
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Impact:
Abstract

US Nationwide Prescription Fill Patterns of Evidence-Based Medical Therapies for Heart Failure During the COVID-19 Pandemic.

Vaduganathan M, Li D, van Meijgaard J, Warraich HJ
Background
Maintaining a steady medication supply during a public health crisis is a major health priority. We leveraged a large US pharmacy claims database to understand utilization of evidence-based therapies used in heart failure (HF) care during the coronavirus disease-2019 (COVID-19) pandemic.
Methods
We analyzed 27,027,650 individual claims from an all-payer pharmacy claims database across 56,155 chain, independent, and mail-order pharmacies in 14,164 zip codes in 50 states. Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 were indexed to comparable timeframes in 2019. We normalized these year-over-year changes in HF medical therapies relative to those observed with a stable basket of drugs.
Results
Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends towards increased relative use during 2020. Fills of empagliflozin (+75%), dapagliflozin (+65%), and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-over-year trends of the overall basket of drugs. For all 3 therapies, fills of all quantity sizes relatively increased throughout 2020. For both generic and brand-name therapies, prescription fill patterns from mail order pharmacies increased substantially over expected trends beginning in March 2020
Conclusion:
Prescription fills of most established generic therapies used in HF care were maintained, while those of sacubitril/valsartan and the sodium-glucose cotransporter-2 inhibitors steeply increased during the COVID-19 pandemic. These nationwide pharmacy claims data provide reassurance about therapeutic access to evidence-based medications used in HF care during a public health crisis.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 27 Jun 2021; epub ahead of print
Vaduganathan M, Li D, van Meijgaard J, Warraich HJ
J Card Fail: 27 Jun 2021; epub ahead of print | PMID: 34214650
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Impact:
Abstract

The potential roles of osmotic and non-osmotic sodium handling in mediating effects of SGLT2 inhibitors on heart failure.

Bjornstad P, Greasley PJ, Wheeler DC, Chertow GM, ... Heerspink HJL, van Raalte DH
Concomitant type 2 diabetes and chronic kidney disease (CKD) increases the risk of heart failure (HF). Recent STUDIES: demonstrate beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on CKD progression and HF hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2i reduce proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2i\'s natriuretic and osmotic diuretic effects mediate their cardio-protective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2i could also modulate non-osmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional two-compartment model of sodium balance to provide support for a three-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on non-osmotic sodium storage, as well as direct cardiac effects of SGLT2i, provides possibilities for other ways in which SGLT2i might mitigate HF risk. Overall, we review the effects of SGLT2i on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and non-osmotic sodium storage.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 17 Jul 2021; epub ahead of print
Bjornstad P, Greasley PJ, Wheeler DC, Chertow GM, ... Heerspink HJL, van Raalte DH
J Card Fail: 17 Jul 2021; epub ahead of print | PMID: 34289398
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Impact:
Abstract

Routine Use of Contrast at Admission Transthoracic Echocardiogram for Heart Failure Reduces the Rate of Repeat Echocardiograms During Index Admission.

Lee KC, Liu S, Callahan P, Green T, ... Flueckiger P, Vannan MA
Background
We retrospectively evaluated the impact of UEA use in the first TTE, regardless of the baseline image quality, on the number of repeat TTEs and length of stay (LOS) during a HF admission.
Methods
There were 9,115 HF admissions associated with an admission TTE over a 4 year period (5,337 men; mean age 67.6 ± 15.0 years). Patients were grouped into those who received a UEA (contrast group) in the first TTE and those who did not (non-contrast group). Repeat TTEs were classified as justified if performed for concrete clinical indications during hospitalization.
Results
In the 9,115 admissions for HF (n = 5,600 contrast group, 3,515 non-contrast group) 927 patients had repeat TTEs (n = 505 contrast group, 422 non-contrast group), which was considered justified in 823 patients. Of the 104 patients who had unjustified repeat TTEs, 80 belonged to the non-contrast group (76.7%) and 24 belonged to the contrast group. Also, UEA usage increased from 50.4% in 2014 to 74.3%, and the rate of unjustified repeats decreased from 1.3% to 0.9%. The rates of unjustified repeat TTE were 2.3% and 0.4% (non-contrast and contrast groups, respectively), and patients in the contrast group were less likely to receive an unjustified repeat echo (OR = 0.18, 95% CI: 0.12 to 0.29, p < 0.0001). The mean LOS was significantly lower in the contrast group (9.5 ± 10.5 days versus 11.1 ± 13.7 days). The use of UEA in the first TTE was also associated with a reduced LOS (linear regression, β1 = -0.47, p = 0.036), with 20% lower odds for odds of prolonged (>6 days) LOS.
Conclusions
The routine use of UEA in the first TTE for HF irrespective of image quality is associated with reduced unjustified repeat TTE testing and may reduce LOS during an index HF admission.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 16 Jul 2021; epub ahead of print
Lee KC, Liu S, Callahan P, Green T, ... Flueckiger P, Vannan MA
J Am Soc Echocardiogr: 16 Jul 2021; epub ahead of print | PMID: 34284098
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Impact:
Abstract

Hemodynamic changes during transcatheter atrial septal defect closure predict midterm heart failure deterioration in adults.

Yamamoto H, Shinke T, Otake H, Terashita D, ... Tanaka H, Hirata KI
Objectives
To investigate whether hemodynamic changes during balloon occlusion test (BOT) predict future heart failure (HF) deterioration after transcatheter atrial septal defect closure (tASD-closure).
Background
Midterm HF deterioration can sometimes occur after tASD-closure in adults. Whether hemodynamic changes during tASD-closure can help identify patients at risk is unknown.
Methods
This prospective observational study enrolled 86 consecutive adult patients who underwent tASD-closure. Hemodynamic parameters, including pulmonary capillary wedge pressure (PCWP), were measured at baseline, during BOT, and after tASD-closure. The changes in PCWP during BOT and after tASD-closure were defined as ΔPCWP (Occ-Pre) and ΔPCWP (Post-Pre), respectively. Clinical parameters were evaluated before tASD-closure and during the 3-month follow-up. We assessed the occurrence of HF deterioration (HF requiring hospitalization or additional diuretics) during a 2-year follow-up period and categorized patients into HF (+) and HF (-) groups accordingly. The aforementioned parameters were compared between groups.
Results
Midterm HF deterioration occurred in 12 patients (13.9%). Compared to the HF (-) group, the HF (+) group presented a significantly higher ΔPCWP (Occ-Pre) (9.5 ± 4.4 mmHg vs. 3.0 ± 3.3 mmHg; p < 0.001) and ΔPCWP (Post-Pre) (4.0 ± 2.8 mmHg vs. 0.6 ± 1.8 mmHg; p = 0.004). Receiver operating characteristic curve analysis showed that the ΔPCWP (Occ-Pre) cutoff value of 5.5 mmHg had excellent ability to predict HF deterioration (Area under the curve 0.886 [0.779-0.993], p < 0.001; sensitivity 0.917, specificity 0.824).
Conclusions
Increases in PCWP during BOT predict midterm HF deterioration after tASD-closure. Close surveillance may be needed in patients with a ΔPCWP (Occ-Pre) >5 mmHg.

© 2021 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 05 Jul 2021; epub ahead of print
Yamamoto H, Shinke T, Otake H, Terashita D, ... Tanaka H, Hirata KI
Catheter Cardiovasc Interv: 05 Jul 2021; epub ahead of print | PMID: 34227726
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Impact:
Abstract

Contributions of cardiac dysfunction and volume status to central haemodynamics in chronic heart failure.

