Journal: JACC Heart Fail

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Abstract

Contemporary Applications of Machine Learning for Device Therapy in Heart Failure.

Gautam N, Ghanta SN, Clausen A, Saluja P, ... Fudim M, Al\'Aref SJ
Despite a better understanding of the underlying pathogenesis of heart failure (HF), pharmacotherapy, surgical, and percutaneous interventions do not prevent disease progression in all patients, and a significant proportion of patients end up requiring advanced therapies. Machine learning (ML) is gaining wider acceptance in cardiovascular medicine because of its ability to incorporate large, complex, and multidimensional data and to potentially facilitate the creation of predictive models not constrained by many of the limitations of traditional statistical approaches. With the coexistence of \"big data\" and novel advanced analytic techniques using ML, there is ever-increasing research into applying ML in the context of HF with the goal of improving patient outcomes. Through this review, the authors describe the basics of ML and summarize the existing published reports regarding contemporary applications of ML in device therapy for HF while highlighting the limitations to widespread implementation and its future promises.

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

JACC Heart Fail: 01 Sep 2022; 10:603-622
Gautam N, Ghanta SN, Clausen A, Saluja P, ... Fudim M, Al'Aref SJ
JACC Heart Fail: 01 Sep 2022; 10:603-622 | PMID: 36049812
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Abstract

Pathophysiologic Processes and Novel Biomarkers Associated With Congestion in Heart Failure.

Pandhi P, Ter Maaten JM, Anker SD, Ng LL, ... Voors AA, Sama IE
Background
Congestion is the main driver behind symptoms of heart failure (HF), but pathophysiology related to congestion remains poorly understood.
Objectives
Using pathway and differential expression analyses, the authors aim to identify biological processes and biomarkers associated with congestion in HF.
Methods
A congestion score (sum of jugular venous pressure, orthopnea, and peripheral edema) was calculated in 1,245 BIOSTAT-CHF patients with acute or worsening HF. Patients with a score ranking in the bottom or top categories of congestion were deemed noncongested (n = 408) and severely congested (n = 142), respectively. Plasma concentrations of 363 unique proteins (Olink Proteomics Multiplex CVD-II, CVD-III, Immune Response and Oncology II panels) were compared between noncongested and severely congested patients. Results were validated in an independent validation cohort of 1,342 HF patients (436 noncongested and 232 severely congested).
Results
Differential protein expression analysis showed 107/363 up-regulated and 6/363 down-regulated proteins in patients with congestion compared with those without. FGF-23, FGF-21, CA-125, soluble ST2, GDF-15, FABP4, IL-6, and BNP were the strongest up-regulated proteins (fold change [FC] >1.30, false discovery rate [FDR], P < 0.05). KITLG, EGF, and PON3 were the strongest down-regulated proteins (FC <-1.30, FDR P < 0.05). Pathways most prominently involved in congestion were related to inflammation, endothelial activation, and response to mechanical stimulus. The validation cohort yielded similar findings.
Conclusions
Severe congestion in HF is mainly associated with inflammation, endothelial activation, and mechanical stress. Whether these pathways play a causal role in the onset or progression of congestion remains to be established. The identified biomarkers may become useful for diagnosing and monitoring congestion status.

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

JACC Heart Fail: 01 Sep 2022; 10:623-632
Pandhi P, Ter Maaten JM, Anker SD, Ng LL, ... Voors AA, Sama IE
JACC Heart Fail: 01 Sep 2022; 10:623-632 | PMID: 36049813
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Abstract

Electronic Health Record-Based Deep Learning Prediction of Death or Severe Decompensation in Heart Failure Patients.

