Topic: Heart Failure

Abstract

Cardiac Rehabilitation for Patients With Heart Failure: JACC Expert Panel.

Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
Cardiac rehabilitation is defined as a multidisciplinary program that includes exercise training, cardiac risk factor modification, psychosocial assessment, and outcomes assessment. Exercise training and other components of cardiac rehabilitation (CR) are safe and beneficial and result in significant improvements in quality of life, functional capacity, exercise performance, and heart failure (HF)-related hospitalizations in patients with HF. Despite outcome benefits, cost-effectiveness, and strong practice guideline recommendations, CR remains underused. Clinicians, health care leaders, and payers should prioritize incorporating CR as part of the standard of care for patients with HF.

Published by Elsevier Inc.

J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469
Bozkurt B, Fonarow GC, Goldberg LR, Guglin M, ... Wolfel E, ACC’s Heart Failure and Transplant Section and Leadership Council
J Am Coll Cardiol: 22 Mar 2021; 77:1454-1469 | PMID: 33736829
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Abstract

Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced.

Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
Background
Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction.
Objectives
This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization.
Results
The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group.
Conclusions
In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407
Ferreira JP, Zannad F, Pocock SJ, Anker SD, ... Schueler E, Packer M
J Am Coll Cardiol: 22 Mar 2021; 77:1397-1407 | PMID: 33736821
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Abstract

Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.

Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Background
Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention.
Objectives
This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload.
Methods
This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment.
Results
Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients.
Conclusions
Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

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

J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392
Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 22 Mar 2021; 77:1381-1392 | PMID: 33736819
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Abstract

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
Background
Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.
Objectives
The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.
Methods
The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.
Results
CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.
Conclusions
Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.

Copyright © 2021. Published by Elsevier Inc.

J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759
Pascual-Figal DA, Bayes-Genis A, Díez-Díez M, Hernández-Vicente Á, ... Sánchez-Cabo F, Fuster JJ
J Am Coll Cardiol: 12 Apr 2021; 77:1747-1759 | PMID: 33832602
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Abstract

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
Background
The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.
Objectives
This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.
Methods
Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.
Results
AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.
Conclusions
The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

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

J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743
Pavo N, Prausmüller S, Spinka G, Goliasch G, ... Zuckermann A, Hülsmann M
J Am Coll Cardiol: 12 Apr 2021; 77:1731-1743 | PMID: 33832600
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Abstract

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Aims
In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction.
Methods and results
Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains.
Conclusion
Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

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

Eur Heart J: 30 Mar 2021; 42:1203-1212
Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Eur Heart J: 30 Mar 2021; 42:1203-1212 | PMID: 33420498
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Abstract

Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial.

Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Background
In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation).
Methods
The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial\'s primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest.
Results
Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2).
Conclusions
In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.



Circulation: 05 Apr 2021; 143:1377-1390
Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, ... Mark DB, CABANA Investigators
Circulation: 05 Apr 2021; 143:1377-1390 | PMID: 33554614
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Abstract

Development and Validation of Machine Learning-Based Race-Specific Models to Predict 10-Year Risk of Heart Failure: A Multi-Cohort Analysis.

Segar MW, Jaeger BC, Patel KV, Nambi V, ... de Lemos JA, Pandey A
Background: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and elucidate important contributors of HF development across races.
Methods:
We performed a retrospective analysis of four large, community cohort studies (ARIC, DHS, JHS, and MESA) with adjudicated HF events. Participants were aged >40 years and free of HF at baseline. Race-specific ML models for HF risk prediction were developed in the JHS cohort (for Black race-specific model) and White adults from ARIC (for White rate-specific model). The models included 39 candidate variables across demographic, anthropometric, medical history, laboratory, and electrocardiographic domains. The ML models were externally validated and compared with prior established traditional and non-race specific ML models in race-specific subgroups of the pooled MESA/DHS cohort and Black participants of ARIC. Harrell\'s C-index and Greenwood-Nam-D\'Agostino chi-square tests were used to assess discrimination and calibration, respectively.
Results:
The ML models had excellent discrimination in the derivation cohorts for Black (N=4,141 in JHS, C-index=0.88) and White (N=7,858 in ARIC, C-index=0.89) participants. In the external validation cohorts, the race-specific ML model demonstrated adequate calibration and superior discrimination (C-indices=0.80-0.83 [for Black individuals] and 0.82 [for White individuals]) compared with established HF risk models or with non-race specific ML models derived using race as a covariate. Among the risk factors, natriuretic peptide levels were the most important predictor of HF risk across both races, followed by troponin levels in Black and EKG-based Cornell voltage in White individuals. Other key predictors of HF risk among Black individuals were glycemic parameters and socioeconomic factors. In contrast, prevalent cardiovascular (CV) disease and traditional CV risk factors were stronger predictors of HF risk in White adults. Conclusions: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance when compared with traditional HF risk and non-race specific ML models. This approach identifies distinct race-specific contributors of HF.




Circulation: 12 Apr 2021; epub ahead of print
Segar MW, Jaeger BC, Patel KV, Nambi V, ... de Lemos JA, Pandey A
Circulation: 12 Apr 2021; epub ahead of print | PMID: 33845593
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Abstract

Exercise Stress Real-Time Cardiac Magnetic Resonance Imaging for Noninvasive Characterization of Heart Failure With Preserved Ejection Fraction: The HFpEF-Stress Trial.

Backhaus SJ, Lange T, George EF, Hellenkamp K, ... Seidler T, Schuster A
Background
Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF.
Methods
The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e\'>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time-volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain.
Results
Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e\' (12.5 versus 9.15), NT-proBNP (N-terminal pro-B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m2) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; P≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress (P≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early (P<0.001) diastolic emptying in patients with HFpEF during exercise stress. RT-CMR exercise stress LA long axis strain was independently associated with HFpEF (adjusted odds ratio, 0.657 [95% CI, 0.516-0.838]; P=0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; P=0.029).
Conclusions
RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17.



Circulation: 12 Apr 2021; 143:1484-1498
Backhaus SJ, Lange T, George EF, Hellenkamp K, ... Seidler T, Schuster A
Circulation: 12 Apr 2021; 143:1484-1498 | PMID: 33472397
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Abstract

Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure with Reduced Ejection Fraction: An Analysis of DAPA-HF.

Jhund PS, Ponikowski P, Docherty KF, Gasparyan SB, ... Solomon SD, McMurray JJV
Background: Patients with heart failure and reduced ejection fraction (HFrEF) will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (i.e. first and repeat) hospitalizations for heart failure in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
Methods:
The total number of HF hospitalizations and cardiovascular deaths was examined using the proportional rates approach of Lei-Wei-Ying-Yang (LWYY) and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable LWYY model.
Results:
Of 2371 participants randomized to placebo, 318 experienced 469 hospitalizations for heart failure among; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher NT-proBNP and NYHA class. In the LWYY model the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or CV death was 0.75 (95%CI 0.65-0.88), p=0.0002. In the joint frailty model, rate ratio for total HF hospitalizations was 0.71 (95% CI 0.61-0.82), p<0.0001 while for cardiovascular death the hazard ratio was 0.81(95%CI 0.67-0.98), p=00282. Conclusions: Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03036124.




Circulation: 08 Apr 2021; epub ahead of print
Jhund PS, Ponikowski P, Docherty KF, Gasparyan SB, ... Solomon SD, McMurray JJV
Circulation: 08 Apr 2021; epub ahead of print | PMID: 33832352
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Abstract

Heart Failure Primary Prevention: What Does SPRINT Add?: Recent Advances in Hypertension.

Raby K, Rocco M, Oparil S, Gilbert ON, Upadhya B
Hypertension is the most prevalent modifiable factor for the development of heart failure. However, the optimal blood pressure (BP) target for preventing heart failure remains uncertain. The SPRINT (Systolic BP Intervention Trial) was a large, randomized open-label trial (n=9361 participants) that showed the superiority of a systolic BP target of <120 mm Hg compared with <140 mm Hg, with a 36% lower rate of acute decompensated heart failure (ADHF) events. This beneficial effect was consistent across all the key prespecified subgroups, including advanced age, chronic kidney disease, and prior cardiovascular disease. Participants who had an ADHF event had a markedly increased risk of subsequent cardiovascular disease events, including recurrent ADHF. Randomization to the intensive arm did not affect the recurrence of ADHF after the initial ADHF event (hazard ratio, 0.93 [95% CI, 0.50-1.67]; P=0.81). A separate analysis demonstrated that the reduction in ADHF events in the intensive treatment group in SPRINT was not due to the differential use of diuretics between the 2 treatment groups. Although intensive BP treatment resulted in a lower cardiovascular disease event rate, this was not significantly associated with changes in left ventricular mass, function, or fibrosis, as assessed in SPRINT HEART, an ancillary study to SPRINT. Intensive BP treatment, however, significantly attenuated increases in carotid-femoral pulse wave velocity. Overall, these data highlight the importance of preventing ADHF in high cardiovascular risk hypertensive patients by optimal BP reduction as tested in SPRINT.



Hypertension: 04 Apr 2021:HYPERTENSIONAHA12116503; epub ahead of print
Raby K, Rocco M, Oparil S, Gilbert ON, Upadhya B
Hypertension: 04 Apr 2021:HYPERTENSIONAHA12116503; epub ahead of print | PMID: 33813850
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Abstract

Concurrent diabetes and heart failure: interplay and novel therapeutic approaches.

Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun QY, Lopaschuk GD
Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in the diabetic patients, collectively termed as \"diabetic cardiomyopathy\". However, the factors that contribute to the development of diabetic cardiomyopathies is not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and posttranslational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.

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

Cardiovasc Res: 29 Mar 2021; epub ahead of print
Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun QY, Lopaschuk GD
Cardiovasc Res: 29 Mar 2021; epub ahead of print | PMID: 33783483
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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-FXa therapy in APS patients leads to a greater number of patients with arterial thrombosis than with warfarin. We hypothesise 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 (ELISAs) 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 IgG 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.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 27 Mar 2021; epub ahead of print
Chayoua W, Nicolson PLR, Meijers JCM, Kardeby C, ... Watson SP, de Groot PG
J Thromb Haemost: 27 Mar 2021; epub ahead of print | PMID: 33774918
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Abstract

Telomere length is independently associated with all-cause mortality in chronic heart failure.

Romaine SPR, Denniff M, Codd V, Nath M, ... Nelson CP, Samani NJ
Objective
Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.
Methods
We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.
Results
In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10-5), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10-3). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10-3). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).
Conclusion
In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Mar 2021; epub ahead of print
Romaine SPR, Denniff M, Codd V, Nath M, ... Nelson CP, Samani NJ
Heart: 30 Mar 2021; epub ahead of print | PMID: 33789973
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Abstract

Prognostic significance of natriuretic peptide levels in atrial fibrillation without heart failure.

Hamatani Y, Iguchi M, Ueno K, Aono Y, ... Morita S, Akao M
Objectives
Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice.
Methods
The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes.
Results
Of 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders.
Conclusion
NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value.
Trial registration number
UMIN000005834.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:705-712
Hamatani Y, Iguchi M, Ueno K, Aono Y, ... Morita S, Akao M
Heart: 29 Apr 2021; 107:705-712 | PMID: 33219109
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Abstract

Clinical and echocardiographic outcomes in heart failure associated with methamphetamine use and cessation.

Bhatia HS, Nishimura M, Dickson S, Adler E, Greenberg B, Thomas IC
Objective
Methamphetamine use is associated with systolic dysfunction, pulmonary arterial hypertension and may also be associated with diastolic dysfunction. The impact of methamphetamine cessation on methamphetamine-associated heart failure (MethHF) remains poorly characterised. We aimed to longitudinally characterise methamphetamine-associated heart failure patients with reduced (METHrEF) and preserved (METHpEF) left ventricular ejection fraction (EF), and evaluate the relationship between methamphetamine cessation and clinical outcomes.
Methods
We performed a retrospective cohort study, and reviewed medical records of patients with METHrEF, METHpEF and heart failure controls without methamphetamine use. Echocardiographic variables were recorded for up to 12 months, with clinical follow-up extending to 24 months.
Results
Among METHrEF patients (n=28, mean age 51±9 years, 82.1% male), cessation was associated with improvement in EF (+10.6±13.1%, p=0.009) and fewer heart failure admissions per year compared with continued use (median 0.0, IQR 0.0-1.0 vs median 2.0, IQR 1.0-3.0, p=0.039). METHpEF patients (n=28, mean age 50±8 years, 60.7% male) had higher baseline right ventricular systolic pressure (median 53.44, IQR 43.70-84.00 vs median 36.64, IQR 29.44-45.95, p=0.011), and lower lateral E/E\' ratio (8.1±3.6 vs 11.2±4., p<0.01) compared with controls (n=32). Significant improvements in echocardiographic parameters and clinical outcomes were not observed following cessation in this group.
Conclusions
METHrEF patients who cease methamphetamine use have significant improvement in left ventricular systolic function and fewer heart failure admissions, suggesting that METHrEF may be reversible. Echocardiographic parameters suggest that some patients with METHpEF may have pulmonary hypertension in the absence of overt signs of left ventricular diastolic dysfunction, but additional study is needed to characterise this patient cohort.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Apr 2021; 107:741-747
Bhatia HS, Nishimura M, Dickson S, Adler E, Greenberg B, Thomas IC
Heart: 29 Apr 2021; 107:741-747 | PMID: 33020227
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Abstract

Cell Therapy in Patients with Heart Failure: A Comprehensive Review and Emerging Concepts.

Bolli R, Solankhi M, Tang XL, Kahlon A
This review summarizes the results of clinical trials of cell therapy in patients with heart failure (HF). In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF the results of Phase I-II trials are encouraging, both in ischemic and nonischemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used. That an efficacy signal was seen 6-12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged. Amongst the various cell types tested, mesenchymal stromal cells (MSCs) derived from bone marrow, umbilical cord, or adipose tissue show the greatest promise. In contrast, embryonic stem cells are not likely to become a clinical therapy. Unfractionated bone marrow cells and cardiosphere-derived cells have been abandoned. The cell products used for HF will most likely be allogeneic. New approaches, such as repeated cell treatment and intravenous delivery, may revolutionize the field. As is the case for most new therapies, the development of cell therapies for HF has been slow, plagued by multifarious problems, and punctuated by many setbacks; at present, the utility of cell therapy in HF remains to be determined. What the field needs is rigorous, well-designed Phase III trials. The most important things to move forward are to keep an open mind, avoid preconceived notions, and let ourselves be guided by the evidence.

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

Cardiovasc Res: 18 Apr 2021; epub ahead of print
Bolli R, Solankhi M, Tang XL, Kahlon A
Cardiovasc Res: 18 Apr 2021; epub ahead of print | PMID: 33871588
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Abstract

The association between indices of blood pressure waveforms (PTC1 and PTC2) and incident heart failure.