Miller WL, Sorimachi H, Grill DE, Fischer K, Borlaug BA
Aims
Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF.
Methods and results
Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator-dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume (\'euvolaemia\') (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e\' velocity, r = -0.44), and left atrial strain (r = -0.47). In multivariable regression TBV, left ventricular e\', and left atrial strain were independently associated with PCWP (all P < 0.05).
Conclusions
While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1097-1105
Miller WL, Sorimachi H, Grill DE, Fischer K, Borlaug BA
Eur J Heart Fail: 29 Jun 2021; 23:1097-1105 | PMID: 33565251
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Impact:
Abstract

Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial.

Lang NN, Ahmad FA, Cleland JG, O\'Connor CM, ... Felker GM, McMurray JJV
Aims
Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Methods and results
In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m2 and was lower with cimlanod (29 ± 9 mL/m2 ; P = 0.03) and NTG (28 ± 8 mL/m2 ; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e\' (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo.
Conclusion
In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1147-1155
Lang NN, Ahmad FA, Cleland JG, O'Connor CM, ... Felker GM, McMurray JJV
Eur J Heart Fail: 29 Jun 2021; 23:1147-1155 | PMID: 33620131
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Impact:
Abstract

Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low-dose loop diuretic therapy.

Dauw J, Martens P, Tersalvi G, Schouteden J, ... Dupont M, Mullens W
Aims
To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics.
Methods and results
Urine collections were performed on two consecutive days in 40 ambulatory HF patients with 40-80 mg furosemide (day 1 with loop diuretic; day 2 without loop diuretic). Three phases were collected each day: (i) first 6 h; (ii) rest of the day; and (iii) night. On the day of loop diuretic intake, the total natriuresis was 125.9 (86.9-155.0) mmol/24 h and urine output was 1650 (1380-2025) mL/24 h. There was a clear loop diuretic response with a natriuresis of 9.4 (6.7-15.9) mmol/h and a urine output of 117 (83-167) mL/h during the first 6 h, followed by a significant drop in natriuresis and urine output during the rest of the day [2.6 (1.8-4.8) mmol/h and 55 (33-71) mL/h] and night [2.2 (1.6-3.5) mmol/h and 44 (34-73) mL/h]. On day 2, after loop diuretic omission, the natriuresis and urine output remained similarly low the entire day, resulting in a 50% reduction in natriuresis [55.1 (33.5-77.7) mmol/24 h; P < 0.001] and a 31% reduction in urine output [1035 (875-1425) mL/24 h; P < 0.001] compared with the day of loop diuretic intake.
Conclusion
Patients with HF on chronic loop diuretic treatment still have a clear diuretic response phase, while loop diuretic omission leads to a significant drop in natriuresis and urine output, arguing against routine cessation of low-dose loop diuretics.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1110-1119
Dauw J, Martens P, Tersalvi G, Schouteden J, ... Dupont M, Mullens W
Eur J Heart Fail: 29 Jun 2021; 23:1110-1119 | PMID: 33641220
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Impact:
Abstract

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

Gupta P, Voors AA, Patel P, Lane D, ... Squire IB, Ng LL
Aims
Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).
Methods and results
This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and β-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to β-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome.
Conclusion
Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1182-1190
Gupta P, Voors AA, Patel P, Lane D, ... Squire IB, Ng LL
Eur J Heart Fail: 29 Jun 2021; 23:1182-1190 | PMID: 33759308
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Impact:
Abstract

Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study.

Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Aims
Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary \'GDMT Team\' on medical therapy prescription for HFrEF.
Methods and results
Consecutive hospitalizations in patients with HFrEF (ejection fraction ≤40%) were prospectively identified from 3 February to 1 March 2020 (usual care group) and 2 March to 28 August 2020 (intervention group). Patients with critical illness, de novo heart failure, and systolic blood pressure <90 mmHg in the preceeding 24 hs prior to enrollment were excluded. In the intervention group, a pharmacist-physician GDMT Team provided optimization suggestions to treating teams based on an evidence-based algorithm. The primary outcome was a GDMT optimization score, the sum of positive (+1 for new initiations or up-titrations) and negative therapeutic changes (-1 for discontinuations or down-titrations) at hospital discharge. Serious in-hospital safety events were assessed. Among 278 consecutive encounters with HFrEF, 118 met eligibility criteria; 29 (25%) received usual care and 89 (75%) received the GDMT Team intervention. Among usual care encounters, there were no changes in GDMT prescription during hospitalization. In the intervention group, β-blocker (72% to 88%; P = 0.01), angiotensin receptor-neprilysin inhibitor (6% to 17%; P = 0.03), mineralocorticoid receptor antagonist (16% to 29%; P = 0.05), and triple therapy (9% to 26%; P < 0.01) prescriptions increased during hospitalization. After adjustment for clinically relevant covariates, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% confidence interval +0.09 to +1.07; P = 0.02). There were no serious in-hospital adverse events.
Conclusions
Non-cardiovascular hospitalizations are a potentially safe and effective setting for GDMT optimization. A virtual GDMT Team was associated with improved heart failure therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1191-1201
Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Eur J Heart Fail: 29 Jun 2021; 23:1191-1201 | PMID: 33768599
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Impact:
Abstract

Decongestion discriminates risk for one-year mortality in patients with improving renal function in acute heart failure.

Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Aims
Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion.
Methods and results
We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B-type natriuretic peptide (BNP), and 1-year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% were men, 72% were white, and median admission eGFR was 49 mL/min/1.73 m2 . IRF patients had more severe heart failure reflected by lower admission eGFR, higher blood urea nitrogen, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher 1-year mortality (25%) than non-IRF patients (15%) (P < 0.01). However, this relationship differed by BNP trajectory (P-interaction = 0.03). When stratified by BNP change, non-IRF patients and IRF patients with decreasing BNP had lower 1-year mortality than either non-IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality [adjusted hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.7-1.5] while BNP was (adjusted HR 0.5, 95% CI 0.3-0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality.
Conclusion
Improving renal function is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than IRF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1122-1130
Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Eur J Heart Fail: 29 Jun 2021; 23:1122-1130 | PMID: 33788989
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Impact:
Abstract

Cognitive impairment as a determinant of response to management plans after heart failure admission.

Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Aims
Cognitive impairment (CI) is highly prevalent in heart failure (HF), and increases patients\' risks of readmission. This study sought to determine whether the presence and degree of CI could identify patients most likely to benefit from a HF disease management programme (DMP) to reduce readmissions.
Methods and results
A total of 1152 consecutive Australian patients admitted with HF (2014-2017) were prospectively followed up for 12 months. Of these, 324 patients who received DMP (1-month duration, including post-discharge home visits, medication reconciliation, exercise guidance and early clinical review) were matched (1:2 ratio) with 648 usual care patients. Cognitive function was assessed either on the day of or one day before discharge using the Montreal Cognitive Assessment (MoCA). Outcomes included readmission or death at 1, 3 and 12 months, and days at home within 12 months of discharge. Poorer cognitive function was associated with all adverse outcomes. Compared with usual care, DMP was associated with lower odds of 30-day [odds ratio (OR) 0.60, 95% confidence interval 0.40, 0.91] and 90-day (OR 0.53, 95% confidence interval 0.36, 0.77) readmission or death, and with 19 more days at home within 12 months, independent of HF therapy. The effect sizes of these associations were greater for patients with diminished cognition than those with normal cognition (interaction P = 0.036), and might have been more pronounced among those with mild CI compared with those with more severe CI (MoCA score 17-22; OR 0.42, 95% confidence interval 0.21, 0.87) at 30 days (OR 0.31, 95% confidence interval 0.16, 0.60 at 90 days). Patients with normal cognition had fewer events, irrespective of DMP.
Conclusions
Cognitive function may determine how HF patients respond to a DMP. Cognitive screening before implementation of a DMP may allow personalized plans for patients with different levels of cognitive function.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1205-1214
Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Eur J Heart Fail: 29 Jun 2021; 23:1205-1214 | PMID: 33788985
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Impact:
Abstract

Heart failure outcomes in Aboriginal and Torres Strait Islander peoples in the Hunter New England region of New South Wales.