McGilvray MMO, Heaton J, Guo A, Masood MF, ... Pasque MK, Foraker R
Background
Surgical mechanical ventricular assistance and cardiac replacement therapies, although life-saving in many heart failure (HF) patients, remain high-risk. Despite this, the difficulty in timely identification of medical therapy nonresponders and the dire consequences of nonresponse have fueled early, less selective surgical referral. Patients who would have ultimately responded to medical therapy are therefore subjected to the risk and life disruption of surgical therapy.
Objectives
The purpose of this study was to develop deep learning models based upon commonly-available electronic health record (EHR) variables to assist clinicians in the timely and accurate identification of HF medical therapy nonresponders.
Methods
The study cohort consisted of all patients (age 18 to 90 years) admitted to a single tertiary care institution from January 2009 through December 2018, with International Classification of Disease HF diagnostic coding. Ensemble deep learning models employing time-series and densely-connected networks were developed from standard EHR data. The positive class included all observations resulting in severe progression (death from any cause or referral for HF surgical intervention) within 1 year.
Results
A total of 79,850 distinct admissions from 52,265 HF patients met observation criteria and contributed >350 million EHR datapoints for model training, validation, and testing. A total of 20% of model observations fit positive class criteria. The model C-statistic was 0.91.
Conclusions
The demonstrated accuracy of EHR-based deep learning model prediction of 1-year all-cause death or referral for HF surgical therapy supports clinical relevance. EHR-based deep learning models have considerable potential to assist HF clinicians in improving the application of advanced HF surgical therapy in medical therapy nonresponders.

Copyright © 2022 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 01 Sep 2022; 10:637-647
McGilvray MMO, Heaton J, Guo A, Masood MF, ... Pasque MK, Foraker R
JACC Heart Fail: 01 Sep 2022; 10:637-647 | PMID: 36049815
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Abstract

Chemoreflex and Baroreflex Sensitivity Hold a Strong Prognostic Value in Chronic Heart Failure.

Giannoni A, Gentile F, Buoncristiani F, Borrelli C, ... Emdin M, Passino C
Background
Novel treatments targeting in baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS) heart failure (HF) are grounded on small prognostic studies, partly performed in the pre-beta-blockade era.
Objectives
This study assesses the clinical/prognostic significance of BRS and CRS in a large cohort of patients with chronic HF on modern treatments.
Methods
Outpatients with chronic HF with either reduced (≤40%) or mildly reduced left ventricular ejection fraction (LVEF) (41% to 49%) underwent BRS (SD method) and CRS to hypoxia and hypercapnia (rebreathing technique) assessment and were followed up for a composite endpoint of cardiac death, implantable cardioverter-defibrillator shock, or HF hospitalization.
Results
A total of 425 patients were enrolled (65 ± 12 years of age, LVEF 32% [IQR: 25%-38%], 94% on beta blockers). Patients with decreased BRS (n = 96 of 267, 36%) had lower exercise tolerance and heart rate variability (P < 0.05), whereas those with increased CRS to both hypoxia and hypercapnia (n = 74 of 369, 20%) had higher plasma norepinephrine and central apneas across the 24-hour period (P < 0.01). During a median 50-month follow-up (IQR: 24-94 months), the primary endpoint occurred more often in patients with decreased BRS (log-rank: 11.64; P = 0.001), mainly for increased cardiac deaths/implantable cardioverter-defibrillator shocks, and in those with increased CRS (log-rank: 34.81; P < 0.001), mainly for increased HF hospitalizations. Patients with both abnormal BRS and CRS showed the worst outcome. Reduced BRS (HR: 2.76 [95% CI: 1.36-5.63]; P = 0.005) and increased CRS (HR: 2.91 [95% CI: 1.34-6.31]; P = 0.007) were independently associated with the primary outcome and increased risk stratification when added to standard HF prognosticators (P < 0.05).
Conclusions
In subjects with HF on modern treatment, abnormal BRS and CRS are frequently observed. BRS and CRS elicit autonomic imbalance, exercise limitation, unstable ventilation, and predict adverse outcomes.

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

JACC Heart Fail: 01 Sep 2022; 10:662-676
Giannoni A, Gentile F, Buoncristiani F, Borrelli C, ... Emdin M, Passino C
JACC Heart Fail: 01 Sep 2022; 10:662-676 | PMID: 36049816
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Abstract

Sequential Evaluation of NT-proBNP in Heart Failure: Insights Into Clinical Outcomes and Efficacy of Vericiguat.