Brumback LC, Andrews LIB, Jacobs DR, Duprez DA, ... Denenberg JO, Allison MA
Objectives
The radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle, and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown.
Methods
Among 6229 adults (mean age 62 years) from four race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000-2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure.
Results
Mean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 ms, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63--0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56--0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure.
Conclusion
The PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 31 Mar 2021; 39:661-666
Brumback LC, Andrews LIB, Jacobs DR, Duprez DA, ... Denenberg JO, Allison MA
J Hypertens: 31 Mar 2021; 39:661-666 | PMID: 33239550
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Abstract

Insulin-like growth factor-binding protein 7 and risk of congestive heart failure hospitalization in patients with atrial fibrillation.

Blum S, Aeschbacher S, Meyre P, Kühne M, ... Conen D, BEAT-AF and Swiss-AF Investigators
Background
The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker.
Objective
The purpose of this study was to assess whether insulin-like growth factor-binding protein 7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication.
Methods
We analyzed 2 prospective multicenter observational cohort studies that included 3691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox regression analyses were constructed.
Results
Mean patient age was 69 ± 12 years, 1028 (28%) were female, and 879 (24%) had a history of CHF. The incidence per 1000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32, and 85. The corresponding multivariable adjusted hazard ratios (aHRs) (95% confidence interval [CI]) were 1.0, 1.05 (0.63-1.77), 2.38 (1.50-3.79), and 4.37 (2.72-7.04) (P for trend <.001). In a subgroup of 2812 patients without pre-existing CHF at baseline, the corresponding aHRs were 1.0, 0.90 (0.47-1.72), 1.69 (0.94-3.04), and 3.48 (1.94-6.24) (P for trend <.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20; 3.35-8.09) compared to those with only 1 elevated marker (elevated IGFBP-7 aHR 2.17; 1.30-3.60); elevated NT-proBNP aHR 1.97; 1.17-3.33); or no elevated marker (reference).
Conclusion
Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP.

Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 30 Mar 2021; 18:512-519
Blum S, Aeschbacher S, Meyre P, Kühne M, ... Conen D, BEAT-AF and Swiss-AF Investigators
Heart Rhythm: 30 Mar 2021; 18:512-519 | PMID: 33278630
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Abstract

Effect of Obesity on Response to Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction.

Elkholey K, Papadimitriou L, Butler J, Thadani U, Stavrakis S
Obesity is common in heart failure with preserved ejection fraction (HFpEF). Whether obesity modifies the response to spironolactone in patients with HFpEF remains unclear. We aimed to investigate the effect of obesity, defined by body mass index (BMI) and waist circumference (WC), on response to spironolactone in patients with HFpEF enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. This was a post-hoc, exploratory analysis of the Americas cohort of Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. BMI≥30 kg/m2 was used to define the obese group and WC≥102 cm in men and ≥88 cm in women were defined as high WC. In separate analyses, BMI and WC were treated as continuous variables. The effect of spironolactone versus placebo on outcomes was calculated by BMI and WC using Cox proportional hazard models. Obese patients were younger and had more co-morbidities. In multivariate analysis, spironolactone use was associated with a significant reduction in the primary end point, compared with placebo in obese [hazard ratio (HR = 0.618, 95% CI 0.460 to 0.831, p = 0.001), but not in nonobese subjects (HR = 0.946, 95% CI 0.623 to 1.437, p = 0.796; p for interaction = 0.056). There was a linear association between continuous BMI and the effect of spironolactone, with the effect becoming significant at 33kg/m2. Similar results were obtained for the WC-based analysis. In conclusion, use of spironolactone in obese patients with HFpEF was associated with a decreased risk of the primary end point, cardiovascular death and HF hospitalizations, compared with placebo. Further prospective randomized studies in obese subjects are required.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 30 Apr 2021; 146:36-47
Elkholey K, Papadimitriou L, Butler J, Thadani U, Stavrakis S
Am J Cardiol: 30 Apr 2021; 146:36-47 | PMID: 33529620
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Abstract

The Impact of Environmental Factors on the Mortality of Patients With Chronic Heart Failure.

Lopez PD, Cativo-Calderon EH, Otero D, Rashid M, Atlas S, Rosendorff C
Outcomes of acute heart failure hospitalizations are worse during the winter than the rest of the year. Seasonality data are more limited for outcomes in chronic heart failure and the effect of environmental variables is unknown. In this population-level study, we merged 20-year data for 555,324 patients with heart failure from the national Veterans Administration database with data on climate from the National Oceanic and Atmospheric Administration and air pollutants by the Environmental Protection Agency. The outcome was the all-cause mortality rate, stratified by geographical location and each month. The impact of environmental factors was assessed through Pearson\'s correlation and multiple regression with a family-wise α = 0.05. The monthly all-cause mortality was 13.9% higher in the winter than the summer, regardless of gender, age group, and heart failure etiology. Winter season, lower temperatures, and higher concentrations of nitrogen dioxide were associated with a higher mortality rate in multivariate analysis of the overall population. Different environmental factors were associated in regions with similar patterns of temperature and precipitation. The only environmental factor associated with the mortality rate of patients dwelling in large urban centers was the air quality index. In conclusion, the mortality in chronic heart failure exhibits a seasonal pattern, regardless of latitude or climate. In this group of patients, particularly those of male gender, a higher mortality was associated with environmental factors and incorporating these factors in treatment plans and recommendations could have a favorable cost-benefit ratio.

Copyright © 2021. Published by Elsevier Inc.

Am J Cardiol: 30 Apr 2021; 146:48-55
Lopez PD, Cativo-Calderon EH, Otero D, Rashid M, Atlas S, Rosendorff C
Am J Cardiol: 30 Apr 2021; 146:48-55 | PMID: 33577810
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Abstract

Left axis deviation in patients with non-ischemic heart failure and left bundle branch block is a purely electrical phenomenon.

Abu-Alrub S, Strik M, Huntjens P, Ramirez FD, ... Bordachar P, Ploux S
Background
Possible mechanisms of left axis deviation (LAD) in the setting of left bundle branch block (LBBB) include differences in cardiac electrophysiology, structure, or anatomical axis.
Objectives
We sought to clarify the mechanism(s) responsible for LAD in patients with LBBB.
Methods
Twenty-nine patients with non-ischemic cardiomyopathies and LBBB underwent non-invasive electrocardiographic mapping (ECGi), cardiac computed tomography, and magnetic resonance imaging in order to define ventricular electrical activation, characterize cardiac structure, and determine the heart anatomical axis.
Results
Sixteen patients had a normal QRS axis (NA, mean axis: 8±23°) whereas 13 patients had LAD (mean axis: -48±13°, p<0.001). Total activation times were longer in the LAD group (112±25 vs 91±14ms, p=0,01) due to delayed activation of the basal anterolateral region (107±10 vs 81±17ms, p<0.001). Left ventricular (LV) activation in patients with LAD was from apex-to-base, contrasting with a circumferential pattern of activation in patients with NA. The apex-to-base delay was therefore longer in the LA group (95±13 vs 64±21ms, p<0.001) and correlated with the QRS frontal axis (R2=0,67, p<0.001). Both groups were comparable in LV end diastolic volume (295±84vs LAD: 310±91ml; p=0.69), LV mass (177±33 vs LAD: 180±37g, p=0.83) and anatomical axis.
Conclusion
Left axis deviation in left bundle branch block appears to be due to electrophysiological abnormalities rather than structural factors or the cardiac anatomical axis.

Copyright © 2021. Published by Elsevier Inc.

Heart Rhythm: 04 Apr 2021; epub ahead of print
Abu-Alrub S, Strik M, Huntjens P, Ramirez FD, ... Bordachar P, Ploux S
Heart Rhythm: 04 Apr 2021; epub ahead of print | PMID: 33831543
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Abstract

Soluble ST2 and Diuretic Efficiency in Acute Heart Failure and Concomitant Renal Dysfunction.

Espriella R, Bayés-Genis A, Revuelta-LóPEZ E, Miñana G, ... Núñez J, IMPROVE-HF Investigators
Background
Identifying patients at risk of poor diuretic response in acute heart failure (AHF) is critical to make prompt adjustments in therapy. The objective of this study was to investigate whether the circulating levels of soluble ST2 predict the cumulative diuretic efficiency (DE) at 24 and 72 hours in patients with AHF and concomitant renal dysfunction.
Methods and results
This is a post hoc analysis of the IMPROVE-HF trial, in which we enrolled 160 patients with AHF and renal dysfunction (estimated glomerular filtrate rate of <60 mL/min/1.73 m2). DE was calculated as the net fluid output produced per 40 mg of furosemide equivalents. The association between sST2 and DE was evaluated by using multivariate linear regression analysis. The median cumulative DE at 24 and 72 hour was 747 mL (interquartile range 490-1167 mL) and 1844 mL (interquartile range 1142-2625 mL), respectively. The median sST2 and mean estimated glomerular filtrate rate were 72 ng/mL (interquartile range 47-117 ng/mL), and 34.0 ± 8.5 mL/min/1.73 m2, respectively. In a multivariable setting, higher sST2 were significant and nonlinearly related to lower DE both at 24 and 72 hours (P = .002 and P = .019, respectively).
Conclusions
In patients with AHF and renal dysfunction at presentation, circulating levels of sST2 were independently and negatively associated with a poor diuretic response, both at 24 and 72 hours.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:427-434
Espriella R, Bayés-Genis A, Revuelta-LóPEZ E, Miñana G, ... Núñez J, IMPROVE-HF Investigators
J Card Fail: 30 Mar 2021; 27:427-434 | PMID: 33038531
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Abstract

Prevalence and prognostic association of ventricular arrhythmia in non-ischaemic heart failure patients: results from the DANISH trial.

Boas R, Thune JJ, Pehrson S, Køber L, ... Svendsen JH, Dixen U
Aims
Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD.
Methods and results
A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low (<30) and high burden (≥30) groups. Outcome measures were overall mortality, sudden cardiac death (SCD), and cardiovascular death (CVD). In total, 193 patients died, 49 from SCD and 125 from CVD. Non-sustained ventricular tachycardia (365 patients) was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.47; 95% confidence interval (CI) 1.07-2.03; P = 0.02] and to CVD (HR 1.89; CI 1.25-2.87; P = 0.003). High burden PVC (352 patients) was associated with increased all-cause mortality (HR1.38; CI 1.00-1.90; P = 0.046) and with CVD (HR 1.78; CI 1.19-2.66; P = 0.005). There was no statistically significant association with SCD for neither NSVT nor PVC. In interaction analyses, neither NSVT (P = 0.56) nor high burden of PVC (P = 0.97) was associated with survival benefit from ICD implantation.
Conclusion
Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Europace: 05 Apr 2021; 23:587-595
Boas R, Thune JJ, Pehrson S, Køber L, ... Svendsen JH, Dixen U
Europace: 05 Apr 2021; 23:587-595 | PMID: 33257933
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Abstract

Age-specific trends and outcomes of hospitalizations with acute heart failure in the United States.

Elbadawi A, Dang A, Elgendy IY, Thakker R, ... Khalife WI, Almustafa A
Objective
To analyze the age-specific temporal trends, in-hospital outcomes and readmissions for acute heart failure (HF).
Background
There is a paucity of data on the age-specific differences in the trends and outcomes of hospitalizations with acute HF.
Methods
The National Inpatients Sample database years 2002-2016 and the National Readmissions Database years 2013-2016 were used to identify primary hospitalizations for acute HF. We analyzed the age-specific temporal trends, in-hospital outcomes, and readmissions for acute HF.
Results
The annual rate of hospitalizations for acute HF declined from 456 per 100,000 people in 2002 to 356 per 100,000 people in 2016 (Ptrend < 0.001). The decline was observed among all age groups, except those aged 18-44 years. There was a decline in in-hospital mortality among all age groups, except for those aged 18-34 years. Compared with 18-34 years, adjusted in-hospital mortality was lower among 35-44 years (odds ratio 0.78, 95% confidence interval [CI] 0.74-0.82) and 45-54 years (OR 0.87; 95% CI 0.83-0.91) but higher among 55-64 years (OR 1.60; 95% CI 1.54-1.67) and ≥ 75 year (OR 2.54; 95% CI 2.44-2.64). Compared with 18-34 years, 30-day HF-related readmissions were significantly lower in older age groups (>34 years).
Conclusions
This nationwide contemporary analysis demonstrated a decline in the annual rates of hospitalizations with acute HF across all age categories except those aged 18-44 years. There was a reduction in rates of in-hospital mortality among middle-aged and older patients, but not in those aged 18-34. In-hospital mortality exhibited a dichotomous relationship with age. There was an inverse relationship between age and 30-days HF readmissions.

Published by Elsevier B.V.

Int J Cardiol: 30 Apr 2021; 330:98-105
Elbadawi A, Dang A, Elgendy IY, Thakker R, ... Khalife WI, Almustafa A
Int J Cardiol: 30 Apr 2021; 330:98-105 | PMID: 33609592
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Abstract

Validity of Hemodynamic Monitoring Using Inert Gas Rebreathing Method in Patients With Chronic Heart Failure and Those Implanted With a Left Ventricular Assist Device.

Okwose NC, Bouzas-Cruz N, Fernandez OG, Koshy A, ... Macgowan GA, Jakovljevic DG
Objective
The present study assessed agreement between resting cardiac output estimated by inert gas rebreathing (IGR) and thermodilution methods in patients with heart failure and those implanted with a left ventricular assist device (LVAD).
Methods and results
Hemodynamic measurements were obtained in 42 patients, 22 with chronic heart failure and 20 with implanted continuous flow LVAD (34 males, aged 50 ± 11 years). Measurements were performed at rest using thermodilution and IGR methods. Cardiac output derived by thermodilution and IGR were not significantly different in LVAD (4.4 ± 0.9 L/min vs 4.7 ± 0.8 L/min, P = .27) or patients with heart failure (4.4 ± 1.4 L/min vs 4.5 ± 1.3 L/min, P = .75). There was a strong relationship between thermodilution and IGR cardiac index (r = 0.81, P = .001) and stroke volume index (r = 0.75, P = .001). Bland-Altman analysis showed acceptable limits of agreement for cardiac index derived by thermodilution and IGR, namely, the mean difference (lower and upper limits of agreement) for patients with heart failure -0.002 L/min/m2 (-0.65 to 0.66 L/min/m2), and -0.14 L/min/m2 (-0.78 to 0.49 L/min/m2) for patients with LVAD.
Conclusions
IGR is a valid method for estimating cardiac output and should be used in clinical practice to complement the evaluation and management of chronic heart failure and patients with an LVAD.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:414-418
Okwose NC, Bouzas-Cruz N, Fernandez OG, Koshy A, ... Macgowan GA, Jakovljevic DG
J Card Fail: 30 Mar 2021; 27:414-418 | PMID: 33035686
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Impact:
Abstract

Ventilation Dispersion Index as an Objective Evaluation Tool of Exercise Oscillatory Ventilation in Patients With Heart Failure.