McGee M, Sugito S, Al-Omary MS, Hartnett D, ... Sverdlov AL, Boyle AJ

Background:
Aboriginal and Torres Strait Islander suffer poor health outcomes, driven predominately by cardiovascular disease. Previous work has focused on remote communities although majority of Aboriginal and Torres Strait Islander patients live in urban New South Wales. We describe the heart failure characteristics and outcomes of the Aboriginal and Torres Strait Islander patients in Hunter New England Health, New South Wales, Australia. Methods A large retrospective, multi-centre cohort study from 2007 till 2016 in a geographically diverse Local Health District. The primary outcomes were all-cause mortality and all-cause readmission. The Aboriginal and Torres Strait Islander cohort was described by demographics, locality, and outcomes relative to the non-Indigenous patients from the same time period. Findings During the study period there were 20,480 index admissions, of which 3.1% identified as Aboriginal and/or Torres Strait Islander. Aboriginal and Torres Strait Islander people admitted were younger by an average of 15 years (81 vs 66 years, p < 0.001), were more likely to live in a non-metropolitan locality (80 vs 61%, p < 0.001). Once adjustments were made for age, there was no significant difference in all-cause mortality. Indigenous status was a strong predictor of readmission on multivariate analysis, hazard ratio of 1.31 (p < 0.001). Interpretation Aboriginal and Torres Strait Islander patients, compared to non-Indigenous patients, who are admitted with heart failure are younger, more commonly live in rural localities and suffer from a higher burden of comorbidities. Once adjustments are made for age and co-morbidities, indigenous status does not portend a worse outcome.


Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Jun 2021; 334:65-71
McGee M, Sugito S, Al-Omary MS, Hartnett D, ... Sverdlov AL, Boyle AJ
Int J Cardiol: 30 Jun 2021; 334:65-71 | PMID: 33839176
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Impact:
Abstract

Splanchnic nerve modulation in heart failure: mechanistic overview, initial clinical experience, and safety considerations.

Fudim M, Ponikowski PP, Burkhoff D, Dunlap ME, ... Engelman ZJ, Shah SJ
Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long-term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1076-1084
Fudim M, Ponikowski PP, Burkhoff D, Dunlap ME, ... Engelman ZJ, Shah SJ
Eur J Heart Fail: 29 Jun 2021; 23:1076-1084 | PMID: 33886137
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Impact:
Abstract

Metagenomic analysis of gut microbiota reveals its role in trimethylamine metabolism in heart failure.

Emoto T, Hayashi T, Tabata T, Yamashita T, ... Yamada T, Hirata KI
Background
We had previously reported an increase in trimethylamine N-oxide (TMAO) levels in patients with both compensated and decompensated heart failure (HF) and alteration in gut microbiota composition using 16S rRNA gene amplicon analysis. Although a metagenome-wide analysis showed that choline-TMA lyase levels increased in HF patients, which TMA generation pathway from choline, carnitine, or betaine contributes to the increase in TMAO levels in HF needs to be elucidated.
Methods
We conducted a metagenome-wide shotgun sequencing analysis of gut microbiota and measured the TMAO levels in plasma of 22 HF patients during the compensated phase and 11 age-, sex-, and comorbidity-matched control subjects, whose gut microbiota compositions were reported in a previous 16S rRNA-based analysis.
Results
The abundance of cntA/B was positively correlated with TMAO, especially in HF patients, whereas that of cutC/D or betaine reductase was not correlated either in controls or HF patients. The abundance of cntA/B was mainly derived from the genera Escherichia and Klebsiella either in controls or HF patients.
Conclusion
TMAO levels in plasma depend on the abundance of cntA/B in HF. Although it is difficult to exclude the involvement of confounding factors, microbial dysbiosis connecting the abundance of cntA/B in the gut and the increase of TMAO in plasma can be a therapeutic target for HF.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Aug 2021; 338:138-142
Emoto T, Hayashi T, Tabata T, Yamashita T, ... Yamada T, Hirata KI
Int J Cardiol: 31 Aug 2021; 338:138-142 | PMID: 34102245
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Impact:
Abstract

Associations of time-varying obesity and metabolic syndrome with risk of incident heart failure and its subtypes: Findings from the Multi-Ethnic Study of Atherosclerosis.

Liu L, Lima JAC, Post WS, Szklo M
Objective
Most previous studies have examined associations between metabolic disorders measured at a single point in time and risk of heart failure (HF). However, there are many situations where the values of exposures vary over time before HF occurs. We aimed to examine the associations of time-varying obesity and metabolic syndrome (MetSyn) measured at multiple points in time with HF.
Methods
A total of 6750 participants in the Multi-Ethnic Study of Atherosclerosis from 2000 were included in the study. Follow-up was completed through December 2015. MetSyn was defined using the American Heart Association criteria. Incident HF was diagnosed by clinical criteria. Subtypes HF (reduced ejection fraction (HFrEF) and preserved (HFpEF) were classified by left ventricular EF.
Results
A total of 331 HF cases were identified during 82,609 person-years of observation. The incidence (95%CI) of total HF was 4.0 (3.4-4.4) per 1000 person-years. Of the total HF cases, 45.6% were HFrEF (n = 151), 40.8% HFpEF (n = 135), and 13.6% were unclassified HF subtypes (n = 45). After adjusting for key covariates, time-varying obesity (BMI ≥ 30 kg/m2) and MetSyn were significantly associated with HF, with a stronger association for HFpEF than for HFrEF. The corresponding hazards ratios (HR, 95%CI) were 1.97 (1.43-2.72) and 1.86 (1.43-2.42) for HFpEF, and 1.46 (1.07-1.98), and 1.39 (1.06-1.82) for HFrEF respectively. Time-varying large waist circumference was significantly associated with for HFpEF, but not with HFrEF.
Conclusion
Time-varying obesity and MetSyn were significantly associated with HF risk, with a stronger association with HFpEF than with HFrEF. Continued effort to control these risk factors is recommended.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Aug 2021; 338:127-135
Liu L, Lima JAC, Post WS, Szklo M
Int J Cardiol: 31 Aug 2021; 338:127-135 | PMID: 34089770
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Impact:
Abstract

Treating Symptoms and Reversing Remodeling: Clinical and Echocardiographic 1-Year Outcomes with Percutaneous Mitral Valve Annuloplasty for Mild to Moderate Secondary Mitral Regurgitation.