Armstrong PW, Zheng Y, Troughton RW, Lund LH, ... Ezekowitz JA, VICTORIA Study Group
Background
The effect of vericiguat on sequential N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown.
Objectives
This study assessed the relationship between changes in NT-proBNP and the primary outcome (cardiovascular death or heart failure hospitalization); evaluated the effect of vericiguat on changes in NT-proBNP; and explored the association between the efficacy of vericiguat and changes in NT-proBNP.
Methods
NT-proBNP was measured at randomization and at 16, 32, 48, and 96 weeks in 4,805 of 5,050 patients. The association between NT-proBNP change at week 16 and the primary outcome was assessed. The relationship between changes in NT-proBNP and the primary outcome according to treatment group was assessed by using joint modeling and mediation analysis.
Results
A significant and sustained decline in NT-proBNP levels was seen in both treatment groups. After week 16, NT-proBNP levels decreased more with vericiguat vs placebo (any reduction: odds ratio [OR]: 1.45 [95% CI: 1.28-1.65]; P < 0.001; ≥50% reduction: OR: 1.27 [95% CI: 1.10-1.47]; P = 0.001) and were less likely to increase (≥20% increase: OR: 0.68 [95% CI: 0.59-0.78]; P < 0.001; ≥50% increase: OR: 0.70 [95% CI: 0.59-0.82]; P < 0.001). The treatment effect related to serial NT-proBNP on the primary composite outcome was HR: 0.96 (95% CI: 0.95-0.99) at week 16, which increased to HR: 0.90 (95% CI: 0.85-0.96) at week 48; the average extent of mediation of the composite outcome related to NT-proBNP was 45%.
Conclusions
In patients with worsening HFrEF, vericiguat significantly decreased NT-proBNP levels compared with placebo. This change appeared associated with a modest relative improvement in the primary outcome of cardiovascular death or heart failure hospitalization. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

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

JACC Heart Fail: 01 Sep 2022; 10:677-688
Armstrong PW, Zheng Y, Troughton RW, Lund LH, ... Ezekowitz JA, VICTORIA Study Group
JACC Heart Fail: 01 Sep 2022; 10:677-688 | PMID: 36049817
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Abstract

Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.

Myhre PL, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD
Background
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT-proBNP levels.
Objectives
To assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF.
Methods
This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria (≥300 ng/L for non-atrial fibrillation or flutter [AFF]; ≥600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events.
Results
Among the 6,262 included patients (mean 71.7 years and 3,516 [56%] men), the median (Q1-Q3) baseline concentration of NT-proBNP was 716 (469-1,280) ng/L and 1,399 (962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log2NTpro-BNP was 1.53 [1.46, 1.62] and Q4 vs Q1: 3.46 [95%CI 2.48-4.22]; P < 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles.
Conclusions
Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Copyright © 2022. Published by Elsevier Inc.

JACC Heart Fail: 27 Aug 2022; epub ahead of print
Myhre PL, Vaduganathan M, Claggett BL, Miao ZM, ... McMurray JJV, Solomon SD
JACC Heart Fail: 27 Aug 2022; epub ahead of print | PMID: 36114137
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Abstract

Obesity Status and Physical Rehabilitation in Older Patients Hospitalized With Acute HF: Insights From REHAB-HF.