Corte RC, De Sá J, Carlos R, Felismino AS, ... Pereira E, Bruno S
Background
Exercise oscillatory ventilation (EOV) is related to worse prognosis in patients with heart failure (HF). However, its determination is subjective and there is no standard measure to identify it. The aim of the study was to evaluate and characterize the EOV of patients with HF using the ventilation dispersion index (VDI).
Methods and results
Patients underwent cardiopulmonary exercise testing (CPX), EOV was assessed by 2 reviewers and the VDI was calculated. The receiver operator curve analysis was used to assess the ability of the VDI to predict EOV. Pearson\'s correlation test was performed to determine the relationship between VDI and CPX variables. Forty-three patients with HF underwent CPX and were divided into 2 groups: with a VDI of less than 0.601 and a VDI of 0.601 or greater. An area under the curve of 0.759 was observed in the receiver operator curve analysis between VDI and EOV (P = .008). The VDI showed a significant correlation with the ventilatory CPX variables. According to the cut-off point obtained on the receiver operator curve, patients with a VDI of 0.601 or greater had lower left ventricular ejection fraction and higher values of resting minute ventilation and peak minute ventilation.
Conclusions
The VDI proved to be a good predictor of EOV in patients with HF.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:419-426
Corte RC, De Sá J, Carlos R, Felismino AS, ... Pereira E, Bruno S
J Card Fail: 30 Mar 2021; 27:419-426 | PMID: 33038533
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Impact:
Abstract

Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life.

Cohen LP, Vittinghoff E, Pletcher MJ, Allen NB, ... Moran AE, Zhang Y
Background
Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.
Methods
We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.
Results
A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.
Conclusions
Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:435-444
Cohen LP, Vittinghoff E, Pletcher MJ, Allen NB, ... Moran AE, Zhang Y
J Card Fail: 30 Mar 2021; 27:435-444 | PMID: 33238139
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Impact:
Abstract

Diuresis-Related Weight Loss Reflects Interstitial Compartment Decongestion with Minimal Impact on Intravascular Volume Expansion or Outcomes in Post-Acute Heart Failure: Metrics of Decongestion and Volume Status.

Miller WL, Lobo R, Grill DE, Mullan BP
Background
Findings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF.
Methods and results
Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (-6.5 ± 4.4%) and PV (-7.5 ± 11%); however, absolute decreases in the PV (-254 mL, interquartile range -11 to -583 mL) were less than 10% of interstitial volume loss (-5040 mL, interquartile range -2800 to -7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430).
Conclusions
Diuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:445-452
Miller WL, Lobo R, Grill DE, Mullan BP
J Card Fail: 30 Mar 2021; 27:445-452 | PMID: 33347996
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Impact:
Abstract

Exercise Tolerance in Patients Treated With a Durable Left Ventricular Assist Device: Importance of Myocardial Recovery.

Dridi NP, Vishram-Nielsen JKK, Gustafsson F
The number of patients supported with left ventricular assist devices (LVADs) is growing and support times are increasing. This has led to a greater focus on functional capacity of these patients. LVADs greatly improve heart failure symptoms, but surprisingly, improvement in peak oxygen uptake (pVO2) is small and remains decreased at approximately 50% of normal values. Inadequate increase in cardiac output during exercise is the main responsible factor for the low pVO2 in LVAD recipients. Some patients experience LV recovery during mechanical unloading and these patients have a higher pVO2. Here we review the various components determining exercise cardiac output in LVAD recipients and discuss the potential impact of cardiac recovery on these components. LV recovery may affect several components, leading to improved hemodynamics during exercise and, in turn, physical capacity in patients with advanced heart failure undergoing LVAD implantation.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:486-493
Dridi NP, Vishram-Nielsen JKK, Gustafsson F
J Card Fail: 30 Mar 2021; 27:486-493 | PMID: 33347995
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Impact:
Abstract

Delirium Among Hospitalized Older Adults With Acute Heart Failure Exacerbation.

Kwak MJ, Avritscher E, Holmes HM, Jantea R, ... Balan P, Dhoble A
Background
Delirium among older adults hospitalized with acute heart failure is associated with increased mortality. However, studies concomitantly assessing the association of delirium with both clinical and economic outcomes in this population, such as mortality, hospital cost, or length of stay, are lacking.
Methods and results
We conducted a retrospective observational study using National Inpatient Sample data from 2011 to 2014. Using multivariable logistic regression, we assessed the association of delirium with in-hospital mortality, then estimated the incremental hospital cost and excessive length of stay adjusting for demographic and clinical factors using multivariable generalized linear regression. The association of other medical complications on clinical and economic outcomes was also assessed. A total of 568,565 (weighted N = 2,826,131) hospitalizations of patients 65 years or older with acute heart failure from 2011 to 2014 were included in the final analysis. The reported prevalence of delirium was 4.53%. After multivariable adjustment, delirium was associated with a 2.35-fold increase in the odds of in-hospital mortality (95% confidence interval [CI] 2.23-2.47), which was lower than the odds ratio for sepsis/septicemia (5.36; 95% CI, 5.02-5.72) or respiratory failure (4.53; 95% CI, 4.38-4.69), but similar to that for acute kidney injury (2.39; 95% CI, 2.31-2.48) and higher than for non-ST elevation myocardial infarct (1.57; 95% CI, 1.46-1.68). Delirium increased the total hospital cost by $4,262 (95% CI, $4,002-4,521) and the length of stay by 1.73 days (95% CI, 1.68-1.78), which was slightly lower than, but similar to, acute kidney injury ($4,771; 95% CI, $4,644-4,897) and 1.82 days (95% CI, 1.79-1.84), and higher than non-ST elevation myocardial infarct ($1,907; 95% CI, $1,629-2,185) and 0.31 days (95% CI, 0.25-0.37).
Conclusions
Delirium was associated with increased in-hospital mortality, total hospital cost, and length of stay, and the magnitude of the effect was similar to that for acute kidney injury. Enhanced efforts to prevent delirium are needed to decrease its adverse impact on clinical and economic outcomes for hospitalized older adults with acute heart failure.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:453-459
Kwak MJ, Avritscher E, Holmes HM, Jantea R, ... Balan P, Dhoble A
J Card Fail: 30 Mar 2021; 27:453-459 | PMID: 33347994
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Impact:
Abstract

Phosphodiesterase-5 Inhibitors and Outcomes During Left Ventricular Assist Device Support: A Systematic Review and Meta-Analysis.

Kittipibul V, Blumer V, Angsubhakorn N, Hernandez GA, ... Tedford RJ, Agarwal R
Background
Phosphodiesterase-5 inhibitors (PDE5i) have been used to treat pulmonary hypertension and right ventricular failure in patients with left ventricular assist devices (LVAD). The effects of PDE5i on post-LVAD outcomes including hemocompatibility-related adverse events are not well-established. This systematic review and meta-analysis aims to evaluate the effects of PDE5i on post-LVAD outcomes.
Methods and results
A comprehensive literature search was conducted using Pubmed and Embase databases from inception through November 25, 2020, to compare post-LVAD outcomes in patients with or without PDE5i use. Pooled odds ratio (OR) with 95% confidence intervals (CI) and I2 statistic were calculated. Thirteen observational studies were included in this analysis. The use of PDE5i was not significantly associated with lower postoperative right ventricular failure (OR 0.38, 95% CI 0.02-5.96, P = .41). There was no significant association between PDE5i and gastrointestinal bleeding (OR 1.23, 95% CI 0.76-1.98, P = .2), overall stroke (OR 0.60, 95% CI 0.21-1.68, P = .17), ischemic stroke (OR 0.61, 95% CI 0.09-4.07, P = .38), or pump thrombosis (OR 0.71, 95% CI 0.14-3.54, P = .46).
Conclusions
Our meta-analysis showed no significant association between PDE5i and post-LVAD right ventricular failure. Despite the antiplatelet effects of PDE5i, there was no significant association between PDE5i and gastrointestinal bleeding, overall stroke, ischemic stroke, or pump thrombosis. Randomized controlled studies are warranted to evaluate the net benefits or harms of PDE5i in the LVAD population.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:477-485
Kittipibul V, Blumer V, Angsubhakorn N, Hernandez GA, ... Tedford RJ, Agarwal R
J Card Fail: 30 Mar 2021; 27:477-485 | PMID: 33385522
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Impact:
Abstract

Social Determinants of Health and Rates of Implantation for Patients Considering Destination Therapy Left Ventricular Assist Device.

Flint K, Chaussee EL, Henderson K, Breathett K, ... Matlock DD, Allen LA
Background
A left ventricular assist device (LVAD) is a treatment option available to select patients with advanced heart failure. However, there are important social determinants of health that can play a role in determining patients\' outcomes after device placement.
Methods and results
We leveraged the DECIDE-LVAD Trial to assess social determinants of health-relationship status, household income, race/ethnicity, educational attainment, and health insurance-at the time of evaluation, and their association with rate of LVAD placement in the subsequent year. About a quarter of patients were unpartnered (i.e., single/divorced/widowed/separated; n = 55 [26%]). A similar proportion had a household income of less than $20,000 per year (n = 50 [24%]). Few patients were other race (n = 39 [18%]), had less than a high school education (n = 14 [6.6%]), or had Medicaid as their primary payor (n = 17 [8.4%]). LVAD implantation was significantly lower among patients who were unpartnered compared with patients who were married or partnered. LVAD implantation was not associated with income, race, educational attainment or insurance status.
Conclusions
Our data from diverse LVAD centers at U.S. private and academic hospitals found that, among a broad sample of patients being evaluated for LVAD, married or partnered status was favorably associated with LVAD implantation, but other social determinants of health were not. Future research and policy changes should consider novel interventions for improving access to LVAD implantation for patients with inadequate social support.

Copyright © 2020 Elsevier Inc. All rights reserved.

J Card Fail: 30 Mar 2021; 27:497-500
Flint K, Chaussee EL, Henderson K, Breathett K, ... Matlock DD, Allen LA
J Card Fail: 30 Mar 2021; 27:497-500 | PMID: 33346077
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Impact:
Abstract

Center procedural volume and adverse in-hospital outcomes for patients undergoing percutaneous transvenous edge-to-edge mitral valve repair using MitraClip® technique in Germany.

Keller K, Hobohm L, Schmidtmann I, Münzel T, Baldus S, von Bardeleben RS
Aims
The number of transcatheter mitral valve repairs increased substantially during last years. A better understanding of the relationship between hospital volume of transcatheter transvenous mitral valve repairs using MitraClip® (TMVr) and patient outcomes may provide information for future policy decisions to improve patients´ management.
Methods and results
We analysed patients\' characteristics and in-hospital outcomes for all TMVr using MitraClip® performed in Germany 2011-2017. Hospitals were stratified regarding center volumes and patients were compared for baseline characteristics and adverse in-hospital events. Overall, 24,709 in-patients were treated during the observation period. Patients treated in centers with ≤10 procedures annually developed more often pulmonary embolism (OR 2.22 [95%CI 1.19-4.13], P=0.012) compared to those treated in centers with >10 procedures annually, whereas no association of center volume (≤10 or >10) was found with in-hospital mortality (P=0.728). Although patients treated in centers with TMVr volume >25 annually had higher numbers of comorbidities compared to those in centers ≤25 procedures, in-hospital mortality did not differ (3.6% vs. 3.5%, P=0.485). Similarly, when center volumes were stratified for ≤50 vs. >50 procedural volumes, these were not associated with in-hospital mortality (P=0.792). A decreasing number of mitral valve surgical interventions after MitraClip® was observed over time particularly in high-volume centers.
Conclusion
Annual numbers of MitraClip® implantations increased from 2011 to 2017 in Germany, whereas in-hospital mortality remained stable. Although patients treated by high-volume centers had a more unfavorable risk-profile, in-hospital mortality is comparable.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 22 Mar 2021; epub ahead of print
Keller K, Hobohm L, Schmidtmann I, Münzel T, Baldus S, von Bardeleben RS
Eur J Heart Fail: 22 Mar 2021; epub ahead of print | PMID: 33759319
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Impact:
Abstract

Race- and Sex-Specific Population Attributable Fractions of Incident Heart Failure: A Population-Based Cohort Study From the Lifetime Risk Pooling Project.

Sinha A, Ning H, Carnethon MR, Allen NB, ... Lloyd-Jones DM, Khan SS
Background
Race- and sex-specific differences in heart failure (HF) risk may be related to differential burden and effect of risk factors. We estimated the population attributable fraction (PAF), which incorporates both prevalence and excess risk of HF associated with each risk factor (obesity, hypertension, diabetes, current smoking, and hyperlipidemia), in specific race-sex groups.
Methods
A pooled cohort was created using harmonized data from 6 US longitudinal population-based cohorts. Baseline measurements of risk factors were used to determine prevalence. Relative risk of incident HF was assessed using a piecewise constant hazards model adjusted for age, education, other modifiable risk factors, and the competing risk of death from non-HF causes. Within each race-sex group, PAF of HF was estimated for each risk factor individually and for all risk factors simultaneously.
Results
Of 38 028 participants, 55% were female and 22% Black. Hypertension had the highest PAF among Black men (28.3% [18.7-36.7]) and women (25.8% [16.3%-34.2%]). In contrast, PAF associated with obesity was the highest in White men (21.0% [14.6-27.0]) and women (17.9% [12.8-22.6]). Diabetes disproportionately contributed to HF in Black women (PAF, 16.4% [95% CI, 12.7%-19.9%]). The cumulative PAF of all 5 risk factors was the highest in Black women (51.9% [39.3-61.8]).
Conclusions
The observed differences in contribution of risk factors across race-sex groups can inform tailored prevention strategies to mitigate disparities in HF burden. This novel competing risk analysis suggests that a sizeable proportion of HF risk may not be associated with modifiable risk factors.



Circ Heart Fail: 24 Mar 2021:CIRCHEARTFAILURE120008113; epub ahead of print
Sinha A, Ning H, Carnethon MR, Allen NB, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 24 Mar 2021:CIRCHEARTFAILURE120008113; epub ahead of print | PMID: 33761754
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Impact:
Abstract

Change in Ejection Fraction and Long-Term Mortality in Adults Referred for Echocardiography.

