Journal: JACC Heart Fail

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Abstract

Plasma Amyloid-β in Relation to Cardiac Function and Risk of Heart Failure in General Population.

Zhu F, Wolters FJ, Yaqub A, Leening MJG, ... Ikram MA, Kavousi M
Background
Amyloid-β (Aβ) may be related to cardiac function. However, there are limited data on the association of plasma Aβ with cardiac function and risk of heart failure (HF) in the general population.
Objectives
This study sought to determine the associations of plasma amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) with echocardiographic measurements of cardiac dysfunction and with incident HF in the general population.
Methods
The study included 4,156 participants of the population-based Rotterdam Study (mean age: 71.4 years; 57.1% women), who had plasma Aβ samples collected between 2002 and 2005 and had no established dementia and HF at baseline. Multivariable linear regression models were used to explore the cross-sectional association of plasma Aβ with echocardiographic measures. Participants were followed up until December 2016. Cox proportional hazards models were used to assess the association of Aβ levels with incident HF. Models were adjusted for cardiovascular risk factors.
Results
A per 1-SD increase in log-transformed plasma Aβ40 was associated with a 0.39% (95% CI: -0.68 to -0.10) lower left ventricular ejection fraction and a 0.70 g/m2 (95% CI: 0.06-1.34) larger left ventricular mass indexed by body surface area. Aβ42 was not significantly associated with echocardiographic measures cross-sectionally. During follow-up (median: 10.2 years), 472 incident HF cases were identified. A per 1-SD increase in log-transformed Aβ40 was associated with a 32% greater risk of HF (HR: 1.32; 95% CI: 1.15-1.51), and the association was significant in men, but not in women. Higher plasma Aβ42 levels were associated with an increased risk of HF (HR: 1.12; 95% CI: 1.02-1.24), although the association was attenuated after further adjustment for concomitant Aβ40 (HR: 1.03; 95% CI: 0.92-1.16).
Conclusions
Higher levels of Aβ40 were associated with worse cardiac function and higher risk of new onset HF in the general population, in particular among men.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 09 Nov 2022; epub ahead of print
Zhu F, Wolters FJ, Yaqub A, Leening MJG, ... Ikram MA, Kavousi M
JACC Heart Fail: 09 Nov 2022; epub ahead of print | PMID: 36372727
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Abstract

Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure.

Packer M
In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the \"cytosolic iron depletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe2+ that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the \"cytosolic iron repletion hypothesis,\" the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe2+, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the \"cytosolic iron repletion hypothesis\" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 05 Nov 2022; epub ahead of print
Packer M
JACC Heart Fail: 05 Nov 2022; epub ahead of print | PMID: 36396554
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Abstract

Retinal Microvasculature: A Potential Window Into Heart Failure Prevention.

Chaikijurajai T, Ehlers JP, Tang WHW
Endothelial dysfunction and microvascular disease have been shown to play an important role in the development and progression of heart failure (HF). Retinal imaging provides a unique opportunity to noninvasively assess vascular structure and function, vessel features, and microcirculation within the retina. Accumulating evidence suggests that retinal vessel caliber, microvascular features, and vascular characteristics extracted from various imaging modalities are associated with alterations in left ventricular structure and function in stage B HF, as well as incident development of symptomatic HF in the general population. Moreover, dynamic retinal vessel analysis has been shown to differentiate HF patients based on their phenotypes. Given the increasing availability of rapid image acquisition devices (eg, nonmydriatic widefield systems and smartphone-based retinal cameras) and the integration of artificial intelligence-based interrogation/assessment techniques, retinal imaging is a promising noninvasive tool, in conjunction with cardiac imaging and biomarkers, to prevent HF and risk stratify those at risk of developing HF. This review focuses on the current evidence on retinal microvasculature changes, and potential clinical relevance and promising utility of retinal imaging in HF.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:785-791
Chaikijurajai T, Ehlers JP, Tang WHW
JACC Heart Fail: 01 Nov 2022; 10:785-791 | PMID: 36328644
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Abstract

Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up.