Peters AE, Kitzman DW, Chen H, Nelson MB, ... Whellan DJ, Mentz RJ
Background
In the REHAB-HF trial, a novel, early, transitional, multidomain rehabilitation intervention improved physical function, frailty, quality of life (QOL), and depression in older patients hospitalized for acute decompensated heart failure (ADHF), but the potential impact of baseline obesity on this intervention has not been studied.
Objectives
This study assessed for treatment interactions by body mass index (BMI) subgroups for a novel rehabilitation intervention in ADHF.
Methods
Three-month outcomes including Short Physical Performance Battery (SPPB) (primary outcome), 6-minute walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ) were assessed by baseline BMI (≥30 kg/m2 vs <30 kg/m2). Six-month end points included all-cause rehospitalization and death. All analyses were adjusted for age, sex, clinical site, and ejection fraction category, and 3-month outcomes were also adjusted for baseline measure. The prespecified significance level for treatment interaction by BMI category was P ≤ 0.10.
Results
Of 349 trial participants, 204 (58%) had BMI ≥30 kg/m2 and 145 (42%) <30 kg/m2. Compared with patients with BMI <30 kg/m2, participants with BMI ≥30 kg/m2 were younger (age 71 ± 7 years vs 75 ± 9 years), more frequently women (57% vs 46%), and had significantly worse baseline physical function and QOL. Although interaction P values for 3-month outcomes by BMI were not significant (interaction P > 0.15 for overall measures), adjusted SPPB effect sizes were nominally larger for participants with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2: +1.7 (95% CI: 0.8-2.7) vs +1.1 (95% CI: -0.1 to 2.2). This difference in SPPB effect size was due largely to improvements in the balance component of the SPPB for participants with BMI ≥30 kg/m2: +0.6 (95% CI: 0.2-1.0) vs 0.0 (-0.6 to 0.5) for those with BMI <30 kg/m2 (interaction P = 0.02). In contrast, adjusted 6MWD and KCCQ effect sizes were smaller for participants with BMI ≥30 kg/m2 compared with those with BMI <30 kg/m2: +21 meters (-17 to 59) vs +53 meters (6-100), and +5.0 (-4 to 14) vs +11 (-0.5 to 22), respectively. There was no significant interaction by BMI for 6-month clinical outcomes (all interaction P > 0.3).
Conclusions
Older patients with ADHF benefit from the rehabilitation therapy regardless of BMI. Benefits for patients with obesity may be more evident in the multidomain measure of physical function (SPPB), compared with the 6MWD or KCCQ, which may be driven, in part, by the unique aspects of the novel rehabilitation intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

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

JACC Heart Fail: 17 Aug 2022; epub ahead of print
Peters AE, Kitzman DW, Chen H, Nelson MB, ... Whellan DJ, Mentz RJ
JACC Heart Fail: 17 Aug 2022; epub ahead of print | PMID: 36164731
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Abstract

Angiotensinogen: More Than Its Downstream Products: Evidence From Population Studies and Novel Therapeutics.

Kahlon T, Carlisle S, Otero Mostacero D, Williams N, Trainor P, DeFilippis AP
The renin-angiotensin-aldosterone system (RAAS) is a well-defined pathway playing a key role in maintaining circulatory homeostasis. Abnormal activation of RAAS contributes to development of cardiovascular disease, including heart failure, cardiac hypertrophy, hypertension, and atherosclerosis. Although several key RAAS enzymes and peptide hormones have been thoroughly investigated, the role of angiotensinogen-the precursor substrate of the RAAS pathway-remains less understood. The study of angiotensinogen single-nucleotide polymorphisms (SNPs) has provided insight into associations between angiotensinogen and hypertension, congestive heart failure, and atherosclerotic cardiovascular disease. Targeted drug therapy of RAAS has dramatically improved clinical outcomes for patients with heart failure, myocardial infarction, and hypertension. However, all such therapeutics block RAAS components downstream of angiotensinogen and elicit compensatory pathways that limit their therapeutic efficacy as monotherapy. Upstream RAAS targeting by an angiotensinogen inhibitor has the potential to be more efficacious in patients with suboptimal RAAS inhibition and has a better safety profile than multiagent RAAS blockade. Newly developed therapeutics that target angiotensinogen through antisense oligonucleotides or silencer RNA technologies are providing a novel perspective into the pathobiology of angiotensinogen and show promise as the next frontier in the treatment of cardiovascular disease.