Strange G, Playford D, Scalia GM, Celermajer DS, ... Stewart S, NEDA Investigators
Aims
We investigated long-term mortality associated with changes in left ventricular ejection fraction (LVEF) in a large, real-world patient cohort.
Methods and results
117 275 adults (46% women, 63 ± 16 years) had LVEF quantified by the same method ≥6 months apart. This included 17 343 cases (48% women, 66 ± 15 years) being initially investigated for heart failure (HF). During 3.3 (IQR 1.7 to 6.0) years from first-to-last echocardiogram, median change in LVEF was -1 (IQR -8 to +5) units from a baseline of 62% (IQR 54% to 69%). During subsequent 7.6 (IQR 4.3 to 10.1) years follow-up, 11 397 (9.7%) and 34 101 (29.1%) cases died from cardiovascular disease and all-causes, respectively. Actual 5-year, all-cause mortality increased from 12% to 29% among those with the smallest to the largest decrease in LVEF (from <5 units to >50 units); the adjusted risk of cardiovascular-related mortality increased 2- to 8-fold beyond a > 10-unit decline in LVEF (versus minimal change; p < 0.001 all comparisons). Among those initially investigated for HF (32% with initial LVEF <50%), the adjusted hazard ratio for cardiovascular-related mortality ranged from 0.35 (95% CI 0.28-0.49) to 4.21 (95% CI 3.30-5.22) for a > 30-unit increase to >30-unit decline in LVEF (versus minimal change; p < 0.001 for both comparisons). A distinctive, bi-directional plateau of improved versus worsening mortality was evident around a final LVEF of 50% to 55%.
Conclusions
These data, derived from a large, heterogeneous cohort of adults being followed-up with echocardiography, suggest that modest LVEF changes (particularly around an LVEF of 50% to 55%) may be of clinical significance. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 24 Mar 2021; epub ahead of print
Strange G, Playford D, Scalia GM, Celermajer DS, ... Stewart S, NEDA Investigators
Eur J Heart Fail: 24 Mar 2021; epub ahead of print | PMID: 33768605
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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
HFrEF GDMT implementation 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≤40% were prospectively identified from February 3 to March 1, 2020 (usual care group) and March 2 to August 28, 2020 (intervention group). Patients with critical illness, de-novo HF, and SBP<90mmHg 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 net of positive (+1 for new initiations or up-titrations) & 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), ARNI (6% to 17%; P=0.03), MRA (16% to 29%; P=0.05), and triple therapy (9% to 26%; P<0.01) prescriptions increased during hospitalization. After adjustment, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% CI: +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 HF therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 25 Mar 2021; epub ahead of print
Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Eur J Heart Fail: 25 Mar 2021; epub ahead of print | PMID: 33768599
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Impact:
Abstract

Identification of Distinct Phenotypic Clusters in Heart Failure with Preserved Ejection Fraction.

Uijl A, Savarese G, Vaartjes I, Dahlström U, ... Hoes AW, Koudstaal S
Aims
We aimed to derive and validate clinically useful clusters of patients with heart failure with preserved ejection fraction (HFpEF; left ventricular ejection fraction ≥50%).
Methods and results
We derived a cluster model from 6909 HFpEF patients from the Swedish Heart Failure Registry (SwedeHF) and externally validated this in 2153 patients from the Chronic Heart Failure ESC-guideline based Cardiology Practice Quality project (CHECK-HF) registry. In SwedeHF, the median age was 80 [interquartile range 72-86] years, 52% of patients were female and most frequent comorbidities were hypertension (82%), atrial fibrillation (68%), and ischaemic heart disease (48%). Latent class analysis identified five distinct clusters: Cluster 1 (10% of patients) were young patients with a low comorbidity burden and the highest proportion implantable devices, cluster 2 (30%) patients had atrial fibrillation, hypertension without diabetes, cluster 3 (25%) patients were the oldest with many cardiovascular comorbidities and hypertension, cluster 4 (15%) patients had obesity, diabetes and hypertension, and cluster 5 (20%) patients were older with ischaemic heart disease, hypertension and renal failure and were most frequently prescribed diuretics. The clusters were reproduced in the CHECK-HF cohort. Patients in cluster 1 had the best prognosis, while patients in cluster 3 and 5 had the worst age- and sex adjusted prognosis.
Conclusions
Five distinct clusters of HFpEF patients were identified that differed in clinical characteristics, HF drug therapy and prognosis. These results confirm the heterogeneity of HFpEF and form a basis for tailoring trial design to individualised drug therapy in HFpEF patients. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 28 Mar 2021; epub ahead of print
Uijl A, Savarese G, Vaartjes I, Dahlström U, ... Hoes AW, Koudstaal S
Eur J Heart Fail: 28 Mar 2021; epub ahead of print | PMID: 33779119
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Impact:
Abstract

Metabolically Healthy/Unhealthy Overweight/Obesity Associations With Incident Heart Failure in Postmenopausal Women: The Women\'s Health Initiative.

Cordola Hsu AR, Xie B, Peterson DV, LaMonte MJ, ... Wong ND, Short List of WHI Investigators
Background
Obesity is associated with an increased risk of heart failure (HF); however, how metabolic weight groups relate to HF risk, especially in postmenopausal women, has not been demonstrated.
Methods
We included 19 412 postmenopausal women ages 50 to 79 without cardiovascular disease from the Women\'s Health Initiative. Normal weight was defined as a body mass index ≥18.5 and <25 kg/m2 and waist circumference <88 cm and overweight/obesity as a body mass index ≥25 kg/m2 or waist circumference ≥88 cm. Metabolically healthy was based on <2 and unhealthy ≥2 cardiometabolic traits: triglycerides ≥150 mg/dL, systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg or blood pressure medication, fasting glucose ≥100 mg/dL or diabetes medication, and HDL-C (high-density lipoprotein cholesterol) <50 mg/dL. Risk factor-adjusted Cox regression examined the hazard ratios (HRs) for incident hospitalized HF among metabolically healthy normal weight (reference), metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese.
Results
Among our sample, 455 (2.34%) participants experienced HF hospitalizations over a mean follow-up time of 11.3±1.1 years. Compared with metabolically healthy normal weight individuals, HF risk was greater in metabolically unhealthy normal weight (HR, 1.66 [95% CI, 1.01-2.72], P=0.045) and metabolically unhealthy overweight/obese individuals (HR, 1.95 [95% CI, 1.35-2.80], P=0.0004), but not metabolically healthy overweight/obese individuals (HR, 1.15 [95% CI, 0.78-1.71], P=0.48). Subdividing the overweight/obese into separate groups showed HRs for metabolically unhealthy obese of 2.62 (95% CI, 1.80-3.83; P<0.0001) and metabolically healthy obese of 1.52 (95% CI, 0.98-2.35; P=0.06).
Conclusions
Metabolically unhealthy overweight/obese and metabolically unhealthy normal weight are associated with an increased risk of HF in postmenopausal women.



Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007297; epub ahead of print
Cordola Hsu AR, Xie B, Peterson DV, LaMonte MJ, ... Wong ND, Short List of WHI Investigators
Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007297; epub ahead of print | PMID: 33775111
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Impact:
Abstract

Prognostic Role of Prior Heart Failure Hospitalization Among Patients Hospitalized for Worsening Chronic Heart Failure.

Blumer V, Mentz RJ, Sun JL, Butler J, ... O\'Connor CM, Greene SJ
Background
Hospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear.
Methods
After excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors.
Results
Overall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14-1.59]; P<0.01). After adjustment, the point estimate was attenuated and the association not statistically significant (HR, 1.18 [95% CI, 0.99-1.40]; P=0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0-4 months: HR, 1.10 [95% CI, 0.87-1.39], P=0.41; 4-8 months: HR, 0.95 [95% CI, 0.70-1.27]; P=0.72; 8-12 months: HR, 1.06 [95% CI, 0.74-1.51], P=0.77; >12 months: HR, 0.81 [95% CI, 0.63-1.06], P=0.12).
Conclusions
In this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT00475852.



Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007871; epub ahead of print
Blumer V, Mentz RJ, Sun JL, Butler J, ... O'Connor CM, Greene SJ
Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007871; epub ahead of print | PMID: 33775110
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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 one-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% men, 72% were white, and median admission eGFR was 49 ml/min/1.73m2 . IRF patients had more severe HF reflected by lower admission eGFR, higher BUN, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher one-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 one-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
IRF 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 improving kidney function.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 30 Mar 2021; epub ahead of print
Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Eur J Heart Fail: 30 Mar 2021; epub ahead of print | 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 program (DMP) to reduce readmissions.
Methods and results
1152 consecutive Australian patients admitted with HF (2014-17) 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, from discharge. Poorer cognitive function was associated with all adverse outcomes. Compared with usual care, DMP was associated with lower odds of 30-day (OR=0.60 [0.40, 0.91]) and 90-day (OR=0.53 [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 [0.21, 0.87] at 30-day, OR=0.31 [0.16, 0.60] at 90-day). 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.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 30 Mar 2021; epub ahead of print
Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Eur J Heart Fail: 30 Mar 2021; epub ahead of print | PMID: 33788985
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Impact:
Abstract

Characteristics and Outcomes of COVID-19 in Patients on Left Ventricular Assist Device Support.

Birati EY, Najjar SS, Tedford RJ, Houston BA, ... Moss N, Genuardi MV
Background
The coronavirus disease 2019 (COVID-19) pandemic continues to afflict millions of people worldwide. Patients with end-stage heart failure and left ventricular assist devices (LVADs) may be at risk for severe COVID-19 given a high prevalence of complex comorbidities and functional impaired immunity. The objective of this study is to describe the clinical characteristics and outcomes of COVID-19 in patients with end-stage heart failure and durable LVADs.
Methods
The Trans-CoV-VAD registry is a multi-center registry of LVAD and cardiac transplant patients in the United States with confirmed COVID-19. Patient characteristics, exposure history, presentation, laboratory data, course, and clinical outcomes were collected by participating institutions and reviewed by a central data repository. This report represents the participation of the first 9 centers to report LVAD data into the registry.
Results
A total of 40 patients were included in this cohort. The median age was 56 years (interquartile range, 46-68), 14 (35%) were women, and 21 (52%) were Black. Among the most common presenting symptoms were cough (41%), fever, and fatigue (both 38%). A total of 18% were asymptomatic at diagnosis. Only 43% of the patients reported either subjective or measured fever during the entire course of illness. Over half (60%) required hospitalization, and 8 patients (20%) died, often after lengthy hospitalizations.
Conclusions
We present the largest case series of LVAD patients with COVID-19 to date. Understanding these characteristics is essential in an effort to improve the outcome of this complex patient population.



Circ Heart Fail: 04 Apr 2021:CIRCHEARTFAILURE120007957; epub ahead of print
Birati EY, Najjar SS, Tedford RJ, Houston BA, ... Moss N, Genuardi MV
Circ Heart Fail: 04 Apr 2021:CIRCHEARTFAILURE120007957; epub ahead of print | PMID: 33813838
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Impact:
Abstract

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

Bolli R, Mitrani RD, Hare JM, Pepine CJ, ... Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN)
Aims
CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.
Methods and results
Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.
Conclusions
This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 02 Apr 2021; epub ahead of print
Bolli R, Mitrani RD, Hare JM, Pepine CJ, ... Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN)
Eur J Heart Fail: 02 Apr 2021; epub ahead of print | PMID: 33811444
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Impact:
Abstract

Small decreases in biventricular pacing percentages are associated with multiple metrics of worsening heart failure as measured from a cardiac resynchronization therapy defibrillator.

Cao M, Stolen CM, Ahmed R, Schloss EJ, ... Varma N, Boehmer JP
Background
Lower BiVentricular (BiV) pacing percentages have been associated with significantly worse survival in patients with chronic heart failure (HF). However, the pathophysiology behind this observation has not been further delineated. This analysis evaluated whether small incremental decreases in BiV pacing percentages were associated with worse measures, related to HF physiology using individual sensor trends and the HeartLogic composite index.
Methods
Sensor data was obtained from 900 ambulatory HF patients with implanted CRT devices . The percent of cardiac cycles with BiV pacing was assessed for periods (median = 7.3 days) between data downloads (median = 55 periods/patient).
Results
The third heart sound (S3), respiration rate, RSBI, and night-time heart rate were significantly elevated with sub-optimal pacing (<98%), while the first heart sound (S1), thoracic impedance, and activity were significantly lower. All sensor changes were in the direction associated with worsening HF. While IN the HeartLogic alert state (threshold above an Index of 16) the odds of optimal BiV pacing (≥98%) were less than when OUT of the HeartLogic alert state for a given subject (OR: 0.655; 95% CI: 0.626-0.686; p < 0.0001). The percent BiV pacing was reduced and the HeartLogic Index was increased in the periods surrounding HFhospitalizations.
Conclusion
Lower BiV pacing percent is associated with multiple sensor changes indicative of worsening HF, and patients in HeartLogic alert are more likely to have suboptimal BiV pacing. Collectively, these data provide strong evidence that even small decreases in BiV percent pacing can lead to worsening HF.

Copyright © 2021. Published by Elsevier B.V.

Int J Cardiol: 31 Mar 2021; epub ahead of print
Cao M, Stolen CM, Ahmed R, Schloss EJ, ... Varma N, Boehmer JP
Int J Cardiol: 31 Mar 2021; epub ahead of print | PMID: 33812951
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Impact:
Abstract

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

© European Society of Cardiology 2021.

Eur J Heart Fail: 06 Apr 2021; epub ahead of print
Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Eur J Heart Fail: 06 Apr 2021; epub ahead of print | PMID: 33826207
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Impact:
Abstract

The bidirectional interaction between atrial fibrillation and heart failure: consequences for the management of both diseases.

Verhaert DVM, Brunner-La Rocca HP, van Veldhuisen DJ, Vernooy K
Atrial fibrillation (AF) and heart failure (HF) are both highly prevalent diseases and are accompanied by a significant disease burden and increased mortality. Although the conditions may exist independently, they often go hand in hand as each is able to provoke, sustain, and aggravate the other. In addition, the diseases share a risk profile with several coinciding cardiovascular risk factors, promoting the odds of developing both AF and HF separately from each other. When the diseases coexist, this provides additional challenges but also opportunities for the optimal treatment. The recommended management of the comorbidities has been much debated in the past decades. In this review, we describe the pathophysiological coherence of AF and HF, illustrate the current knowledge on the management of them as comorbidities of each other and look forward to future developments in this field.

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

Europace: 09 Apr 2021; 23:ii40-ii45
Verhaert DVM, Brunner-La Rocca HP, van Veldhuisen DJ, Vernooy K
Europace: 09 Apr 2021; 23:ii40-ii45 | PMID: 33837758
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Impact:
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
Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography (CPETecho) in a tertiary care dyspnea clinic. ID was defined as ferritin <300µg/l and transferrin saturation (TSAT)<20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed.
Results
Of 272 CPETecho patients, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6±7.6 vs 17.8±8.8ml/kg/min; p=0.009) and maximal workload (89±50 vs 108±56 watt p=0.047), 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<0.05) and depressed RV function by tricuspid s\' (p=0.004), tricuspid annular plane systolic excursion (TAPSE; p=0.034) and RV end-systolic pressure-area ratio (RVESPAR; p=0.038), with more RV-pulmonary artery uncoupling measured by TAPSE/systolic pulmonary arterial pressure ratio (p=0.023). RVESPAR change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09±0.72 vs. 2.58±1.14 mmHg/cm2; p<0.001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; p=0.036). CPETecho resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e\' ratio above 14, with equal distribution in patients with (28.6%) or without ID (25.4%, p=0.611). None of the aforementioned findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.
Conclusion
In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with reduced exercise capacity, diminished biventricular contractile reserve and reduced peripheral oxygen extraction.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 06 Apr 2021; epub ahead of print
Martens P, Claessen G, Van De Bruaene A, Verbrugge FH, ... Dendale P, Verwerft J
J Card Fail: 06 Apr 2021; epub ahead of print | PMID: 33838251
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Impact:
Abstract

Effects of SGLT2 inhibitors on cardiovascular, renal, and major safety outcomes in heart failure: A meta-analysis of randomized controlled trials.