Witte KK, Kaye DM, Lipiecki J, Siminiak T, ... Levy W, Starling RC
Aim
To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR).
Methods and results
This was a pooled analysis of patients (n=68) who, despite guideline-directed medical therapy (GDMT) had symptomatic heart failure (HF) with mild (n=25) or moderate (n=43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6 minute walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At one year, NYHA status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units (95%CI 3 to17;p<0.01) and mean 6-minute walk test distance increased by 34 meters (95%CI 12 to 57;p<0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of -7ml (95%CI -11 to -3;p<0.001), vena contracta -0.11 cm (95%CI -0.20 to -0.02;p<0.05), and EROA -0.03 cm2 (95%CI -0.06 to -0.01;p<0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank p=0.22). Progression-free survival was 70% (82% in mild and 63% in moderate SMR (p=0.16)). Freedom from HF hospitalization was 73% (mild SMR 87% vs. moderate SMR 66%;p=0.07).
Conclusion
Among patients with symptomatic HF and mild or moderate SMR on GDMT, percutaneous mitral valve annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 18 Jul 2021; epub ahead of print
Witte KK, Kaye DM, Lipiecki J, Siminiak T, ... Levy W, Starling RC
Eur J Heart Fail: 18 Jul 2021; epub ahead of print | PMID: 34288287
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Impact:
Abstract

Temporal Trends and Clinical Trial Characteristics Associated With the Inclusion of Women in Heart Failure Trial Steering Committees: A Systematic Review.

Eliya Y, Whitelaw S, Thabane L, Voors AA, Douglas PS, Van Spall HGC
Background
Trial steering committees (TSCs) steer the conduct of randomized controlled trials (RCTs). We examined the gender composition of TSCs in impactful heart failure RCTs and explored whether trial leadership by a woman was independently associated with the inclusion of women in TSCs.
Methods
We systematically searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with impact factor ≥10 between January 2000 and May 2019. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression to explore trial characteristics associated with TSC inclusion of women.
Results
Of 403 RCTs that met inclusion criteria, 127 (31.5%) reported having a TSC but 20 of these (15.7%) did not identify members. Among 107 TSCs that listed members, 56 (52.3%) included women and 6 of these (10.7%) restricted women members to the RCT leaders. Of 1213 TSC members, 11.1% (95% CI, 9.4%-13.0%) were women, with no change in temporal trends (P=0.55). Women had greater odds of TSC inclusion in RCTs led by women (adjusted odds ratio, 2.48 [95% CI, 1.05-8.72], P=0.042); this association was nonsignificant when analysis excluded TSCs that restricted women to the RCT leaders (adjusted odds ratio 1.46 [95% CI, 0.43-4.91], P=0.36).
Conclusions
Women were included in 52.3% of TSCs and represented 11.1% of TSC members in 107 heart failure RCTs, with no change in trends since 2000. RCTs led by women had higher adjusted odds of including women in TSCs, partly due to the self-inclusion of RCT leaders in TSCs.



Circ Heart Fail: 19 Jul 2021:CIRCHEARTFAILURE120008064; epub ahead of print
Eliya Y, Whitelaw S, Thabane L, Voors AA, Douglas PS, Van Spall HGC
Circ Heart Fail: 19 Jul 2021:CIRCHEARTFAILURE120008064; epub ahead of print | PMID: 34281362
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Impact:
Abstract

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index.

Adamson C, Jhund PS, Docherty KF, Bělohlávek J, ... Sjöstrand M, McMurray JJ
Background
In heart failure with reduced ejection fraction (HFrEF), there is an \"obesity paradox\", where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a SGLT2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
Methods and results
BMI was examined using standard categories i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 Kg/m2 ); overweight (25.0-29.9 Kg/m2 ); obesity class I (30.0-34.9 Kg/m2 ); class II (35.0-39.9 Kg/m2 ) and class III (≥40 Kg/m2 ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% CI) for the primary outcome with obesity category 1, the lowest risk group, as reference was: under-/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI e.g., HR for primary outcome: under-/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00); P for interaction=0.79. The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) Kg (p<0.001).
Conclusion
We confirmed an \"obesity survival paradox\" in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.
Clinical trial registration
ClinicalTrials.gov number NCT03036124 (https://clinicaltrials.gov/ct2/show/NCT03036124).

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Jul 2021; epub ahead of print
Adamson C, Jhund PS, Docherty KF, Bělohlávek J, ... Sjöstrand M, McMurray JJ
Eur J Heart Fail: 15 Jul 2021; epub ahead of print | PMID: 34272791
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Impact:
Abstract

Cardiac Output States in Patients with Severe Functional Tricuspid Regurgitation - Impact on Treatment Success and Prognosis.

Unterhuber M, Kresoja KP, Besler C, Rommel KP, ... Thiele H, Lurz P
Aims
To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome.
Methods and results
A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centers. Patients were clustered according to k-means clustering into low (C-1: CI<1.7 l/min/m2 ), intermediate (C-2: CI=1.7-2.6 l/min/m2 ) and high CO (C-3: CI>2.6 l/min/m2 ) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO-clusters. Mortality rates were highest for patients in a low - (24%) and high CO state (42%, log-rank p<0.001). High CO patients were characterized by larger vena cava inferior diameters (p=0.003), reduced liver function, higher incidence of ascites (p=0.006) and markedly reduced systemic vascular resistance (p<0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (p=0.01) and right ventricular dimensions (p<0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low- and high CO patients.
Conclusions
Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Jul 2021; epub ahead of print
Unterhuber M, Kresoja KP, Besler C, Rommel KP, ... Thiele H, Lurz P
Eur J Heart Fail: 15 Jul 2021; epub ahead of print | PMID: 34272792
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Impact:
Abstract

ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.

Feyen E, Ricke-Hoch M, Van Fraeyenhove J, Vermeulen Z, ... Hilfiker-Kleiner D, De Keulenaer GW
Background
Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM.
Methods
miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice (Erbb4F/+ αMHC-Cre+, n=9) with their age-matched nonpregnant CTRLs (n=9-10).
Results
Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; P<0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P<0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P<0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, P=0.07; -27±20%, P<0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P<0.05) but without signs of myocardial apoptosis and inflammation.
Conclusions
ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.



Circ Heart Fail: 29 Jun 2021; 14:e006898
Feyen E, Ricke-Hoch M, Van Fraeyenhove J, Vermeulen Z, ... Hilfiker-Kleiner D, De Keulenaer GW
Circ Heart Fail: 29 Jun 2021; 14:e006898 | PMID: 34247489
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Impact:
Abstract

Liberation From Venoarterial Extracorporeal Membrane Oxygenation: A Review.

Brahmbhatt DH, Daly AL, Luk AC, Fan E, Billia F
Venoarterial extracorporeal membrane oxygenation may be used for circulatory support in cardiogenic shock as a bridge to recovery, a bridge to a ventricular assist device (VAD), or a bridge to transplant. While the determination of potential exit strategies is essential before cannulation, the final determination of a patient\'s options may change, in part, through their in-hospital clinical course. We propose that liberation from venoarterial extracorporeal membrane oxygenation should be conceptualized as a process of discovery in the assessment of a patient\'s underlying clinical status and a key driver of further clinical decision-making. A trial of liberation from support should be considered when the goals of the weaning trial are well-defined and, ideally, in the absence of potentially confounding clinical factors. In this review, we will discuss readiness to wean criteria from venoarterial extracorporeal membrane oxygenation, as well as specific clinical, biochemical, and echocardiographic parameters that may prove useful in determining weaning timing and revealing the patient\'s underlying hemodynamic status and prognosis. The role of various cannula configurations, support devices, and pharmacological adjuncts will also be discussed. Finally, we highlight current gaps in evidence and suggest areas of future research.



Circ Heart Fail: 29 Jun 2021; 14:e007679
Brahmbhatt DH, Daly AL, Luk AC, Fan E, Billia F
Circ Heart Fail: 29 Jun 2021; 14:e007679 | PMID: 34247519
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Impact:
Abstract

Association of heart failure subtypes and atrial fibrillation: Data from the Atherosclerosis Risk in Communities (ARIC) study.