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

JACC Heart Fail: 04 Aug 2022; epub ahead of print
Kahlon T, Carlisle S, Otero Mostacero D, Williams N, Trainor P, DeFilippis AP
JACC Heart Fail: 04 Aug 2022; epub ahead of print | PMID: 35963818
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Abstract

Validation of the Kansas City Cardiomyopathy Questionnaire in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

Nassif M, Fine JT, Dolan C, Reaney M, ... Gosch K, Spertus JA
Background
The primary goal for treating patients with obstructive hypertrophic cardiomyopathy (oHCM) is to improve their symptoms, function, and quality of life. Although the Kansas City Cardiomyopathy Questionnaire (KCCQ) is a valid, reliable, and sensitive measure for other etiologies of heart failure, its appropriateness for patients with oHCM is unknown.
Objectives
The purpose of this study was to establish the interpretability, validity, reliability, and responsiveness of the KCCQ in patients with oHCM.
Methods
Cognitive debriefing of the KCCQ was performed in 26 patients with oHCM. The validity, reliability, responsiveness, and interpretability of the KCCQ were tested in 196 participants from the EXPLORER-HCM trial by comparing each scale with relevant comparators, describing the internal reliability and the mean change in stable patients, and comparing the mean change in patients who reported different degrees of clinical change using a patient-reported global impression of change (PGIC).
Results
All KCCQ domains demonstrated strong correlations with external standards of symptoms, function, social limitation, and quality of life, including a recently designed instrument measuring symptoms not captured by the KCCQ (P < 0.0001 for all). Mean changes in stable patients were nonsignificant, ranging from 0.21 to 2.3 points (P > 0.30 for all), with high intraclass correlation coefficients. The mean changes in patients with small, moderate, and large clinical changes were consistent with the 5-, 10-, and 20-point mean differences observed in other etiologies of heart failure.
Conclusions
The KCCQ is well understood by patients with oHCM and has strong evidence of good psychometric performance. It can not only serve as a relevant endpoint in clinical trials of oHCM therapy, but may also prove useful in the clinical care of patients with oHCM. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).

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

JACC Heart Fail: 01 Aug 2022; 10:531-539
Nassif M, Fine JT, Dolan C, Reaney M, ... Gosch K, Spertus JA
JACC Heart Fail: 01 Aug 2022; 10:531-539 | PMID: 35902155
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Abstract

Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score: Insights From DAPA-HF.

Butt JH, Dewan P, DeFilippis EM, Biering-Sørensen T, ... Fiuzat M, McMurray JJV
Background
The Heart Failure Collaboratory (HFC) has developed a score integrating classes and doses of guideline-directed medical therapies prescribed for patients with heart failure (HF) and reduced ejection fraction. One potential use of this score is to test whether new treatments demonstrate incremental benefits, even in patients receiving comprehensive guideline-directed medical therapy.
Objectives
The authors investigated the efficacy of dapagliflozin according to a modified HFC score in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.
Methods
In DAPA-HF, 4,744 patients with HF and reduced ejection fraction were randomized to dapagliflozin or placebo. The modified HFC score accounted for race and electrocardiogram rhythm and rate, with a maximum possible score of 100%. The primary outcome was the composite of worsening HF or cardiovascular death.
Results
The median modified HFC score was 50% (IQR: 27.5%-62.5%; range 0%-100%). Compared with the lowest tertile, the highest tertile of the treatment score was associated with a lower risk of worsening HF or cardiovascular death (tertile 1, reference; tertile 2, HR: 0.97 [95% CI: 0.82-1.14]; tertile 3, HR: 0.83 [95% CI: 0.70-0.99]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of treatment score (the HRs for dapagliflozin vs placebo from tertile 1 to 3 were: 0.76 [95% CI: 0.61-0.94], 0.76 [95% CI: 0.60-0.97], and 0.71 [95% CI: 0.55-0.90]), respectively; Pinteraction = 0.89). Consistent benefits were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TTS).
Conclusions
Dapagliflozin, compared with placebo, improved all outcomes examined, regardless of the modified HFC score. This score can be easily calculated in clinical trials and used to evaluate the incremental effects of new treatments. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

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

JACC Heart Fail: 01 Aug 2022; 10:543-555
Butt JH, Dewan P, DeFilippis EM, Biering-Sørensen T, ... Fiuzat M, McMurray JJV
JACC Heart Fail: 01 Aug 2022; 10:543-555 | PMID: 35902157
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Abstract

Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines.

Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, ... Nohria A, Neilan TG
Background
Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.
Objectives
This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.
Methods
This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.
Results
Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013).
Conclusions
SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

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

JACC Heart Fail: 01 Aug 2022; 10:559-567
Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, ... Nohria A, Neilan TG
JACC Heart Fail: 01 Aug 2022; 10:559-567 | PMID: 35902159
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Abstract

Expenditure on Heart Failure in the United States: The Medical Expenditure Panel Survey 2009-2018.

Bhatnagar R, Fonarow GC, Heidenreich PA, Ziaeian B
Background
With rising United States health care expenditure, estimating current spending for patients with heart failure (HF) informs the value of preventative health interventions.
Objectives
The purpose of this study was to estimate current health care expenditure growth for patients with HF in the United States.
Methods
The authors pooled MEPS (Medical Expenditure Panel Survey) data from 2009-2018 to calculate total HF-related expenditure across clinical settings in the United States. A 2-part model adjusted for demographics, comorbidities, and year was used to estimate annual mean and incremental expenditures associated with HF.
Results
In the United States, an average of $28,950 (2018 inflation-adjusted dollars) is spent per year for health care-related expenditure for individuals with HF compared with $5,727 for individuals without HF. After adjusting for demographics and comorbidities, a diagnosis of HF was associated with $3,594 in annual incremental expenditure compared with those without HF. HF-related expenditure increased from $26,864 annual per person in 2009-2010 to $32,955 in 2017-2018, representing a 23% rise over 10 years. In comparison, expenditure on myocardial infarction, type 2 diabetes mellitus, and cancer grew by 16%, 28%, and 16%, respectively. Most of the cost was related to hospitalization: $12,569 per year. Outpatient office-based care and prescription medications saw the greatest growth in cost over the period, 41% and 24%, respectively. Estimated incremental national expenditure for HF per year was $22.3 billion; total annual expenditure for adults with HF was $179.5 billion.
Conclusions
HF is a costly condition for which expenditure is growing faster than that of other chronic conditions.

Published by Elsevier Inc.

JACC Heart Fail: 01 Aug 2022; 10:571-580
Bhatnagar R, Fonarow GC, Heidenreich PA, Ziaeian B
JACC Heart Fail: 01 Aug 2022; 10:571-580 | PMID: 35902161
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Abstract

Supranormal Left Ventricular Ejection Fraction, Stroke Volume, and Cardiovascular Risk: Findings From Population-Based Cohort Studies.

Shah S, Segar MW, Kondamudi N, Ayers C, ... Longstreth WT, Pandey A
Background
Supranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)-assessed by cardiac magnetic resonance (CMR)-in healthy, community-dwelling individuals is unknown.
Objectives
The purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD.
Methods
Participants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index.
Results
The study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume.
Conclusions
Among community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.

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

JACC Heart Fail: 01 Aug 2022; 10:583-594
Shah S, Segar MW, Kondamudi N, Ayers C, ... Longstreth WT, Pandey A
JACC Heart Fail: 01 Aug 2022; 10:583-594 | PMID: 35902163
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Abstract

Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In.

Vader JM, Givertz MM, Starling RC, McNulty SE, ... Mann DL, LIFE Investigators
Background
The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction.
Objectives
The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction.
Methods
In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan.
Results
Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance.
Conclusions
Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736).

Copyright © 2022 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 01 Jul 2022; 10:449-456
Vader JM, Givertz MM, Starling RC, McNulty SE, ... Mann DL, LIFE Investigators
JACC Heart Fail: 01 Jul 2022; 10:449-456 | PMID: 35772853
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Abstract

Happy Heart Syndrome: Frequency, Characteristics, and Outcome of Takotsubo Syndrome Triggered by Positive Life Events.