Li X, Zhang Q, Zhu L, Wang G, ... Hu A, Sun X
Aims
Sodium-glucose co-transporter 2 inhibitor (SGLT2i), initially introduced for the treatment of diabetes mellitus (DM), demonstrates cardiovascular and renal benefits in patients with heart failure (HF). We aimed to conduct a meta-analysis of its effects on cardiovascular, renal, and major safety outcomes in HF.
Methods and results
PubMed, Embase, Cochrane Library, and Web of Science were searched using the terms of \"SGLT2i and HF\" or \"SGLT2i *\". Seven randomized, placebo-controlled trials comprising 14,113 HF patients (mean age, 66.0 years; female, 27.6%; DM, 58.9%) were included. SGLT2i treatment was associated with lower incidences (compared with placebo) of the composite outcomes of cardiovascular death or hospitalization for HF (HHF) (ratio risk [RR] 0.773; 95% confidence interval [CI], 0.719-0.831; p < 0.001; I2 = 8.1%), cardiovascular death (RR 0.872; 95% CI, 0.788-0.964; p = 0.008; I2 = 0.0%), HHF (RR 0.722; 95% CI, 0.657-0.793; p < 0.001; I2 = 15.4%) and serious decrease in renal function (RR 0.673; 95% CI, 0.549-0.825; p < 0.001; I2 = 17.7%). SGLT2i treatment was associated with a lower incidence of serious adverse events (SAEs) (RR 0.867; 95% CI, 0.808-0.930; p < 0.001; I2 = 60.1%), but a higher incidence of volume depletion (RR 1.177; 95% CI, 1.040-1.333; p = 0.010; I2 = 0.0%). Analysis on patients without DM showed consistent results, except for cardiovascular death.
Conclusion
SGLT2i treatment contributed to better cardiovascular and renal outcomes in patients with HF, regardless of the presence or absence of DM. SGLT2i also resulted in a lower incidence of SAEs, although a higher incidence of volume depletion was observed.

Copyright © 2021. Published by Elsevier B.V.

Int J Cardiol: 06 Apr 2021; epub ahead of print
Li X, Zhang Q, Zhu L, Wang G, ... Hu A, Sun X
Int J Cardiol: 06 Apr 2021; epub ahead of print | PMID: 33838152
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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 Ireland Ltd. All rights reserved.

Int J Cardiol: 07 Apr 2021; epub ahead of print
McGee M, Sugito S, Al-Omary MS, Hartnett D, ... Sverdlov AL, Boyle AJ
Int J Cardiol: 07 Apr 2021; epub ahead of print | PMID: 33839176
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Impact:
Abstract

Cost of inpatient heart failure care and 30-day readmissions in the United States.

Kwok CS, Abramov D, Parwani P, Ghosh RK, ... Van Spall HGC, Mamas MA
Background
Heart failure hospitalizations are a major financial cost to healthcare systems. This study aimed to evaluate the costs associated with inpatient hospitalization.
Methods
Patients with a primary diagnosis of heart failure during a hospital admission between 2010 and 2014 in the U.S. Nationwide Readmission Database were included. The primary outcome was total cost defined by direct cost of index admission and first readmission within 30-days.
Results
A total of 2,645,336 patients with primary heart failure were included in the analysis. The mean ± SD total cost overall was $13,807 ± 24,145; with mean total costs of $15,618 ± 25,264 for patients with 30-day readmission and $11,845 ± 22,710 for patients without a readmission. The comorbidities strongly associated with increased cost were pulmonary circulatory disorder (OR 26.24 95% CI 20.06-34.33), valvular heart disease (OR 25.42 95% CI 20.65-31.28) and bleeding (OR 5.96 95% CI 5.47-6.50). Among hospitalized patients, 12.6% underwent an invasive diagnostic procedure or treatment. The mean cost for patients without invasive care was $10,995. This increased by $129,547, $119,769, $251,110 and $293,575 for receipt of circulatory support, intra-aortic balloon pump, LV assist device and heart transplant. The greatest mean additional cost annually was associated with receipt of coronary angiogram ($26,282 per person for a total of ($728.5 million) and mechanical ventilation ($54,529 per person for a total of $501.7 million).
Conclusion
In conclusion, the costs associated with inpatient heart failure care are significant, and the major contributors to inpatient costs are comorbidities, invasive procedures and readmissions.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Apr 2021; 329:115-122
Kwok CS, Abramov D, Parwani P, Ghosh RK, ... Van Spall HGC, Mamas MA
Int J Cardiol: 14 Apr 2021; 329:115-122 | PMID: 33321128
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Impact:
Abstract

New measures of right ventricle-pulmonary artery coupling in heart failure: An all-cause mortality echocardiographic study.

Pestelli G, Fiorencis A, Trevisan F, Luisi GA, Smarrazzo V, Mele D
Aims
Right ventricle-pulmonary artery coupling (RVPAC) has emerged from pathophysiology to clinical interest for prognostic implication in heart failure and is commonly measured as the ratio between tricuspid annular plane systolic excursion and systolic pulmonary artery pressure (TAPSE/SPAP). However, feasibility of SPAP is limited (down to 60% in trials, and maybe lower in clinical practice). We ought to assess the prognostic value of the TAPSE times pulmonary acceleration time (TAPSE x pACT) product and TAPSE to peak tricuspid regurgitation velocity (TAPSE/TRV) ratio as new alternative measures of RVPAC.
Methods and results
Two-hundred patients hospitalized with heart failure were followed-up (median time of 2.7 years) and 82 died. Non survivors had significantly lower TAPSE/SPAP, TAPSE x pACT and TAPSE/TRV than survivors (0.31 vs 0.40 mm/mmHg, 130 vs 156 cm·ms, 5.0 vs 5.8 ms, respectively). Four multivariate models were performed, each one including TAPSE, TAPSE/SPAP, TAPSE x pACT or TAPSE/TRV. TAPSE/SPAP resulted the most powerful predictor of mortality (HR 0.74 per mm/mmHg increase, P < 0.001, C-Statistic 0.778), followed by TAPSE x pACT (HR 0.95 per 10 cm·ms increase, P = 0.013, C-Statistic 0.776), TAPSE/TRV (HR 0.76 per ms increase, P < 0.001, C-Statistic 0.774) and TAPSE (HR 0.91 per mm increase, P = 0.003, C-Statistic 0.769). Cutoff values of 140 cm·ms and 5.5 ms were respectively identified for TAPSE x pACT and TAPSE/TRV with receiving operating characteristic analysis for mortality.
Conclusion
TAPSE x pACT product and TAPSE/TRV ratio are alternative measures of RVPAC for prognostic assessment in heart failure that can be applied if TAPSE/SPAP is not feasible.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Apr 2021; 329:234-241
Pestelli G, Fiorencis A, Trevisan F, Luisi GA, Smarrazzo V, Mele D
Int J Cardiol: 14 Apr 2021; 329:234-241 | PMID: 33359279
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Impact:
Abstract

Effect of a quality improvement intervention for acute heart failure in South India: An interrupted time series study.

Agarwal A, Mohanan PP, Kondal D, Baldridge A, ... Huffman MD, Prabhakaran D
Background
Although quality improvement interventions for acute heart failure have been studied in high-income countries, none have been studied in low- or middle-income country settings where quality of care can be lower. We evaluated the effect of a quality improvement toolkit on process of care measures and clinical outcomes in patients hospitalized for acute heart failure in 8 hospitals in Kerala, India utilizing an interrupted time series design from February 2018 to August 2018.
Methods
The quality improvement toolkit included checklists, audit-and-feedback reports, and patient education materials. The primary outcome was rate of discharge guideline-directed medical therapy for patients with heart failure with reduced ejection fraction. We used mixed effect logistic regression and interrupted time series models for analysis.
Results
Among 1400 participants, mean (SD) age was 66.6 (12.2) years, and 38% were female. Mean (SD) left ventricular ejection fraction was 35.2% (9.7%). The primary outcome was observed in 41.3% of participants in the intervention period and 28.1% of participants in the control period (difference 13.2%; 95% CI 6.8, 19.0; adjusted OR = 1.70; 95% CI 1.17, 2.48). Interrupted time series model demonstrated highest rate of guideline-directed medical therapy at discharge in the initial weeks following intervention delivery with a concomitant decline over time. Improvements were observed in discharge process of care measures, including diet counseling, weight monitoring instructions, and scheduling of outpatient clinic follow-up but not hospital length of stay nor inpatient mortality.
Conclusions
Higher rates of guideline-directed medical therapy at discharge were observed in Kerala. Broader implementation of this quality improvement intervention may improve heart failure care in low- and middle-income countries.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Apr 2021; 329:123-129
Agarwal A, Mohanan PP, Kondal D, Baldridge A, ... Huffman MD, Prabhakaran D
Int J Cardiol: 14 Apr 2021; 329:123-129 | PMID: 33358838
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Impact:
Abstract

Impact of a pharmacist-based multidimensional intervention aimed at decreasing the risk of hyperkalemia in heart failure patients: A Latin-American experience.

Gallo-Bernal S, Calixto CA, Molano-González N, Moreno MPD, ... Medina HM, Rodríguez MJ
Aims
Hyperkalemia is a potentially life-threatening condition associated with the use of heart failure (HF) medications, which can lead to increased morbidity and mortality. Novel approaches for hyperkalemia prevention are needed, especially in limited-resource settings. Despite multiple studies showing the beneficial impact of pharmaceutical-counseling in several outcomes, there is a knowledge-gap regarding its impact on hyperkalemia prevention.
Methods
A case-control study was performed in patients from the Adult Heart Failure Clinic Registry in our institution. Cases were selected using a definition of serum potassium K+ ≥5.5 mmol/L. To study the association between hyperkalemia and relevant risk factors, we performed a multivariate logistic regression analysis using the Least Absolute Shrinkage and Selection Operator (LASSO) method for variable selection. We also fitted a Classification and Regression Tree (CART) to establish complex interactions and effect modifiers between the selected variables.
Results
We matched 483 controls (eligible HF patients without hyperkalemia) to 132 cases (eligible HF patients with hyperkalemia based on age and calendar, yielding a total sample size of 615 patients (270 females) for this study. Cases had statistically significant lower odds of receiving a pharmacist-based multidimensional intervention (PBMI) (OR 0.57; 95% CI, 0.43-0.80) or having HF with reduced ejection fraction (OR 0.56; 95% CI, 0.18-0.72). On the other hand, patients who presented hyperkalemia had statistically significant higher odds of having a history of chronic kidney disease stage 4 (OR 4.97; 95% CI, 2.24-11.01) or 5 (OR 6.73; 95% CI, 1.69-26.84) and being on enalapril at doses =40 mg/day (OR, 9.90; 95% CI 5.81-16.87).
Conclusions
PBMI is a practical approach to prevent hyperkalemia in HF patients in a limited-resource setting. However, clinical trials are needed to assess its effectiveness.

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

Int J Cardiol: 14 Apr 2021; 329:136-143
Gallo-Bernal S, Calixto CA, Molano-González N, Moreno MPD, ... Medina HM, Rodríguez MJ
Int J Cardiol: 14 Apr 2021; 329:136-143 | PMID: 33412183
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Impact:
Abstract

Application of the heart failure meta-score to predict prognosis in patients with cardiac resynchronization defibrillators.

Theuns DAMJ, Schaer BA, Caliskan K, Hoeks SE, ... Yap SC, Alba AC
Background
The Heart Failure (HF) Meta-score may be useful in predicting prognosis in patients with primary prevention cardiac resynchronization defibrillators (CRT-D) considering the competing risk of appropriate defibrillator shock versus mortality.
Methods
Data from 648 consecutive patients from two centers were used for the evaluation of the performance of the HF Meta-score. The primary endpoint was mortality and the secondary endpoint was time to first appropriate implantable cardioverter-defibrillator (ICD) shock or death without prior appropriate ICD shock. Fine-Gray model was used for competing risk regression analysis.
Results
In the entire cohort, 237 patients died over a median follow-up of 5.2 years. Five-year cumulative incidence of mortality ranged from 12% to 53%, for quintiles 1 through 5 of the HF Meta-score, respectively (log-rank P < 0.001). Compared with the lowest quintile, mortality risk was higher in the highest quintile (HR 6.9; 95%CI 3.7-12.8). The HF Meta-score had excellent calibration, accuracy, and good discrimination in predicting mortality (C-statistic 0.76 at 1-year and 0.71 at 5-year). The risk of death without appropriate ICD shock was higher in risk quintile 5 compared to quintile 1 (sub HR 5.8; 95%CI 3.1-11.0, P < 0.001).
Conclusions
Our study demonstrated a good ability of the HF Meta-score to predict survival in HF patients treated with CRT-D as primary prevention. The HF Meta-score proved to be useful in identifying a subgroup with a significantly poor prognosis despite a CRT-D.

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

Int J Cardiol: 30 Apr 2021; 330:73-79
Theuns DAMJ, Schaer BA, Caliskan K, Hoeks SE, ... Yap SC, Alba AC
Int J Cardiol: 30 Apr 2021; 330:73-79 | PMID: 33516838
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Impact:
Abstract

A new approach to the clinical subclassification of heart failure with preserved ejection fraction.

Nouraei H, Rabkin SW
Objective
Heart failure with preserved ejection (HFpEF) represents nearly half of all patients with heart failure (HF). The objective of this study was to determine whether patient characteristics identify discrete kinds of HFpEF.
Methods
Data were collected on 196 patients with HFpEF in a non-hospitalized setting. Clinical and laboratory variables were collected, and 47 candidate variables were examined by the unsupervised clustering strategy partitioning around medoids. The Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk score was calculated. Follow-up data on all-cause mortality, cardiovascular mortality, and HF exacerbation, were collected and were not part of the data used to identify subgroups.
Results
Six significantly different groups or clusters were found. There were three groups of women (i) individuals with a low proportion of vascular risk factors (HFpEF1) (ii) individuals with a high proportion of hypertension and diabetes, but lower proportion of kidney disease and diastolic dysfunction (HFpEF3) (iii) older individuals with high rates of atrial fibrillation (AF), chronic kidney disease. They had the worst long-term outcomes (HFpEF4). There were three groups of men (i) individuals with a high proportion of coronary artery disease (CAD), dyslipidemia, higher serum creatinine, and diastolic dysfunction (HFpEF2)(ii) individuals with highest BMI, and high proportion of CAD, obstructive sleep apnea, and poorly controlled diabetes (HFpEF5) (iii) individuals with high rates of AF, elevated BNP, biventricular remodeling (HFpEF6). They had a high cardiovascular mortality.
Conclusions
HFpEF consists of a heterogenous group of individuals with six distinct clinical subsets that have different long-term outcomes.

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

Int J Cardiol: 14 May 2021; 331:138-143
Nouraei H, Rabkin SW
Int J Cardiol: 14 May 2021; 331:138-143 | PMID: 33529665
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Impact:
Abstract

Characteristics, trends, outcomes, and costs of stimulant-related acute heart failure hospitalizations in the United States.