Nji MAM, Solomon SD, Chen LY, Shah AM, ... Subramanya V, Alonso A
Aims
To determine the prevalence and incidence of AF among HF subtypes in a biracial community-based cohort.
Methods
We studied 6496 participants in the Atherosclerosis Risk in Community study (mean age, 75.8 ± 5.3, 59% women, 23% black) who attended the 2011-2013 visit. HF was identified from physician adjudicated diagnosis, hospital discharges, and self-report. HF subtypes were based on echocardiography. A left ventricular ejection fraction <40% represents HF with reduced ejection fraction (HFrEF), 40%-49% for HF with midrange ejection fraction (HFmEF), and ≥ 50% for HF with preserved ejection fraction (HFpEF). AF was ascertained through 2017 from study electrocardiograms, hospital discharges, and death certificates. Confounder-adjusted logistic regression and Cox models were used to estimate associations of HF subtype with prevalent and incident AF.
Results
Among eligible participants, 393 had HF (HFpEF = 232, HFmEF = 41, HFrEF = 35 and unclassified HF = 85) and 735 had AF. Compared to those without HF, all HF subtypes were more likely to have prevalent AF [odds ratio (95% confidence interval (CI)) 7.4 (5.6-9.9) for HFpEF, 8.1 (4.3-15.3) for HFmEF, 10.0 (5.0-20.2) for HFrEF, 8.8 (5.6-14.0) for unclassified HF]. Among participants without AF at baseline (n = 5761), 610 of them developed AF. Prevalent HF was associated with increased risk of AF [hazard ratio (95%CI) 2.3 (1.6-3.2) for HFpEF, 5.0 (2.7-9.3) for HFmEF, 3.5 (1.7-7.6) for HFrEF, 1.9 (0.9-3.7) for unclassified HF].
Conclusion
AF and HF frequently co-occur, with small differences by HF subtype, underscoring the importance of understanding the interplay of these two epidemics and evaluating shared preventive and therapeutic strategies.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 07 Jul 2021; epub ahead of print
Nji MAM, Solomon SD, Chen LY, Shah AM, ... Subramanya V, Alonso A
Int J Cardiol: 07 Jul 2021; epub ahead of print | PMID: 34246724
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Impact:
Abstract

Antigen carbohydrate 125 as a biomarker in heart failure: a narrative review.

Núñez J, de la Espriella R, Miñana G, Santas E, ... Lupón J, Bayés-Genís A
Congestion explains many of the signs and symptoms of acute heart failure (AHF) and disease progression. However, accurate quantification of congestion is challenging in daily practice. Antigen carbohydrate 125 (CA125) or mucin 16 (MUC16), a large glycoprotein synthesized by mesothelial cells, has emerged as a reliable proxy of congestion and inflammation in patients with heart failure (HF). In AHF syndromes, CA125 is strongly associated with right-sided HF parameters and a higher risk of adverse clinical events beyond standard prognostic factors, including natriuretic peptides. Furthermore, CA125 has the potential for both monitoring and guide HF treatment following a decompensated HF event. The wide availability of CA125 in most clinical laboratories, together with its standardized measurement and reduced cost, makes this marker attractive for routine use in decompensated HF. Further research is required to understand better its biological role and its promising utility as a tool to guide decongestive therapy in HF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 08 Jul 2021; epub ahead of print
Núñez J, de la Espriella R, Miñana G, Santas E, ... Lupón J, Bayés-Genís A
Eur J Heart Fail: 08 Jul 2021; epub ahead of print | PMID: 34241936
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Impact:
Abstract

Avoidable Hospitalization for Heart Failure Among a Cohort of 18- to 64-Year-Old Italian Citizens and Immigrants: Results From the Italian Network for Longitudinal Metropolitan Studies.

Dalla Zuanna T, Cacciani L, Barbieri G, Batzella E, ... Marino C, Canova C
Background
Heart failure (HF) represents a severe public health burden. In Europe, differences in hospitalizations for HF have been found between immigrants and native individuals, with inconsistent results. Immigrants face many barriers in their access to health services, and their needs may be poorly met. We aimed to compare the rates of avoidable hospitalization for HF among immigrants and native individuals in Italy.
Methods
All 18- to 64-year-old residents of Turin, Venice, Reggio Emilia, Modena, Bologna, and Rome between January 1, 2001 and December 31, 2013 were included in this multicenter open-cohort study. Immigrants from high migratory pressure countries (divided by area of origin) were compared with Italian citizens. Age-, sex-, and calendar year-adjusted hospitalization rate ratios and the 95% CIs of avoidable hospitalization for HF by citizenship were estimated using negative binomial regression models. The hospitalization rate ratios were summarized using a random effects meta-analysis. Additionally, we tested the contribution of socioeconomic status to these disparities.
Results
Of the 4 470 702 subjects included, 15.8% were immigrants from high migratory pressure countries. Overall, immigrants showed a nonsignificant increased risk of avoidable hospitalization for HF (hospitalization rate ratio, 1.26 [95% CI, 0.97-1.68]). Risks were higher for immigrants from Sub-Saharan Africa and for males from Northern Africa and Central-Eastern Europe than for their Italian citizen counterparts. Risks were attenuated adjusting for socioeconomic status, although they remained consistent with nonadjusted results.
Conclusions
Adult immigrants from different geographic macroareas had higher risks of avoidable hospitalization for HF than Italian citizens. Possible explanations might be higher risk factors among immigrants and reduced access to primary health care services.



Circ Heart Fail: 29 Jun 2021; 14:e008022
Dalla Zuanna T, Cacciani L, Barbieri G, Batzella E, ... Marino C, Canova C
Circ Heart Fail: 29 Jun 2021; 14:e008022 | PMID: 34235937
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Impact:
Abstract

Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction.

Kresoja KP, Rommel KP, Wachter R, Henger S, ... Blüher M, Lurz P
Aims
Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes.
Methods and results
From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (P < 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m2 , n = 464] as compared to lean HFpEF (BMI <30 kg/m2 , n = 535) and obese no-HF patients (BMI ≥30 kg/m2 , n = 387) (P < 0.001 for both); these findings were verified in the Aldo-DHF validation cohort (P < 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates.
Conclusion
Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 06 Jul 2021; epub ahead of print
Kresoja KP, Rommel KP, Wachter R, Henger S, ... Blüher M, Lurz P
Eur J Heart Fail: 06 Jul 2021; epub ahead of print | PMID: 34231954
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Impact:
Abstract

Effects of empagliflozin on CA125 trajectory in patients with chronic congestive heart failure.

de la Espriella R, Miñana G, Santas E, Núñez G, ... Bayés-Genís A, Núñez J
Introduction
We aimed to evaluate the trajectory of two surrogates of fluid overload -antigen carbohydrate 125 (CA125) and amino-terminal pro-brain natriuretic peptide (NT-proBNP)- after the addition of oral empagliflozin to usual care in a cohort of patients with chronic heart failure (CHF) and type 2 diabetes (T2D).
Methods and results
From October 2015 to February 2019, 60 ambulatory patients with CHF and T2D were retrospectively included. The primary endpoint was to assess the longitudinal trajectory of plasma levels of CA125 and NT-proBNP after empagliflozin initiation. Changes in quantitative variables were evaluated using linear mixed regression. Median CA125 and NT-proBNP at baseline were 17 (11-75) U/mL and 1662 (647-4230) pg/mL, respectively. A total of 510 outpatient visits were recorded [median (interquartile range) of visits per patient: 6 (4-11)] during a median of 1.78 years. We found a significant and steady decrease in the log of CA125 after empagliflozin initiation (p < 0.001). Conversely, the log of NT-proBNP predicted trajectory did not significantly change (p = 0.425).
Conclusion
In this cohort of patients with CHF and T2D, empagliflozin initiation was associated with a significant decrease in CA125 levels without modifying the trajectory of NT-proBNP. Considering that CA125 has emerged as a surrogate marker of tissue congestion, we hypothesize that empagliflozin might predominantly promote extravascular decongestion.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 29 Jun 2021; epub ahead of print
de la Espriella R, Miñana G, Santas E, Núñez G, ... Bayés-Genís A, Núñez J
Int J Cardiol: 29 Jun 2021; epub ahead of print | PMID: 34216708
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Impact:
Abstract

Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy.