Stiermaier T, Walliser A, El-Battrawy I, Pätz T, ... Santoro F, Eitel I
Background
The association with a preceding stressor is a characteristic feature of takotsubo syndrome (TTS). Negative emotions before TTS are common and led to the popular term \"broken heart syndrome.\" In contrast, pleasant triggers (\"happy heart syndrome\") are rare and are scarcely investigated.
Objectives
The authors analyzed the frequency, clinical characteristics, and prognostic implications of positive emotional stressors in the multicenter GEIST (GErman-Italian-Spanish Takotsubo) Registry.
Methods
Patients enrolled in the registry were categorized according to their stressors. This analysis compared patients with pleasant emotional events with patients with negative emotional events.
Results
Of 2,482 patients in the registry, 910 patients (36.7%) exhibited an emotional trigger consisting of 873 \"broken hearts\" (95.9%) and 37 \"happy hearts\" (4.1%). Consequently, the prevalence of pleasant emotional triggers was 1.5% of all TTS cases. Compared with patients with TTS with negative preceding events, patients with happy heart syndrome were more frequently male (18.9% vs 5.0%; P < 0.01) and had a higher prevalence of atypical ballooning patterns (27.0% vs 12.5%; P = 0.01), particularly midventricular ballooning. In-hospital complications, including death, pulmonary edema, cardiogenic shock, or stroke (8.1% vs 12.3%; P = 0.45), and long-term mortality rates (2.7% vs 8.8%; P = 0.20) were similar in \"happy hearts\" and \"broken hearts.\"
Conclusions
Happy heart syndrome is a rare type of TTS characterized by a higher prevalence of male patients and atypical, nonapical ballooning compared with patients with negative emotional stressors. Despite similar short- and long-term outcomes in our study, additional data are needed to explore whether numerically lower event rates in \"happy hearts\" would be statistically significant in a larger sample size. (GErman-Italian-Spanish Takotsubo Registry [GEIST Registry]; NCT04361994).

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

JACC Heart Fail: 01 Jul 2022; 10:459-466
Stiermaier T, Walliser A, El-Battrawy I, Pätz T, ... Santoro F, Eitel I
JACC Heart Fail: 01 Jul 2022; 10:459-466 | PMID: 35772855
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Abstract

Hospitalization Patterns and Impact of a Magnetically-Levitated Left Ventricular Assist Device in the MOMENTUM 3 Trial.

Vidula H, Takeda K, Estep JD, Silvestry SC, ... Dirckx N, Mehra MR
Background
In the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) pivotal trial, the HeartMate 3 (HM3) fully magnetically levitated left ventricular assist device (LVAD) demonstrated superiority over the axial-flow HeartMate II (HMII) LVAD. The patterns and predictors of hospitalizations with the HM3 LVAD have not been characterized.
Objectives
This study sought to determine causes, predictors, and impact of hospitalizations during LVAD support.
Methods
Patients discharged after LVAD implantation were analyzed. In the pivotal trial, 485 recipients of HM3 were compared with 471 recipients of HMII. The pivotal trial HM3 group was also compared to 949 recipients of HM3 in the postapproval phase within the trial portfolio. Predictors of cause-specific rehospitalization were analyzed.
Results
The rates of rehospitalization were lower with HM3 LVAD than with HMII LVAD in the pivotal trial (225.7 vs 246.4 events per 100 patient-years; P < 0.05). Overall, rehospitalization rates and duration were similar in the HM3 postapproval phase and pivotal trial but prolonged hospitalizations (>7 days) were less frequent (rate ratio: 0.90 [95% CI: 0.80-0.98]; P < 0.05). In HM3 recipients, the most frequent causes of rehospitalization included infection, heart failure (HF)-related events, and bleeding. First rehospitalization caused by HF-related event versus other causes was associated with reduced survival (HR: 2.2 [95% CI: 1.3-3.9]; P = 0.0014). Male sex, non-White race, presence of cardiac resynchronization therapy/implantable cardioverter-defibrillator, obesity, higher right atrial pressure, smaller LV size, longer duration of index hospitalization, and lower estimated glomerular filtration rate at index discharge predicted HF hospitalizations.
Conclusions
Contemporary support with the HM3 fully magnetically levitated LVAD is associated with a lower hospitalization burden than with prior pumps; however, rehospitalizations for infection, HF, and bleeding remain important challenges for progress in the patient journey. (MOMENTUM 3 IDE Clinical Study, NCT02224755; MOMENTUM 3 Continued Access Protocol [MOMENTUM 3 CAP], NCT02892955).