Shetty S, Malik AH, Ali A, Yang YC, Briasoulis A, Alvarez P
Background
Heart failure (HF) hospitalizations remains a significant burden on the health care system. Stimulants including cocaine, amphetamine and its derivatives are amongst the most used illegal substances in the United States. The information regarding stimulant-related HF hospitalizations is scarce. We sought to evaluate the characteristics and trends of stimulant-related HF hospitalizations in the United States and their associated outcomes and resource utilization.
Methods
Using the National Inpatient Sample (NIS), we identified patients with a primary diagnosis of HF hospitalization. These hospitalizations were further divided into those with and without a concomitant diagnosis of stimulant (cocaine or amphetamine) dependence or abuse. Survey specific techniques were employed to compare trends in baseline characteristics, complications, procedures, outcomes and resource utilization between the two cohorts.
Results
We identified 9,932,753 hospitalizations (weighted) with a primary diagnosis of heart failure, of those 138,438 (1.39%) had a diagnosis of active stimulant use. The proportion of stimulant-related HF hospitalization is on the rise (1.1% to 1.9%). Stimulant-related HF hospitalization was highest amongst age group 30-39 years and 7.9% of HF hospitalizations in this age group were due to stimulant use. The proportion of stimulant-related HF hospitalization for the White and Hispanic race has doubled from 2008 to 2017. Stimulant-related HF hospitalization is associated with increased incidence of in-hospital complications like cardiogenic shock, acute kidney injury and ventricular tachycardia. These patients have more than 7-fold higher discharge against medical advice.
Conclusions
Stimulant-related HF hospitalizations have been increasing. It is associate with significant morbidity burden and health care utilization.

Copyright © 2021. Published by Elsevier B.V.

Int J Cardiol: 14 May 2021; 331:158-163
Shetty S, Malik AH, Ali A, Yang YC, Briasoulis A, Alvarez P
Int J Cardiol: 14 May 2021; 331:158-163 | PMID: 33535075
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Abstract

Real-world effectiveness and safety of sacubitril/valsartan in heart failure: A systematic review.

Proudfoot C, Studer R, Rajput T, Jindal R, ... Corda S, Senni M
Background
PARADIGM-HF demonstrated superiority of sacubitril/valsartan (sac/val) over enalapril in patients with heart failure with reduced ejection fraction (HFrEF). However, patients in clinical practice may differ in their characteristics and overall risk compared with patients in clinical trials, and additional outcomes can be observed in real world (RW). Hence, a systematic review was conducted to identify and describe RW data on sac/val.
Methods
RW studies evaluating the effects of sac/val in adult patients with HFrEF with a sample size ≥100 were identified via MEDLINE® and Embase® from 2015 to January 2020. Citations were screened, critically appraised and relevant data were extracted.
Results
A total of 68 unique studies were identified. Nearly half of the studies were conducted in Europe (n = 34), followed by the US (n = 15) and Asia (n = 11). Median follow-up period varied from 1 to 19 months. Mean age ranged between 48.7 and 79.0 years; patients were mostly male and in New York Heart Association (NYHA) functional class II/III, and mean left ventricular ejection fraction varied between 23%and 38%. Of studies performing comparisons, most reported superior efficacy of sac/val in reducing the risk of HF hospitalisations, all-cause hospitalisations, and all-cause mortality as compared to standard-of-care. Many studies reported significant improvements in NYHA functional class and reduction in biomarker levels post sac/val. Hypotension and hyperkalaemia were the most frequently reported adverse events.
Conclusions
This comprehensive overview of currently available RW evidence on sac/val complements the evidence from randomised controlled trials, substantiating its effectiveness in heterogeneous real-world HF populations.

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

Int J Cardiol: 14 May 2021; 331:164-171
Proudfoot C, Studer R, Rajput T, Jindal R, ... Corda S, Senni M
Int J Cardiol: 14 May 2021; 331:164-171 | PMID: 33545266
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Abstract

Responses to exercise training in patients with heart failure. Analysis by oxygen transport steps.

Legendre A, Moatemri F, Kovalska O, Balice-Pasquinelli M, ... Cristofini P, Iliou MC
Background
Exercise training (ET) increases exercise tolerance, improves quality of life and likely the prognosis in heart failure patients with reduced ejection fraction (HFrEF). However, some patients do not improve, whereas exercise training response is still poorly understood. Measurement of cardiac output during cardiopulmonary exercise test might allow ET response assessment according to the different steps of oxygen transport.
Methods
Fifty-three patients with HFrEF (24 with ischemic cardiomyopathy (ICM) and 29 with dilated cardiomyopathy (DCM) had an aerobic ET. Before and after ET program, peak oxygen consumption (VO2peak) and cardiac output using thoracic impedancemetry were measured. Oxygen convection (QO2peak) and diffusion (DO2) were calculated using Fick\'s principle and Fick\'s simplified law. Patients were considered as responders if the gain was superior to 10%.
Results
We found 55% VO2peak responders, 62% QO2peak responders and 56% DO2 responders. Four patients did not have any response. None baseline predictive factor for VO2peak response was found. QO2peak response was related to exercise stroke volume (r = 0.84), cardiac power (r = 0.83) and systemic vascular resistance (SVRpeak) (r = -0.42) responses. Cardiac power response was higher in patients with ICM than in those with DCM (p < 0.05). Predictors of QO2peak response were low baseline exercise stroke volume and ICM etiology. Predictors of DO2 response were higher baseline blood creatinine and prolonged training.
Conclusion
The analysis of the response to training in patients with HFrEF according to the different steps of oxygen transport revealed different phenotypes on VO2peak responses, namely responses in either oxygen convection and/or diffusion.

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

Int J Cardiol: 30 Apr 2021; 330:120-127
Legendre A, Moatemri F, Kovalska O, Balice-Pasquinelli M, ... Cristofini P, Iliou MC
Int J Cardiol: 30 Apr 2021; 330:120-127 | PMID: 33571565
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Abstract

Combining sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors in heart failure patients with reduced ejection fraction and diabetes mellitus: A multi-institutional study.

Hsiao FC, Lin CP, Tung YC, Chang PC, McMurray JJV, Chu PH
Background
Few studies investigated the combination of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and angiotensin receptor-neprilysin inhibitors (ARNIs) in patients with heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (T2DM).
Methods
During 2016 to 2018, patients with HFrEF and T2DM were identified from Chang Gung Research Database; a database deriving from the original electronic medical records of 7 hospitals in Taiwan. They were classified into four subgroups according to the medications received as follows: 1) SGLT2i and ARNI; 2) SGLT2i and no ARNI; 3) ARNI and no SGLT2i; and 4) no SGLT2i and no ARNI. We examined clinical and safety (hyperkalemia and acute renal dysfunction) outcomes over 1-year of follow-up.
Results
A total of 2312 patients were eligible for analysis, including 169, 285, 338, and 1520 in subgroups 1, 2, 3 and 4, respectively. There were large differences in baseline characteristics and treatments among subgroups. Subgroup 1 had the lowest rates of HF hospitalizations, all-cause death, and the composite of both, and subgroup 4 had the highest event rates. A similar pattern was observed for the safety outcomes. These differences were attenuated after adjusting for differences in baseline variables and therapy.
Conclusions
Treatment with a combination of SGLT2i and ARNI was well tolerated in diabetic patients with HFrEF and was associated with lower risk of heart failure hospitalization.

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

Int J Cardiol: 30 Apr 2021; 330:91-97
Hsiao FC, Lin CP, Tung YC, Chang PC, McMurray JJV, Chu PH
Int J Cardiol: 30 Apr 2021; 330:91-97 | PMID: 33587940
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Abstract

Treatment prescription, adherence, and persistence after the first hospitalization for heart failure: A population-based retrospective study on 100785 patients.

Scalvini S, Bernocchi P, Villa S, Paganoni AM, La Rovere MT, Frigerio M
Background
This study evaluates, in a real-world setting, to what extent the recommended therapies by international guidelines, are prescribed after a first hospitalization for heart failure (HF), and to analyse adherence and persistence, and the effect of treatment adherence on mortality and re-hospitalization.
Methods
From the Lombardy healthcare administrative database, we analysed patients discharged after their incident HF, from 2000 to 2012. Adherence was defined as the proportion of days covered (PDC) ≥80% adjusted for hospitalizations and persistence as the absence of discontinuation of therapy for >30 days. A logit model was used to determine the effect of patients\' adherence on mortality and readmissions.
Results
Of 100422 HF patients (52% males, age 75 ± 12 years), 86846 (87%) had a prescription for angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACE/ARBs), 64135 (64%) for beta-blockers (BB), and 36893 (37%) for mineralocorticoid receptor antagonists (MRAs), as mono-, bi- or tri-therapy. In patients on monotherapy, PDC was 78 ± 22% for ACE/ARBs, 69 ± 29% for BB and 54 ± 29% for MRAs; in those on bi-therapy, PDC was 63 ± 31% for ACEI/ARBs+BB, 41 ± 29% for ACEI/ARBs+MRAs, and 40 ± 26% for MRAs+BB; for patients on tri-therapy, PDC was 42 ± 28%. Medication persistence was present in 47% of patients treated with ACEI/ARBs, in 35% of patients treated with BB and in 14% of patients treated with MRAs. Re-hospitalizations and in mortality were significantly reduced in adherent patients (p < 0.000).
Conclusions
Polypharmacy is associated with an increased rate of non-adherence and non-persistence in incident HF. Non-adherence is associated with an increased risk of mortality and re-hospitalizations.

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

Int J Cardiol: 30 Apr 2021; 330:106-111
Scalvini S, Bernocchi P, Villa S, Paganoni AM, La Rovere MT, Frigerio M
Int J Cardiol: 30 Apr 2021; 330:106-111 | PMID: 33582198
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Abstract

Sacubitril-valsartan treatment is associated with decrease in central apneas in patients with heart failure with reduced ejection fraction.

Passino C, Sciarrone P, Vergaro G, Borrelli C, ... Emdin M, Giannoni A
Background
To assess the impact of sacubitril-valsartan on apneic burden in patients with heart failure with reduced ejection fraction (HFrEF), 51 stable HFrEF patients planned for switching from an ACE-i/ARB to sacubitril-valsartan were prospectively enrolled.
Methods and results
At baseline and after 6 months of treatment, all patients underwent echocardiography, 24-h cardiorespiratory monitoring, neurohormonal evaluation, and cardiopulmonary exercise testing. At baseline 29% and 65% of patients presented with obstructive and central apneas, respectively. After 6 months, sacubitril-valsartan was associated with a decrease in NT-proBNP, improvement in LV function, functional capacity and ventilatory efficiency. After treatment, the apnea-hypopnea index (AHI) decreased across the 24-h period (p < 0.001), as well as at daytime (p < 0.001) and at nighttime (p = 0.026), proportionally to baseline severity. When subgrouping according to the type of apneas, daytime, nighttime and 24-h AHI decreased in patients with central apneas (all p < 0.01). Conversely, in patients with obstructive apneas, the effect of drug administration was neutral at nighttime, with significant decrease only in daytime events (p = 0.007), mainly driven by reduction in hypopneas.
Conclusions
Sacubitril-valsartan on top of medical treatment is associated with a reduction in the apneic burden among a real-life cohort of HFrEF patients. The most marked reduction was observed for central apneas.

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

Int J Cardiol: 30 Apr 2021; 330:112-119
Passino C, Sciarrone P, Vergaro G, Borrelli C, ... Emdin M, Giannoni A
Int J Cardiol: 30 Apr 2021; 330:112-119 | PMID: 33581182
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Abstract

Risk of stent failure in patients with diabetes treated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors: A nationwide observational study.

Santos-Pardo I, Lagerqvist B, Ritsinger V, Witt N, Norhammar A, Nyström T
Background
Incretins are a group of glucose-lowering drugs with favourable cardiovascular (CV) effects against neoatherosclerosis. Incretins\' potential effect in stent failure is unknown. The aim of this study is to determine if incretin treatment decreases the risk of stent-thrombosis (ST), and/or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) with implanted drug-eluting stents (DES).
Methods
Observational study including all diabetes patients who underwent PCI with DES in Sweden from 2007 to 2017. By merging 5 national registers, the information on patient characteristics, outcomes and drug dispenses was retrieved. Cox regression analysis with estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) was used to analyse for the occurrence of ST/ISR, and major adverse cardiovascular events (MACE). A subgroup analysis for the type of incretin treatment was performed.
Results
In total 18,505 diabetes patients (30% women) underwent PCI, and 32,463 DES were implanted. Of those, 10% (3449 DES in 1943 patients) were treated with incretins. Median follow-up time was 995 days (Control Group) vs. 771 days (Incretin Group). No significant difference in the risk of ST/ISR was found neither for the main study group (HR:0.98 95% CI:0.80-1.19) nor for the subgroups. No reduction of the risk of MACE (HR:0.96 95% CI:0.88-1.06) was observed. There was a 26% lower risk for CV death in favour of incretin treated patients (HR:0.74 95% CI:0.57-0.95).
Conclusion
In diabetes patients who underwent PCI incretin treatment was not associated with lower risk of stent failure, but with lower risk of CV death.

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

Int J Cardiol: 30 Apr 2021; 330:23-29
Santos-Pardo I, Lagerqvist B, Ritsinger V, Witt N, Norhammar A, Nyström T
Int J Cardiol: 30 Apr 2021; 330:23-29 | PMID: 33621623
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Abstract

Left Ventricular Global Longitudinal Strain as a Predictor of Outcomes in Heart Failure Patients with Secondary Mitral Regurgitation: The COAPT Trial.

Medvedofsky D, Pio SM, Weissman NJ, Namazi F, ... Asch FM, COAPT Investigators
Background
Left ventricular (LV) global longitudinal strain (GLS) is a sensitive marker of LV function and may help identify patients with heart failure (HF) and secondary mitral regurgitation (SMR) who would have a better prognosis and are more likely to benefit from edge-to-edge transcatheter mitral valve repair (TMVr) with the MitraClip. We sought to assess the prognostic utility of baseline LVGLS during 2-year follow-up of HF patients with SMR enrolled in the COAPT trial.
Methods
Symptomatic HF patients with moderate-to-severe or severe SMR who remained symptomatic despite maximally-tolerated guideline directed medical therapy (GDMT) were randomized to TMVr plus GDMT or GDMT alone. Speckle tracking-derived LVGLS from baseline echocardiograms was obtained in 565 patients and categorized by tertiles. Death and HF hospitalization (HFH) at 2-year follow-up were the principal outcomes of interest.
Results
Patients with better baseline LVGLS had higher blood pressure, greater LV ejection fraction and stroke volume, lower levels of B-type natriuretic peptide and smaller LV size. No significant difference in outcomes at 2-year follow-up were noted according to LVGLS. However, the rate of death or HFH between 10 and 24 months was lower in patients with better LVGLS (p=0.03), with no differences before 10 months. There was no interaction between GLS tertiles and treatment group with respect to 2-year clinical outcomes.
Conclusions
Baseline LVGLS did not predict death or HFH throughout 2-year follow-up, but it did predict outcomes after 10 months. The benefit of TMVr over GDMT alone was consistent in all sub-groups irrespective of baseline LVGLS.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 08 Apr 2021; epub ahead of print
Medvedofsky D, Pio SM, Weissman NJ, Namazi F, ... Asch FM, COAPT Investigators
J Am Soc Echocardiogr: 08 Apr 2021; epub ahead of print | PMID: 33845158
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Abstract

Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): Design and Baseline Characteristics.