Vissing CR, Espersen K, Mills HL, Bartels ED, ... Christensen AH, Bundgaard H
Background
According to patterns of inheritance and incomplete penetrance, fewer than half of relatives to dilated cardiomyopathy probands will develop disease.
Objectives
The purpose of this study was to investigate the prevalence and incidence, and to identify predictors of developing familial dilated cardiomyopathy (FDC) in relatives participating in family screening.
Methods
The study was a retrospective, longitudinal cohort study of families screened and followed from 2006 to 2020 at a regional assembly of clinics for inherited cardiomyopathies.
Results
In total, 211 families (563 relatives, 50% women) were included. At baseline, 124 relatives (22%) were diagnosed with FDC. Genetic sequencing identified the etiology in 37% of screened families and classified 101 (18%) relatives as unaffected carriers (n = 43) or noncarriers (ie, not at risk of FDC [n = 58]). The combined clinical and genetic baseline yield was 30%. During follow-up (2,313 person-years, median 5.0 years), 45 developed FDC (incidence rate of 2.0% per person-year; 95% CI: 1.4%-2.8%), increasing the overall yield to 34%. The incidence rate of FDC was high in relatives with baseline abnormalities on electrocardiogram or echocardiography compared with relatives with normal findings (4.7% vs 0.4% per person-year; HR: 12.9; P < 0.001). In total, baseline screening identified 326 (58%) relatives to be at low risk of FDC.
Conclusions
Family screening identified a genetic predisposition to or overt FDC in 1 of 3 relatives at baseline. Genetic and clinical screening was normal in more than half of relatives, and these relatives had a low risk of developing FDC during follow-up. Thus, baseline screening identified a large proportion, in whom follow-up may safely be reduced, allowing focused follow-up of relatives at risk.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:792-803
Vissing CR, Espersen K, Mills HL, Bartels ED, ... Christensen AH, Bundgaard H
JACC Heart Fail: 01 Nov 2022; 10:792-803 | PMID: 36328645
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Abstract

Trends in Ischemic Evaluation in New-Onset Heart Failure Without Known Coronary Artery Disease.

Andersson C, Schou M, Boden WE, Schwartz B, ... Gislason GH, Torp-Pedersen C
Background
Guidelines recommend consideration of an ischemic evaluation (Class IIa-IIb) in new-onset heart failure (HF), but it is not well-known how often this is performed and leads to revascularization.
Objectives
The authors investigated temporal trends in ischemic evaluation and revascularization within 90 days of HF onset in Denmark 2008-2018.
Methods
From the Danish nationwide administrative registries, diagnostic tests and revascularizations within 90 days were identified among patients with new-onset HF between 2008 and 2018, alive 90 days after diagnosis.
Results
Of 61,475 patients (mean age: 72.6 ± 13.8 years, 46% women), 12,503 (20%) underwent an ischemic evaluation, of whom 10,547 (84%) underwent invasive coronary angiography, and 1,956 (16%) underwent an initial noninvasive test, most frequently coronary computed tomographic angiography (n = 1,813, 93%). Of those who were initially referred for coronary computed tomographic angiography, 374 (21%) had a subsequent invasive coronary angiogram undertaken. Among individuals undergoing ischemic testing, percutaneous coronary intervention and coronary artery bypass graft surgery were performed in 1,354 (11%) and 619 (5%), respectively, corresponding to 2.2% and 1.0% of the entire sample. Between 2008 and 2018, the number of patients referred for ischemic evaluations increased, adjusted OR for 1.07 (95% CI: 1.06-1.07) per year high, and was greater among older versus younger individuals (OR: 1.01 [95% CI: 0.99-1.03], OR: 1.04 [95% CI: 1.03-1.06], OR: 1.06 [95% CI: 1.05-1.07], OR: 1.11 [95% CI: 1.09-1.12], and OR: 1.14 [95% CI: 1.10-1.18] per year increase for age group <50, 51-60, 61-75, 76-85, and >85 years, respectively, P for interaction <0.0001).
Conclusions
In clinical practice, few patients with new-onset HF are referred for an ischemic evaluation and a minority undergo revascularization. Studies are needed to establish the appropriateness of this practice.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:807-815
Andersson C, Schou M, Boden WE, Schwartz B, ... Gislason GH, Torp-Pedersen C
JACC Heart Fail: 01 Nov 2022; 10:807-815 | PMID: 36328647
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Abstract

Risks of Depression and Suicide After Diagnosis With Heart Failure: A National Cohort Study.

Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K
Background
Heart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear.
Objectives
In this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort.
Methods
A national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities.
Results
HF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001).
Conclusions
In this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:819-827
Crump C, Sundquist J, Kendler KS, Sieh W, Edwards AC, Sundquist K
JACC Heart Fail: 01 Nov 2022; 10:819-827 | PMID: 36328649
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Abstract

Posterior Wall Thickness Associates With Survival Following Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy.

Sun D, Schaff HV, Nishimura RA, Geske JB, ... Ducharme MT, Ommen SR
Background
The left ventricular (LV) posterior wall thickness (PWT) is a predictor of sudden cardiac death in pediatric patients with hypertrophic cardiomyopathy (HCM), but the prognostic importance of PWT in adults has not been examined.
Objectives
The goal of this study was to evaluate the association of LV PWT with late survival in adult patients undergoing septal myectomy for obstructive HCM.
Methods
This single-center study reviewed 2,418 patients who underwent transaortic septal myectomy for obstructive HCM.
Results
The median preoperative PWT was 13 (IQR: 11-15) mm. Patients with PWT >13 mm tended to have systemic hypertension (55.4% vs 49.1%; P = 0.002) and a larger body mass index (median: 30.8 [IQR: 27.1-35.1] kg/m2 vs 29.6 [IQR: 26.1-33.9] kg/m2; P < 0.001). Preoperatively, PWT >13 mm was associated with increased septal thickness (median: 21 [IQR: 18-24] mm vs 19 [IQR: 17-22] mm; P < 0.001), greater maximum instantaneous left ventricular outflow tract (LVOT) gradient at rest (median: 67 [IQR: 36-96] mm Hg vs 47 [IQR: 19-79] mm Hg), and increased likelihood of moderate or greater mitral valve regurgitation (54.3% vs 47.3%; P = 0.001). However, PWT was not related to the severity of limitations measured by New York Heart Association functional class (P = 0.674). After adjusting for baseline covariates, greater PWT was an independent risk factor for late mortality after septal myectomy (P = 0.003).
Conclusions
PWT is a newly identified predictor of reduced long-term survival after septal myectomy that is independent of septal thickness and severity of LVOT gradient. Future studies are warranted to investigate the mechanisms underlying the association and the potential usefulness of PWT in patient management.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:831-837
Sun D, Schaff HV, Nishimura RA, Geske JB, ... Ducharme MT, Ommen SR
JACC Heart Fail: 01 Nov 2022; 10:831-837 | PMID: 36328651
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Abstract

Steroidal MRA Across the Spectrum of Renal Function: A Pooled Analysis of RCTs.

Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, ... Zannad F, Rossignol P
Background
Mineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain.
Objectives
The goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials.
Methods
This study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula.
Results
A total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m2 (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m2). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m2: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m2: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m2: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m2: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m2: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m2: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002).
Conclusions
Steroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m2.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:842-850
Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, ... Zannad F, Rossignol P
JACC Heart Fail: 01 Nov 2022; 10:842-850 | PMID: 36328653
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Abstract

Trends in Heart Failure-Related Mortality Among Older Adults in the United States From 1999-2019.

Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, ... Butler J, Khan MS
Background
The U.S. population is aging with concurrent increases in heart failure (HF) burden. However, HF-related mortality trends among adults ≥75 years have not been investigated.
Objectives
The purpose of this study was to assess the trends and regional differences in HF-related mortality among older adults in the United States.
Methods
Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2019 for HF-related mortality in adults ≥75 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region.
Results
Between 1999 and 2019, 5,014,919 HF-related deaths occurred among adults ≥75 years. The AAMR declined from 141.0 in 1999 to 108.3 in 2012 (APC: -2.1; 95% CI: -2.4 to -1.9), after which it increased to 121.3 in 2019 (APC: 1.7; 95% CI: 1.2-2.2). Men had consistently higher AAMR than women from 1999 (AAMR men: 158.3 vs women: 131.0) to 2019 (AAMR men: 141.1 vs women: 107.8). Non-Hispanic (NH) White adults had the highest overall AAMR (127.2), followed by NH Black (108.7), NH American Indian/Alaska Native (102.0), Hispanic or Latino (78.0), and NH Asian or Pacific Islander adults (57.1) AAMR also varied substantially by region (overall AAMR: Midwest 133.9; South: 119.2; West: 116.3; Northeast: 113.5), and nonmetropolitan areas had higher HF-related AAMR (147.0) than metropolitan areas (115.2). States in the top 90th percentile of HF-related AAMR were Mississippi, Oklahoma, West Virginia, Oregon, and Indiana, which had approximately double the AAMRs compared with states that fell into the lower 10th percentile.
Conclusions
Following a period of steady decline, HF-related mortality in U.S. adults ≥75 years has increased since 2012. The highest AAMRs were observed among White adults and men, and among patients living in the Midwestern and nonmetropolitan United States. Targeted strategies are needed to prevent and treat HF among older adults to curb increasing levels of HF-related mortality.

Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

JACC Heart Fail: 01 Nov 2022; 10:851-859
Siddiqi TJ, Khan Minhas AM, Greene SJ, Van Spall HGC, ... Butler J, Khan MS
JACC Heart Fail: 01 Nov 2022; 10:851-859 | PMID: 36328654
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Abstract

Finerenone and Heart Failure Outcomes by Kidney Function/Albuminuria in Chronic Kidney Disease and Diabetes.

Filippatos G, Anker SD, Pitt B, Rossing P, ... Ruilope LM, Agarwal R
Background
In patients with type 2 diabetes (T2D), risks of cardiovascular mortality and heart failure (HF) increase with decreasing kidney function (estimated glomerular filtration rate [eGFR]) and increasing albuminuria (urine albumin-to-creatinine ratio [UACR]). Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and T2D in FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis).
Objectives
This study sought to evaluate the effects of finerenone on HF outcomes by eGFR and/or UACR categories.
Methods
FIDELITY included 13,026 patients with T2D and CKD (UACR 30-5,000 mg/g and eGFR ≥25 mL/min/1.73 m2) randomized to finerenone or placebo. Time-to-event outcomes were first hospitalization for heart failure (HHF), cardiovascular death or first HHF, recurrent HHF, and cardiovascular death or recurrent HHF, analyzed in subgroups by baseline eGFR (<60 and ≥60 mL/min/1.73 m2) and/or UACR (<300 and ≥300 mg/g).
Results
Compared with placebo, finerenone significantly reduced risk of first HHF (HR: 0.78 [95% CI: 0.66-0.92]; P = 0.003), cardiovascular death or first HHF (HR: 0.83 [95% CI: 0.74-0.93]; P = 0.002), recurrent HHF (HR: 0.79 [95% CI: 0.64-0.96]; P = 0.021), and cardiovascular death or recurrent HHF (HR: 0.82 [95% CI: 0.72-0.95]; P = 0.006). The risk of outcomes increased across baseline eGFR and UACR categories; lowest incidences were seen in patients with an eGFR ≥60 mL/min/1.73 m2 and a UACR <300 mg/g. Finerenone improved HF outcomes irrespective of baseline eGFR and/or UACR categories (all P interaction values >0.10).
Conclusions
Compared with placebo, finerenone improved HF-related outcomes in patients with CKD and T2D, with consistent benefits across eGFR and/or UACR categories. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Chronic Kidney Disease [FIGARO-DKD], NCT02545049).

Copyright © 2022. Published by Elsevier Inc.

JACC Heart Fail: 01 Nov 2022; 10:860-870
Filippatos G, Anker SD, Pitt B, Rossing P, ... Ruilope LM, Agarwal R
JACC Heart Fail: 01 Nov 2022; 10:860-870 | PMID: 36328655
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This program is still in alpha version.