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

JACC Heart Fail: 01 Jul 2022; 10:470-481
Vidula H, Takeda K, Estep JD, Silvestry SC, ... Dirckx N, Mehra MR
JACC Heart Fail: 01 Jul 2022; 10:470-481 | PMID: 35772857
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Abstract

Association Between Thigh Muscle Fat Infiltration and Incident Heart Failure: The Health ABC Study.

Huynh K, Ayers C, Butler J, Neeland I, ... Barton G, Berry JD
Background
Excess adiposity is a well-known risk factor for heart failure (HF). Fat accumulation in and around the peripheral skeletal muscle may further inform risk for HF.
Objectives
The purpose of this study was to evaluate the association between intramuscular and intermuscular fat deposition and incident HF in a longitudinal cohort of community-dwelling older adults.
Methods
The associations of intramuscular and intermuscular fat with incident HF were assessed using Cox models among 2,399 participants from the Health ABC (Health, Aging and Body Composition) study (70-79 years of age, 48% male, 40.2% Black) without baseline HF. Intramuscular fat was determined by bilateral thigh muscle density on computed tomography and intermuscular fat area was determined with computed tomography.
Results
After a median follow-up of 12.2 years, there were 485 incident HF events. Higher sex-specific tertiles of intramuscular and intermuscular fat were each associated with HF risk. After multivariable adjustment for age, sex, race, education, blood pressure, fasting blood sugar, current smoking, prevalent coronary disease, and creatinine, higher intramuscular fat, but not intermuscular fat, was associated with higher risk for HF (HR: 1.34 [95% CI: 1.06-1.69]; P = 0.012, tertile 3 vs tertile 1). This association remained significant after additional adjustment for body mass index (HR: 1.32 [95% CI: 1.03-1.69]), total percent fat (HR: 1.33 [95% CI: 1.03-1.72]), visceral fat (HR: 1.30 [95% CI: 1.01-1.65]), and indexed thigh muscle strength (HR: 1.30 [95% CI: 1.03-1.64]). The association between higher intramuscular fat and HF appeared specific to higher risk of incident HF with reduced ejection fraction (HR: 1.53 [95% CI: 1.03-2.29]), but not with HF with preserved ejection fraction (HR: 1.28 [95% CI: 0.82-1.98]).
Conclusions
Intramuscular, but not intermuscular, thigh muscle fat is independently associated with HF after adjustment for cardiometabolic risk factors and other measurements of adiposity.

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

JACC Heart Fail: 01 Jul 2022; 10:485-493
Huynh K, Ayers C, Butler J, Neeland I, ... Barton G, Berry JD
JACC Heart Fail: 01 Jul 2022; 10:485-493 | PMID: 35772859
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Abstract

Increase in BNP in Response to Endothelin-Receptor Antagonist Atrasentan Is Associated With Incident Heart Failure.

Smeijer JD, Koomen J, Kohan DE, McMurray JJV, ... de Zeeuw D, Heerspink HJL
Background
The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.
Objectives
The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk.
Methods
Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.
Results
Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).
Conclusions
In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532).

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

JACC Heart Fail: 01 Jul 2022; 10:498-507
Smeijer JD, Koomen J, Kohan DE, McMurray JJV, ... de Zeeuw D, Heerspink HJL
JACC Heart Fail: 01 Jul 2022; 10:498-507 | PMID: 35772861
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This program is still in alpha version.