Jering KS, Claggett B, Pfeffer MA, Granger C, ... Nicolau JC, Braunwald E
Aims
Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven ACE inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.
Methods and results
PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or LVEF ≤ 40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, eGFR <60ml/min/1.73m2 , diabetes, prior MI, atrial fibrillation, LVEF <30%, Killip class ≥III, STEMI without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints [cardiovascular (CV) death, HF hospitalization or outpatient development of HF]. Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation MI; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were Killip class ≥2.
Conclusions
Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and CV death following AMI.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 11 Apr 2021; epub ahead of print
Jering KS, Claggett B, Pfeffer MA, Granger C, ... Nicolau JC, Braunwald E
Eur J Heart Fail: 11 Apr 2021; epub ahead of print | PMID: 33847047
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Abstract

Left Atrial Strain Associated with Functional Recovery in Patients Receiving Optimal Treatment for Heart Failure.

Torii Y, Kusunose K, Hirata Y, Nishio S, ... Wakatsuki T, Sata M
Background
Heart failure with recovered ejection fraction (HFrecEF) has been reported in several previous studies to have a better prognosis than HF with reduced EF (HFrEF). However, the factors associated with HFrecEF have not been identified. We hypothesized that left atrial (LA) strain could help to identify patients with recovered EF among cases of HF with low EF on admission.
Methods
We enrolled 100 consecutive patients hospitalized for the first time due to new-onset HF. Patients were clinically diagnosed with HFrEF on admission (LVEF <40%) and underwent optimal treatment for HF. Twenty-eight patients improved to HFrecEF during 6 months of follow-up.
Results
Regarding clinical background, there were significantly more females and a lower rate of atrial fibrillation in the HFrecEF group than in the HFrEF group. In the multivariable logistic regression analysis, LA strain was an independent predictor of HFrecEF, even after adjustment for gender and LVEF (OR: 4.06, 95% CI: 2.04-8.07, P < 0.001). A cutoff value of 10.8% for LA strain showed high sensitivity (96%) and specificity (82%) in identifying HFrecEF in HF patients presenting with low EF on admission. During a follow-up period of 24 ± 13 months, 31 patients (31%) had cardiovascular death or readmission due to HF. Patients with reduced LA strain (less than 10.8%) had significantly shorter event-free survival than preserved LA strain (P = 0.02).
Conclusion
LA strain is a useful indicator for predicting HFrecEF and should be considered as a routine measurement in patients with HFrEF on admission.

Copyright © 2021. Published by Elsevier Inc.

J Am Soc Echocardiogr: 10 Apr 2021; epub ahead of print
Torii Y, Kusunose K, Hirata Y, Nishio S, ... Wakatsuki T, Sata M
J Am Soc Echocardiogr: 10 Apr 2021; epub ahead of print | PMID: 33852960
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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 (MESA), relationships between angiopoietins, cardiac morphology, and subsequent incidence of heart failure or cardiovascular death were evaluated. In cohorts with pulmonary arterial hypertension (PAH) or left heart disease (LHD), 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 (HR 1.21 per standard deviation, P<0.001). Ang2 was associated with increased right atrial pressure (PAH cohort) and increased wedge pressure and right atrial pressure (LHD cohort). Elevated Ang2 was associated with mortality in the PAH cohort.
Conclusion
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 findings that Ang2 is elevated prior to disease onset and that elevations reflect disease severity, suggest Ang2 may contribute to heart failure pathogenesis.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 15 Apr 2021; epub ahead of print
Peplinski BS, Houston BA, Bluemke DA, Kawut SM, ... Tedford RJ, Leary PJ
J Card Fail: 15 Apr 2021; epub ahead of print | 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].
Objectives
We sought to identify patient and hospital characteristics and outcomes of patients with HF who left AMA compared to those conventionally discharged to home [CDH].
Methods
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. Fully eligible population included 561,823 patients; the Medicare-linked subset included 74,502 patients.
Results
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 to patients CDH, 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 to patients who were CDH. After risk adjustments, the hazard ratio of mortality in the Medicare-linked subset AMA group compared to the CDH group was 1.25 (95% CI 1.03, 1.51), p=0.005.
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 to being conventionally discharged home. Strategies that identify patients at risk of leaving AMA and policies to direct interventional strategies are warranted.
Condensed abstract
We investigated patient characteristics, hospital factors and clinical outcomes associated with patients leaving a HF hospitalization against medical advice compared with being conventionally discharged to home. Using GWTG, a national registry, we found that patients who left AMA were more likely to be younger, minorities, Medicaid insured or uninsured; they had higher readmission and post-discharge mortality rates. Hospital characteristics associated with higher AMA discharges were for-profit structure and Western U.S.
Location
As HF prevalence increases, attention and interventions that support patients who chose to leave AMA and the hospitals from which they leave are needed.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 13 Apr 2021; epub ahead of print
Mitchell JE, Chesler R, Zhang S, Matsouaka RA, ... Chang NL, Fonarow GC
J Card Fail: 13 Apr 2021; epub ahead of print | PMID: 33864931
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Impact:
Abstract

Estimation of stressed blood volume in patients with cardiogenic shock from acute myocardial infarction and decompensated heart failure.

Whitehead EH, Thayer KL, Sunagawa K, Hernandez-Montfort J, ... Kapur NK, Burkhoff D
Background
Sympathetically mediated re-distribution of blood from the unstressed venous reservoir to the hemodynamically active stressed compartment is thought to contribute to congestion in cardiogenic shock. We employed a novel computational method to estimate stressed blood volume in cardiogenic shock and assess its relationship with clinical outcomes.
Methods
Hemodynamic parameters including estimated stressed blood volume (eSBV) were compared among patients from the Cardiogenic Shock Working Group (CSWG) registry with a complete set of hemodynamic data. eSBV was compared across shock etiologies (AMI vs HF-CS), SCAI stage, and between survivors and non-survivors.
Results
Among 528 CS patients analyzed, mean eSBV was 2423 mL/70 kg and increased with increasing SCAI stage (B, 2029; C, 2305; D, 2496; E, 2707 mL/70 kg, p<0.001). eSBV was significantly higher among HF-CS patients who died compared with survivors (2733 vs 2357 mL/70 kg, p<0.001), while no significant difference was observed between outcome groups in AMI-CS (2501 vs 2384 ml/70kg, p=0.19)
Conclusions:
: eSBV is a novel integrated index of congestion which correlates with shock severity. eSBV was higher in patients with HF-CS who died while no difference was observed in AMI-CS, suggesting that congestion may play a more significant role in the deterioration of patients with HF-CS.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 12 Apr 2021; epub ahead of print
Whitehead EH, Thayer KL, Sunagawa K, Hernandez-Montfort J, ... Kapur NK, Burkhoff D
J Card Fail: 12 Apr 2021; epub ahead of print | PMID: 33862252
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Impact:
Abstract

Cardiac thyrotropin-releasing hormone (TRH) inhibition improves ventricular function and reduces hypertrophy and fibrosis after myocardial infarction in rats.

Schuman ML, Diaz LSP, 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 siRNA against TRH was simultaneously applied. The control group received a scrambled siRNA. Cardiac remodeling variables were evaluated one week later. In MI rats, TRH inhibition decreased LV end-diastolic (1.049±0.102 vs. 1.339±0.102 ml, p<0.05), and end-systolic volumes (0.282±0.043 vs. 0.515±0.037 ml, p<0.001), and increased LV ejection fraction (71.89±2.80 vs. 65.69±2.85 %, p<0.05). Although both MI groups presented similar infarct size, siRNA-the 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 TGFβ, collagen I, and III and also the fetal genes (ANP, BNP, and βMHC) expression in the peri-infarct region. Besides, the expression of Hif1α and VEGF significantly increased compared to 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. Published by Elsevier Inc.

J Card Fail: 14 Apr 2021; epub ahead of print
Schuman ML, Diaz LSP, Aisicovich M, Ingallina F, ... Landa MS, García SI
J Card Fail: 14 Apr 2021; epub ahead of print | PMID: 33865967
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Impact:
Abstract

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Tromp J, Claggett BL, Liu J, Jackson AM, ... Lam CSP, PARAGON-HF Investigators
Background
Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial.
Methods
We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region.
Results
Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05).
Conclusions
Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.



Circ Heart Fail: 30 Mar 2021; 14:e007901
Tromp J, Claggett BL, Liu J, Jackson AM, ... Lam CSP, PARAGON-HF Investigators
Circ Heart Fail: 30 Mar 2021; 14:e007901 | PMID: 33866828
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Impact:
Abstract

Trends in 30- and 90-Day Readmission Rates for Heart Failure.

Khan MS, Sreenivasan J, Lateef N, Abougergi MS, ... Fonarow GC, Butler J
Background
The impact of hospital readmission reduction program (HRRP) on heart failure (HF) outcomes has been debated. Limited data exist regarding trends of HF readmission rates beyond 30 days from all-payer sources. The aim of this study was to investigate temporal trends of 30- and 90-day HF readmissions rates from 2010 to 2017 in patients from all-payer sources.
Methods
The National Readmission Database was utilized to identify HF hospitalizations between 2010 and 2017. In the primary analysis, a linear trend in 30-day and 90-day readmissions from 2010 to 2017 was assessed. While in the secondary analysis, a change in aggregated 30- and 90-day all-cause and HF-specific readmissions pre-HRRP penalty phase (2010-2012) and post-HRRP penalties (2013-2017) was compared. Subgroup analyses were performed based on (1) Medicare versus non-Medicare insurance, (2) low versus high HF volume, and (3) HF with reduced versus preserved ejection fraction (heart failure with reduced ejection fraction and heart failure with preserved ejection fraction). Multiple logistic and adjusted linear regression analyses were performed for annual trends.
Results
A total of 6 669 313 index HF hospitalizations for 30-day, and 5 077 949 index HF hospitalizations for 90-day readmission, were included. Of these, 1 213 402 (18.2%) encounters had a readmission within 30 days, and 1 585 445 (31.2%) encounters had a readmission within 90 days. Between 2010 and 2017, both 30 and 90 days adjusted HF-specific and all-cause readmissions increased (8.1% to 8.7%, P trend 0.04, and 18.3% to 19.9%, P trend <0.001 for 30-day and 14.8% to 16.0% and 30.9% to 34.6% for 90-day, P trend <0.001 for both, respectively). Readmission rates were higher during the post-HRRP penalty period compared with pre-HRRP penalty phase (all-cause readmission 30 days: 18.6% versus 17.5%, P<0.001, all-cause readmission 90 days: 32.0% versus 29.9%, P<0.001) across all subgroups except among the low-volume hospitals.
Conclusions
The rates of adjusted HF-specific and all-cause 30- and 90-day readmissions have increased from 2010 to 2017. Readmissions rates were higher during the HRRP phase across all subgroups except the low-volume hospitals.



Circ Heart Fail: 30 Mar 2021; 14:e008335
Khan MS, Sreenivasan J, Lateef N, Abougergi MS, ... Fonarow GC, Butler J
Circ Heart Fail: 30 Mar 2021; 14:e008335 | PMID: 33866827
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Impact:
Abstract

Right Heart Phenotype in Heart Failure With Preserved Ejection Fraction.

Guazzi M, Naeije R
The health burden of heart failure with preserved ejection fraction is increasingly recognized. Despite improvements in diagnostic algorithms and established knowledge on the clinical trajectory, effective treatment options for heart failure with preserved ejection fraction remain limited, mainly because of the high mechanistic heterogeneity. Diagnostic scores, big data, and phenomapping categorization are proposed as key steps needed for progress. In the meantime, advancements in imaging techniques combined to high-fidelity pressure signaling analysis have uncovered right ventricular dysfunction as a mediator of heart failure with preserved ejection fraction progression and as major independent determinant of poor outcome. This review summarizes the current understanding of the pathophysiology of right ventricular dysfunction in heart failure with preserved ejection fraction covering the different right heart phenotypes and offering perspectives on new treatments targeting the right ventricle in its function and geometry.



Circ Heart Fail: 30 Mar 2021; 14:e007840
Guazzi M, Naeije R
Circ Heart Fail: 30 Mar 2021; 14:e007840 | PMID: 33866826
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Impact:
Abstract

Increased Risk of Congestive Heart Failure Following Carbon Monoxide Poisoning.

Huang CC, Chen TH, Ho CH, Chen YC, ... Chang CP, Guo HR
Background
Carbon monoxide poisoning (COP) is an important public health issue around the world. It may increase the risk of myocardial injury, but the association between COP and congestive heart failure (CHF) remains unclear. We conducted a study incorporating data from epidemiological and animal studies to clarify this issue.
Methods
Using the National Health Insurance Database of Taiwan, we identified patients with COP diagnosed between 1999 and 2012 and compared them with patients without COP (non-COP cohort) matched by age and the index date at a 1:3 ratio. The comparison for the risk of CHF between the COP and non-COP cohorts was made using Cox proportional hazards regression. We also established a rat model to evaluate cardiac function using echocardiography and studied the pathological changes following COP.
Results
The 20 942 patients in the COP cohort had a higher risk for CHF than the 62 826 members in the non-COP cohort after adjusting for sex and underlying comorbidities (adjusted hazard ratio, 2.01 [95% CI, 1.74-2.32]). The increased risk of CHF persisted even after 2 years of follow-up (adjusted hazard ratio, 1.85 [95% CI, 1.55-2.21]). In the animal model, COP led to a decreased left ventricular ejection fraction on echocardiography and damage to cardiac cells with remarkable fibrotic changes.
Conclusions
Our epidemiological data showed an increased risk of CHF was associated with COP, which was supported by the animal study. We suggest close follow-up of cardiac function for patients with COP to facilitate early intervention and further studies to identify other long-term effects that have not been reported in the literature.



Circ Heart Fail: 30 Mar 2021; 14:e007267
Huang CC, Chen TH, Ho CH, Chen YC, ... Chang CP, Guo HR
Circ Heart Fail: 30 Mar 2021; 14:e007267 | PMID: 33866825
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Impact:
Abstract

β-blocker and 1-year outcomes among patients hospitalized for heart failure with mid-range ejection fraction.