Shimada YJ, Raita Y, Liang LW, Maurer MS, ... Fifer MA, Reilly MP
Background
Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM.
Methods
We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive.
Results
The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-β pathway-were also upregulated.
Conclusions
This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.



Circ Heart Fail: 29 Jun 2021; 14:e007849
Shimada YJ, Raita Y, Liang LW, Maurer MS, ... Fifer MA, Reilly MP
Circ Heart Fail: 29 Jun 2021; 14:e007849 | PMID: 34192899
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Impact:
Abstract

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device.

Rao SD, Connor DE, Shehab S, Kerr NP, ... Jansz P, Hayward CS
Background
In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents.
Methods
A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity.
Results
Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P=0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points.
Conclusions
In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.



Circ Heart Fail: 29 Jun 2021; 14:e007231
Rao SD, Connor DE, Shehab S, Kerr NP, ... Jansz P, Hayward CS
Circ Heart Fail: 29 Jun 2021; 14:e007231 | PMID: 34210157
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Impact:
Abstract

Cardiotoxicity associated with immune checkpoint inhibitors therapy: A meta-analysis.

Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G
Aims
The study aimed to estimate the cardiac immune-related adverse events (irAEs) incidence in immune checkpoint inhibitors (ICIs)-treated patients.
Methods and results
First, we performed an ICIs-pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than treatment with anti-CTLA-4 (69.4% and 20%, respectively). Then, we analyzed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to August 31, 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the clinicaltrials.gov database, finding an incidence of 3.1% for ICIs monotherapies, 5.8% for dual ICIs therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were found in 2.5% of patients treated solely with chemotherapy.
Conclusions
Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rate of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196077
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Impact:
Abstract

Post-discharge arrhythmic risk stratification of patients with acute myocarditis and life-threatening ventricular tachyarrhythmias.

Gentile P, Merlo M, Peretto G, Ammirati E, ... Frigerio M, Sinagra G
Background
The outcomes of patients presenting with acute myocarditis and life-threatening ventricular tachyarrhythmias (LT-VA) are unclear. The aim of this study was to assess incidence and predictors of recurrence of major arrhythmic events (MAEs) after hospital discharge in such patients.
Methods and results
We retrospectively analysed 156 patients (median age 44 years; 77% males) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or on the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death (SCD) or ventricular fibrillation defibrillated successfully or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up period was 23 months (first to third quartile [Q1-Q3] 7-60). Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median time of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated to MAEs were presentation with sVT (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38-6.11); late gadolinium enhancement (LGE) involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53); and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR.
Conclusions
Among patients discharged with the diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmic recurrence.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Gentile P, Merlo M, Peretto G, Ammirati E, ... Frigerio M, Sinagra G
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196079
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Impact:
Abstract

Stopping mineralocorticoid receptor antagonists after hyperkalaemia: trial emulation in data from routine care.

Trevisan M, Fu EL, Xu Y, Savarese G, ... Sjölander A, Carrero JJ
Aims
Whether to continue or stop mineralocorticoid receptor antagonists (MRA) after an episode of hyperkalaemia is a challenge in clinical practice. While stopping MRA may prevent recurrent hyperkalaemias, it deprives patients of their cardioprotection. We here assessed the association between stopping vs. continuing MRA therapy after hyperkalaemia and the subsequent risks of adverse health events.
Methods and results
Observational study from the Stockholm CREAtinine Measurements (SCREAM) project 2006-2018. We identified patients initiating MRA and surviving a first-detected episode of hyperkalaemia (plasma potassium >5.0 mmol/L). Using target trial emulation methods, we assessed the association between stopping vs. continuing MRA within 6 months after hyperkalaemia and subsequent outcomes. The primary outcome was the composite of hospital admission with heart failure, stroke, myocardial infarction, or death. The secondary outcome was occurrence of another hyperkalaemia event. Among 39 518 patients initiating MRA, we identified 7366 who developed hyperkalaemia. Median age was 76 years, 45% were women and 69% had a history of heart failure. Following hyperkalaemia, 2222 (30%) discontinued treatment. Compared with continuing MRA, stopping therapy was associated with a lower 2-year risk of recurrent hyperkalaemia [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.72-0.79], but a higher risk of the primary outcome (HR 1.10, 95% CI 1.06-1.14). Similar results were observed in patients with heart failure, after censoring when treatment decision was changed, and across pre-specified subgroups.
Conclusions
Stopping MRA after an episode of hyperkalaemia was associated with reduced risk for recurrent hyperkalaemia, but higher risk of death or cardiovascular events. Recurrent hyperkalaemia was common in either strategy.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Trevisan M, Fu EL, Xu Y, Savarese G, ... Sjölander A, Carrero JJ
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196082
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Impact:
Abstract

The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.

Varma N, Auricchio A, Connolly AT, Boehmer J, ... Nabutovsky Y, Gold M
Aims
The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities.
Methods and results
The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014).
Conclusion
Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

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

Europace: 30 Jun 2021; epub ahead of print
Varma N, Auricchio A, Connolly AT, Boehmer J, ... Nabutovsky Y, Gold M
Europace: 30 Jun 2021; epub ahead of print | PMID: 34198334
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Impact:
Abstract

Characteristics and Outcomes of Women Developing Heart Failure After Early Stage Breast Cancer Chemotherapy: A Population-Based Matched Cohort Study.

Abdel-Qadir H, Tai F, Croxford R, Austin PC, ... Lee DS, Thavendiranathan P
Background
The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized.
Methods
Using administrative databases, women diagnosed with HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death.
Results
A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% [95% CI, 12.0%-21.7%]) as controls (17.1% [95% CI, 14.4%-20.1%]); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% [95% CI, 4.7%-16.9%]; controls 16.4% [95% CI, 12.1%-21.3%]; P=0.03) and sequential-HF cohorts (2.7% [95% CI, 1.4%-4.8%]; controls 10.8% [95% CI, 8.9%-13.0%]; P<0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%-5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%-12.6%) in controls, and 1.7% (0.6%-3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1-5.8%) for controls.
Conclusions
Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.



Circ Heart Fail: 29 Jun 2021; 14:e008110
Abdel-Qadir H, Tai F, Croxford R, Austin PC, ... Lee DS, Thavendiranathan P
Circ Heart Fail: 29 Jun 2021; 14:e008110 | PMID: 34187164
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Abstract

Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit.

Logantha SJRJ, Cai XJ, Yanni J, Jones CB, ... Boyett MR, Hart G
Background
Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs.
Methods
Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used.
Results
Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected.
Conclusions
Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.



Circ Heart Fail: 29 Jun 2021; 14:e007505
Logantha SJRJ, Cai XJ, Yanni J, Jones CB, ... Boyett MR, Hart G
Circ Heart Fail: 29 Jun 2021; 14:e007505 | PMID: 34190577
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Impact:
Abstract

Multiparametric Implantable Cardioverter-Defibrillator Algorithm for Heart Failure Risk Stratification and Management: An Analysis in Clinical Practice.

Calò L, Bianchi V, Ferraioli D, Santini L, ... D\'Onofrio A, Full list of participant centers and investigators
Background
The HeartLogic algorithm combines multiple implantable cardioverter-defibrillator sensors to identify patients at risk of heart failure (HF) events. We sought to evaluate the risk stratification ability of this algorithm in clinical practice. We also analyzed the alert management strategies adopted in the study group and their association with the occurrence of HF events.
Methods
The HeartLogic feature was activated in 366 implantable cardioverter-defibrillator and cardiac resynchronization therapy implantable cardioverter-defibrillator patients at 22 centers. The median follow-up was 11 months [25th-75th percentile: 6-16]. The HeartLogic algorithm calculates a daily HF index and identifies periods IN alert state on the basis of a configurable threshold.
Results
The HeartLogic index crossed the threshold value 273 times (0.76 alerts/patient-year) in 150 patients. The time IN alert state was 11% of the total observation period. Patients experienced 36 HF hospitalizations, and 8 patients died of HF during the observation period. Thirty-five events were associated with the IN alert state (0.92 events/patient-year versus 0.03 events/patient-year in the OUT of alert state). The hazard ratio in the IN/OUT of alert state comparison was (hazard ratio, 24.53 [95% CI, 8.55-70.38], P<0.001), after adjustment for baseline clinical confounders. Alerts followed by clinical actions were associated with less HF events (hazard ratio, 0.37 [95% CI, 0.14-0.99], P=0.047). No differences in event rates were observed between in-office and remote alert management.
Conclusions
This multiparametric algorithm identifies patients during periods of significantly increased risk of HF events. The rate of HF events seemed lower when clinical actions were undertaken in response to alerts. Extra in-office visits did not seem to be required to effectively manage HeartLogic alerts.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02275637.



Circ Heart Fail: 29 Jun 2021:CIRCHEARTFAILURE120008134; epub ahead of print
Calò L, Bianchi V, Ferraioli D, Santini L, ... D'Onofrio A, Full list of participant centers and investigators
Circ Heart Fail: 29 Jun 2021:CIRCHEARTFAILURE120008134; epub ahead of print | PMID: 34190592
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Impact:
Abstract

Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF.

McEwan P, Ponikowski P, Davis JA, Rosano G, ... Ramirez de Arellano A, Jankowska EA
Aims
Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives.
Methods and results
A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology.
Conclusion
Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.

© 2021 Vifor Pharma. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; epub ahead of print
McEwan P, Ponikowski P, Davis JA, Rosano G, ... Ramirez de Arellano A, Jankowska EA
Eur J Heart Fail: 29 Jun 2021; epub ahead of print | PMID: 34191394
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Impact:
Abstract

Vericiguat in patients with atrial fibrillation and heart failure with reduced ejection fraction: insights from the VICTORIA trial.

Ponikowski P, Alemayehu W, Oto A, Bahit MC, ... Armstrong PW, VICTORIA Study Group
Aims
We evaluated the relation between baseline and new-onset atrial fibrillation (AF) and outcomes, and assessed whether vericiguat modified the likelihood of new-onset AF in patients with worsening heart failure (HF) with reduced ejection fraction in VICTORIA.
Methods and results
Of 5050 patients randomized, 5010 with recorded AF status at baseline were analysed. Patients were classified into three groups: no known AF (n = 2661, 53%), history of AF alone (n = 992, 20%), and AF on randomization electrocardiogram (n = 1357, 27%). Compared with those with no AF, those with history of AF alone had a higher risk of cardiovascular death [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.01-1.47] without excess myocardial infarction or stroke; neither type of AF was associated with a higher risk of the primary composite outcome (time to cardiovascular death or first HF hospitalization), HF hospitalizations, or all cause-death. The beneficial effect of vericiguat on the primary composite outcome and its components was evident irrespective of AF status at baseline. Over a median follow-up of 10.8 months, new-onset AF occurred in 6.1% of those with no AF and 18.3% with history of AF alone (P < 0.0001). These events were not influenced by vericiguat treatment (adjusted HR 0.93, 95% CI 0.75-1.16; P = 0.51), but were associated with an increase in the hazard of both primary and secondary outcomes.
Conclusions
Atrial fibrillation was present in nearly half of this high-risk population with worsening HF. A history of AF alone at baseline portends an increased risk of cardiovascular death. Neither type of AF affected the beneficial effect of vericiguat. Development of AF post-randomization was associated with an increase in both cardiovascular death and HF hospitalization which was not influenced by vericiguat.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; epub ahead of print
Ponikowski P, Alemayehu W, Oto A, Bahit MC, ... Armstrong PW, VICTORIA Study Group
Eur J Heart Fail: 29 Jun 2021; epub ahead of print | PMID: 34191395
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Impact:
Abstract

Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors.

Herrington WG, Savarese G, Haynes R, Marx N, ... Baigent C, Cosentino F
In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 28 Jun 2021; epub ahead of print
Herrington WG, Savarese G, Haynes R, Marx N, ... Baigent C, Cosentino F
Eur J Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34184823
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Impact:
Abstract

Surgical ablation of the right greater splanchnic nerve for the treatment of heart failure with preserved ejection fraction: first-in-human clinical trial.

Málek F, Gajewski P, Zymliński R, Janczak D, ... Engelman ZJ, Ponikowski PP
Aims
Inappropriate control of blood volume redistribution may be a mechanism responsible for exercise intolerance in heart failure with preserved ejection fraction (HFpEF). We propose to address this underlying pathophysiology with selective blockade of sympathetic signalling to the splanchnic circulation by surgical ablation of the right greater splanchnic nerve (GSN).
Methods and results
In a single-arm, prospective, two-centre trial, 10 patients with HFpEF (50% male, mean age 70 ± 3 years) all with New York Heart Association (NYHA) class III, left ventricular ejection fraction >40%, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry, underwent ablation of the right GSN via thoracoscopic surgery. Patients were evaluated at baseline, 1, 3, 6 and 12 months after the procedure. The primary endpoint was a reduction in exercise PCWP at 3 months. There were no adverse events related to the blockade of the nerve during 12-month follow-up but three patients had significant peri-procedural adverse events related to the surgical procedure itself. At 3 months post-GSN ablation, patients demonstrated a reduction in 20 W exercise PCWP when compared to baseline [-4.5 mmHg (95% confidence interval, CI -14 to -2); P = 0.0059], which carried over to peak exercise [-5 mmHg (95% CI -11 to 0; P = 0.016). At 12 months, improvements were seen in NYHA class [3 (3) vs. 2 (1, 2); P = 0.0039] and quality of life assessed with the Minnesota Living with Heart Failure Questionnaire [60 (51, 71) vs. 22 (16, 27); P = 0.0039].
Conclusion
In this first-in-human study, GSN ablation in HFpEF proved to be feasible, with a suggestion of reduced cardiac filling pressure during exercise, improved quality of life and exercise capacity.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1134-1143
Málek F, Gajewski P, Zymliński R, Janczak D, ... Engelman ZJ, Ponikowski PP
Eur J Heart Fail: 29 Jun 2021; 23:1134-1143 | PMID: 33932262
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Impact:
Abstract

Sex-specific temporal evolution of circulating biomarkers in patients with chronic heart failure with reduced ejection fraction.

Schreuder MM, Schuurman A, Akkerhuis KM, Constantinescu AA, ... Roeters van Lennep JE, Kardys I
Background
We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF.
Methods
We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5-10) urine and 9 (5-10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached.
Results
A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17-21.93), men: HR(95%CI) 3.14 (2.09-4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18-22.46), men: HR(95%CI) 4.91 (2.58-9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43-19.53), men: HR(95%CI) 3.29 [2.27-5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women.
Conclusion
Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Jun 2021; 334:126-134
Schreuder MM, Schuurman A, Akkerhuis KM, Constantinescu AA, ... Roeters van Lennep JE, Kardys I
Int J Cardiol: 30 Jun 2021; 334:126-134 | PMID: 33940096
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Impact:
Abstract

Association between up-titration of medical therapy and total hospitalizations and mortality in patients with recent worsening heart failure across the ejection fraction spectrum.

Bistola V, Simitsis P, Parissis J, Ouwerkerk W, ... Voors AA, Filippatos G
Background
The role of neurohormonal inhibition in chronic heart failure (HF) is well established. There are limited data on the effect of up-titration of renin-angiotensin inhibitors (RASi) and beta-blockers (BBs) on clinical outcomes of patients with worsening HF across the left ventricular ejection fraction (LVEF) spectrum.
Methods and results
We analysed data from 2345 patients from BIOSTAT-CHF (80.9% LVEF <40%), who completed a 3-month up-titration period after recent worsening of HF. Patients were classified by achieved dose (% of recommended): ≥100%, 50-99%, 1-49%, and none. Recurrent event analysis using joint and shared frailty models was used to examine the association between RASi/BB dose and all-cause and HF hospitalizations. In the 21 months following up-titration, 512 patients died and 879 (37.5%) had ≥1 hospitalization. RASi up-titration was associated, incrementally, with reduced risk of all-cause hospitalization at all achieved dose levels compared to no treatment [hazard ratio (95% confidence interval): ≥100%: 0.60 (0.49-0.74), P < 0.001; 50-99%: 0.56 (0.46-0.68), P < 0.001; 1-49%: 0.71 (0.59-0.86), P < 0.001]. This association was consistent up to an LVEF of 49% (P < 0.001), and when considering only HF hospitalizations. Up-titration of BBs was associated with fewer all-cause hospitalizations only when LVEF was <40% (overall P < 0.001), but with more HF hospitalizations when LVEF was ≥50%. Up-titration of both RASi/BBs was associated with lower mortality in LVEF up to 49%.
Conclusion
After recent worsening of HF, up-titration of RASi and BBs was associated with a better prognosis in patients with LVEF ≤49%. Up-titration of BBs was associated with a greater risk of HF hospitalization when LVEF was ≥50%.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1170-1181
Bistola V, Simitsis P, Parissis J, Ouwerkerk W, ... Voors AA, Filippatos G
Eur J Heart Fail: 29 Jun 2021; 23:1170-1181 | PMID: 33998113
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Abstract

Use of diuretics and outcomes in patients with type 2 diabetes: findings from the EMPA-REG OUTCOME trial.

Pellicori P, Fitchett D, Kosiborod MN, Ofstad AP, ... Testani JM, Cleland JGF
Aims
Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial.
Methods and results
The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes).
Conclusion
Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1085-1093
Pellicori P, Fitchett D, Kosiborod MN, Ofstad AP, ... Testani JM, Cleland JGF
Eur J Heart Fail: 29 Jun 2021; 23:1085-1093 | PMID: 34031968
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Abstract

Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.

Solomon SD, de Boer RA, DeMets D, Hernandez AF, ... Petersson M, McMurray JJV
Aims
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering agents, have been shown to reduce heart failure hospitalizations in patients with type 2 diabetes without established heart failure, and in patients with heart failure with and without diabetes. Their role in patients with heart failure with preserved and mildly reduced ejection fraction remains unknown.
Methods
Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) is an international, multicentre, parallel group, event-driven, randomized, double-blind trial in patients with chronic heart failure and left ventricular ejection fraction (LVEF) >40%, comparing the effect of dapagliflozin 10 mg once daily, vs. placebo, in addition to standard of care. Patients with or without diabetes, with signs and symptoms of heart failure, a LVEF >40%, elevation in natriuretic peptides and evidence of structural heart disease are eligible. The primary endpoint is time-to-first cardiovascular death or worsening heart failure event (heart failure hospitalization or urgent heart failure visit), and will be assessed in dual primary analyses - the full population and in those with LVEF <60%. The study is event-driven and will target 1117 primary events. A total of 6263 patients have been randomized.
Conclusions
DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1217-1225
Solomon SD, de Boer RA, DeMets D, Hernandez AF, ... Petersson M, McMurray JJV
Eur J Heart Fail: 29 Jun 2021; 23:1217-1225 | PMID: 34051124
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Abstract

Segment Length in Cine Strain Analysis Predicts Cardiac Resynchronization Therapy Outcome Beyond Current Guidelines.

Zweerink A, Friedman DJ, Klem I, van de Ven PM, ... Allaart CP, Nijveldt R
Background
Patients with a class I recommendation for cardiac resynchronization therapy (CRT) are likely to benefit, but the effect of CRT in class II patients is more heterogeneous and additional selection parameters are needed in this group. The recently validated segment length in cine strain analysis of the septum (SLICE-ESSsep) measurement on cardiac magnetic resonance cine imaging predicts left ventricular functional recovery after CRT but its prognostic value is unknown. This study sought to evaluate the prognostic value of SLICE-ESSsep for clinical outcome after CRT.
Methods
Two hundred eighteen patients with a left bundle branch block or intraventricular conduction delay and a class I or class II indication for CRT who underwent preimplantation cardiovascular magnetic resonance examination were enrolled. SLICE-ESSsep was manually measured on standard cardiovascular magnetic resonance cine imaging. The primary combined end point was all-cause mortality, left ventricular assist device, or heart transplantation. Secondary end points were (1) appropriate implantable cardioverter defibrillator therapy and (2) heart failure hospitalization.
Results
Two-thirds (65%) of patients had a positive SLICE-ESSsep ≥0.9% (ie, systolic septal stretching). During a median follow-up of 3.8 years, 66 (30%) patients reached the primary end point. Patients with positive SLICE-ESSsep were at lower risk to reach the primary end point (hazard ratio 0.36; P<0.001) and heart failure hospitalization (hazard ratio 0.41; P=0.019), but not for implantable cardioverter defibrillator therapy (hazard ratio, 0.66; P=0.272). Clinical outcome of class II patients with a positive ESSsep was similar to those of class I patients (hazard ratio, 1.38 [95% CI, 0.66-2.88]; P=0.396).
Conclusions
Strain assessment of the septum (SLICE-ESSsep) provides a prognostic measure for clinical outcome after CRT. Detection of a positive SLICE-ESSsep in patients with a class II indication predicts improved CRT outcome similar to those with a class I indication whereas SLICE-ESSsep negative patients have poor prognosis after CRT implantation.



Circ Cardiovasc Imaging: 29 Jun 2021; 14:e012350
Zweerink A, Friedman DJ, Klem I, van de Ven PM, ... Allaart CP, Nijveldt R
Circ Cardiovasc Imaging: 29 Jun 2021; 14:e012350 | PMID: 34287001
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