Wang B, Zhang L, Hu S, Bai X, ... Li J, Zheng X
Aims
The beneficial effect of β-blocker on heart failure with reduced ejection fraction (HFrEF) is well established. However, its effect on the 1-year outcome of heart failure with mid-range ejection fraction (HFmrEF) remains unclear.
Methods and results
We analysed the data of the patients with left ventricular ejection fraction (LVEF) between 40%-49% in China Patient-centred Evaluative Assessment of Cardiac Events Prospective Heart Failure Study (China PEACE 5p-HF Study), in which patients hospitalized for heart failure (HF) from 52 Chinese hospitals were recruited from 2016 to 2018. Two primary outcomes were all-cause death and all-cause hospitalization. The associations between β-blocker use at discharge and outcomes were assessed by inverse probability of treatment weighting (IPTW)-weighted Cox regression analyses. To assess consistency, IPTW adjusting medications analyses, multivariable analyses and dose-effect analyses were performed. 1035 HFmrEF patients were included in the analysis. The mean age was 65.5 ±12.7 years and 377 (36.4%) were female. The median (interquartile range) of LVEF was 44% (42%-47%). 661 (63.8%) were treated with β-blocker. Patients using β-blocker were younger with better cardiac function, and more likely to use renin-angiotensin system inhibitor and mineralocorticoid receptor antagonist. During the 1-year follow up, death occurred in 84 (12.7%) treated and 85 (22.7%) untreated patients (P < 0.0001); all-cause hospitalization occurred in 298 (45.1%) treated and 188 (50.3%) untreated patients (P = 0.04). After IPTW-weighted adjustment, β-blocker use was significantly associated with lower risk of all-cause death [hazard ratio (HR): 0.70; confidence interval (95% CI): 0.51-0.96, P = 0.03], but not with lower all-cause hospitalization (HR, 0.92, 95% CI, 0.76-1.10, P = 0.36). Consistency analyses showed consistent favourable effect of β-blocker on all-cause death, but not on all-cause hospitalization.
Conclusions
Among patients with HFmrEF, β-blocker use was associated with lower risk of all-cause death, but not with lower risk of all-cause hospitalization.

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

Eur Heart J Cardiovasc Pharmacother: 26 Mar 2021; epub ahead of print
Wang B, Zhang L, Hu S, Bai X, ... Li J, Zheng X
Eur Heart J Cardiovasc Pharmacother: 26 Mar 2021; epub ahead of print | PMID: 33774652
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Impact:
Abstract

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

Ferreira JP, Collier T, Clark AL, Mamas MA, ... Cleland JG, Zannad F
Background
Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined.
Aims
To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone`s effect.
Methods
HOMAGE (Heart OMics in Aging) was a prospective multicenter randomized open-label blinded Endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, month 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations were used.
Results
The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5)mmHg and DBP by -3.2 (-4.8 to -1.7)mmHg (p < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP < 130/80 mmHg (36 vs. 26%; p = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionp=0.041).
Conclusion
Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

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

Eur Heart J Cardiovasc Pharmacother: 01 Apr 2021; epub ahead of print
Ferreira JP, Collier T, Clark AL, Mamas MA, ... Cleland JG, Zannad F
Eur Heart J Cardiovasc Pharmacother: 01 Apr 2021; epub ahead of print | PMID: 33822033
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Impact:
Abstract

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Pontremoli R, Borghi C, Filardi PP
Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for HF. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin-angiotensin-aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

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

Eur Heart J Cardiovasc Pharmacother: 02 Apr 2021; epub ahead of print
Pontremoli R, Borghi C, Filardi PP
Eur Heart J Cardiovasc Pharmacother: 02 Apr 2021; epub ahead of print | PMID: 33822031
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Impact:
Abstract

Comparison of New York Heart Association Class and Patient-Reported Outcomes for Heart Failure With Reduced Ejection Fraction.

Greene SJ, Butler J, Spertus JA, Hellkamp AS, ... Hernandez AF, Fonarow GC
Importance
It is unclear how New York Heart Association (NYHA) functional class compares with patient-reported outcomes among patients with heart failure (HF) in contemporary US clinical practice.
Objective
To characterize longitudinal changes and concordance between NYHA class and the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS), and their associations with clinical outcomes.
Design, setting, and participants
This cohort study included 2872 US outpatients with chronic HF with reduced ejection fraction across 145 practices enrolled in the CHAMP-HF registry between December 2015 and October 2017. All patients had complete NYHA class and KCCQ-OS data at baseline and 12 months. Longitudinal changes and correlations between the 2 measure were examined. Multivariable models landmarked at 12 months evaluated associations between improvement in NYHA and KCCQ-OS from baseline to 12 months with clinical outcomes occurring from months 12 through 24. Statistical analyses were performed from March to August 2020.
Exposure
Change in health status, as defined by 12-month change in NYHA class or KCCQ-OS.
Main outcomes and measures
All-cause mortality, HF hospitalization, and mortality or HF hospitalization.
Results
In total, 2872 patients were included in this analysis (median [interquartile range] age, 68 [59-75] years; 872 [30.4%] were women; and 2156 [75.1%] were of White race). At baseline, 312 patients (10.9%) were NYHA class I, 1710 patients (59.5%) were class II, 804 patients (28.0%) were class III, and 46 patients (1.6%) were class IV. For KCCQ-OS, 1131 patients (39.4%) scored 75 to 100 (best health status), 967 patients (33.7%) scored 50 to 74, 612 patients (21.3%) scored 25 to 49, and 162 patients (5.6%) scored 0 to 24 (worst health status). At 12 months, 1002 patients (34.9%) had a change in NYHA class (599 [20.9%] with improvement; 403 [14.0%] with worsening) and 2158 patients (75.1%) had a change of 5 or more points in KCCQ-OS (1388 [48.3%] with improvement; 770 [26.8%] with worsening). The most common trajectory for NYHA class was no change (1870 [65.1%]), and the most common trajectory for KCCQ-OS was an improvement of at least 10 points (1047 [36.5%]). After adjustment, improvement in NYHA class was not associated with subsequent clinical outcomes, whereas an improvement of 5 or more points in KCCQ-OS was independently associated with decreased mortality (hazard ratio, 0.59; 95% CI, 0.44-0.80; P < .001) and mortality or HF hospitalization (hazard ratio, 0.73; 95% CI, 0.59-0.89; P = .002).

Conclusions:
and relevance
Findings of this cohort study suggest that, in contemporary US clinical practice, compared with NYHA class, KCCQ-OS is more sensitive to clinically meaningful changes in health status over time. Changes in KCCQ-OS may have more prognostic value than changes in NYHA class.



JAMA Cardiol: 23 Mar 2021; epub ahead of print
Greene SJ, Butler J, Spertus JA, Hellkamp AS, ... Hernandez AF, Fonarow GC
JAMA Cardiol: 23 Mar 2021; epub ahead of print | PMID: 33760037
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Impact:
Abstract

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.

Butt JH, Docherty KF, Petrie MC, Schou M, ... McMurray JJV, Køber L
Importance
Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.
Objective
To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Design, setting, and participants
Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.
Interventions
Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.
Main outcomes and measures
The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.
Results
A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.

Conclusions:
and relevance
Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.
Trial registration
ClinicalTrials.gov Identifier: NCT03036124.



JAMA Cardiol: 30 Mar 2021; epub ahead of print
Butt JH, Docherty KF, Petrie MC, Schou M, ... McMurray JJV, Køber L
JAMA Cardiol: 30 Mar 2021; epub ahead of print | PMID: 33787831
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Impact:
Abstract

Association of Dual Eligibility for Medicare and Medicaid With Heart Failure Quality and Outcomes Among Get With The Guidelines-Heart Failure Hospitals.

Bahiru E, Ziaeian B, Moucheraud C, Agarwal A, ... Yancy CW, Fonarow GC
Importance
The Centers for Medicare & Medicaid Services uses a new peer group-based payment system to compare hospital performance as part of its Hospital Readmissions Reduction Program, which classifies hospitals into quintiles based on their share of dual-eligible beneficiaries for Medicare and Medicaid. However, little is known about the association of a hospital\'s share of dual-eligible beneficiaries with the quality of care and outcomes for patients with heart failure (HF).
Objective
To evaluate the association between a hospital\'s proportion of patients with dual eligibility for Medicare and Medicaid and HF quality of care and outcomes.
Design, setting, and participants
This retrospective cohort study evaluated 436 196 patients hospitalized for HF using the Get With The Guidelines-Heart Failure registry from January 1, 2010, to December 31, 2017. The analysis included patients 65 years or older with available data on dual-eligibility status. Hospitals were divided into quintiles based on their share of dual-eligible patients. Quality and outcomes were analyzed using unadjusted and adjusted multivariable logistic regression models. Data analysis was performed from April 1, 2020, to January 1, 2021.
Main outcomes and measures
The primary outcome was 30-day all-cause readmission. The secondary outcomes included in-hospital mortality, 30-day HF readmissions, 30-day all-cause mortality, and HF process of care measures.
Results
A total of 436 196 hospitalized HF patients 65 years or older from 535 hospital sites were identified, with 258 995 hospitalized patients (median age, 81 years; interquartile range, 74-87 years) at 455 sites meeting the study criteria and included in the primary analysis. A total of 258 995 HF hospitalizations from 455 sites were included in the primary analysis of the study. Hospitals in the highest dual-eligibility quintile (quintile 5) tended to care for patients who were younger, were more likely to be female, belonged to racial minority groups, or were located in rural areas compared with quintile 1 sites. After multivariable adjustment, hospitals with the highest quintile of dual eligibility were associated with lower rates of key process measures, including evidence-based β-blocker prescription, measure of left ventricular function, and anticoagulation for atrial fibrillation or atrial flutter. Differences in clinical outcomes were seen with higher 30-day all-cause (adjusted odds ratio, 1.24; 95% CI, 1.14-1.35) and HF (adjusted odds ratio, 1.14; 95% CI, 1.03-1.27) readmissions in higher dual-eligible quintile 5 sites compared with quintile 1 sites. Risk-adjusted in-hospital and 30-day mortality did not significantly differ in quintile 1 vs quintile 5 hospitals.

Conclusions:
and relevance
In this cohort study, hospitals with a higher share of dual-eligible patients provided care with lower rates of some of the key HF quality of care process measures and with higher 30-day all-cause or HF readmissions compared with lower dual-eligibility quintile hospitals.



JAMA Cardiol: 06 Apr 2021; epub ahead of print
Bahiru E, Ziaeian B, Moucheraud C, Agarwal A, ... Yancy CW, Fonarow GC
JAMA Cardiol: 06 Apr 2021; epub ahead of print | PMID: 33825802
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Impact:
Abstract

CA125 but not NT-proBNP predicts the presence of a congestive intrarenal venous flow in patients with acute heart failure.

Núñez-Marín G, de la Espriella R, Santas E, Lorenzo M, ... Bayés-Genís A, Núñez J
Background
Intrarenal venous flow (IRVF) measured by Doppler ultrasound has gained interest as a potential surrogate marker of renal congestion and adverse outcomes in heart failure. In this work, we aimed to determine if antigen carbohydrate 125 (CA125) and plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with congestive IRVF patterns (i.e., biphasic and monophasic) in acute heart failure (AHF).
Methods and results
We prospectively enrolled a consecutive cohort of 70 patients hospitalized for AHF. Renal Doppler ultrasound was assessed within the first 24-h of hospital admission. The mean age of the sample was 73.5 ± 12.3 years; 47.1% were female, and 42.9% exhibited heart failure with preserved ejection fraction. The median (interquartile range) for NT-proBNP and CA125 were 6149 (3604-12 330) pg/mL and 64 (37-122) U/mL, respectively. The diagnostic performance of both exposures for identifying congestive IRVF patterns was tested using the receiving operating curve (ROC). The cut-off for CA125 of 63.5 U/mL showed a sensibility and specificity of 67% and 74% and an area under the ROC curve of 0.71. After multivariate adjustment, CA125 remained non-linearly and positively associated with congestive IRVF (P-value = 0.008) and emerged as the most important covariate explaining the variability of the model (R2: 47.5%). Under the same multivariate setting, NT-proBNP did not show to be associated with congestive IRVF patterns (P-value = 0.847).
Conclusions
CA125 and not NT-proBNP is a useful marker for identifying patients with AHF and congestive IRVF patterns.

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

Eur Heart J Acute Cardiovasc Care: 07 Apr 2021; epub ahead of print
Núñez-Marín G, de la Espriella R, Santas E, Lorenzo M, ... Bayés-Genís A, Núñez J
Eur Heart J Acute Cardiovasc Care: 07 Apr 2021; epub ahead of print | PMID: 33829233
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Impact:
Abstract

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF.

Ferreira JP, Verdonschot J, Wang P, Pizard A, ... Zannad F, HOMAGE (Heart Omics in AGEing) Consortium
Objectives
This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.
Background
In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.
Methods
Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis.
Results
A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care (\"control\"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).
Conclusions
Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450).

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

JACC Heart Fail: 30 Mar 2021; 9:268-277
Ferreira JP, Verdonschot J, Wang P, Pizard A, ... Zannad F, HOMAGE (Heart Omics in AGEing) Consortium
JACC Heart Fail: 30 Mar 2021; 9:268-277 | PMID: 33549556
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Impact:
Abstract

Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists: An Analysis of DAPA-HF.

Shen L, Kristensen SL, Bengtsson O, Böhm M, ... Jhund PS, McMurray JJV
Objectives
The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial.
Background
MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination.
Methods
A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes.
Results
A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m2), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo.
Conclusions
Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (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 © 2021. Published by Elsevier Inc.

JACC Heart Fail: 30 Mar 2021; 9:254-264
Shen L, Kristensen SL, Bengtsson O, Böhm M, ... Jhund PS, McMurray JJV
JACC Heart Fail: 30 Mar 2021; 9:254-264 | PMID: 33549554
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Impact:
Abstract

The value of urinary sodium assessment in acute heart failure.

Tersalvi G, Dauw J, Gasperetti A, Winterton D, ... Pedrazzini G, Mullens W
Acute heart failure (AHF) is a frequent medical condition that needs immediate evaluation and appropriate treatment. Patients with signs and symptoms of volume overload mostly require intravenous loop diuretics in the first hours of hospitalization. Some patients may develop diuretic resistance, resulting in insufficient and delayed decongestion, with increased mortality and morbidity. Urinary sodium measurement at baseline and/or during treatment has been proposed as a useful parameter to tailor diuretic therapy in these patients. This systematic review discusses the current sum of evidence regarding urinary sodium assessment to evaluate diuretic efficacy in AHF. We searched Medline, Embase, and Cochrane Clinical Trials Register for published studies that tested urinary sodium assessment in patients with AHF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J Acute Cardiovasc Care: 07 Apr 2021; 10:216-223
Tersalvi G, Dauw J, Gasperetti A, Winterton D, ... Pedrazzini G, Mullens W
Eur Heart J Acute Cardiovasc Care: 07 Apr 2021; 10:216-223 | PMID: 33620424
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Impact:
Abstract

Sinergy between drugs and devices in the fight against sudden cardiac death and heart failure.

Boriani G, De Ponti R, Guerra F, Palmisano P, ... D\'Onofrio A, Ricci RP
The impact of sudden cardiac death (SCD) in heart failure (HF) patients is important and prevention of SCD is a reasonable and clinically justified endpoint if associated with a reduction in all-cause mortality. According to literature, in HF with reduced ejection fraction, only three classes of agents were found effective in reducing SCD and all-cause mortality: beta-blockers, mineralcorticoid receptor antagonists and, more recently, angiotensin-receptor neprilysin-inhibitors. In the PARADIGM trial that tested sacubitril/valsartan vs. enalapril, the 20% relative risk reduction in cardiovascular deaths obtained with sacubitril/valsartan was attributable to reductions in the incidence of both SCD and death due to HF worsening and this effect can be added to the known positive effect of implantable cardioverter-defibrillators in appropriately selected patients. In order to maximize the implementation of all the available treatments, patients with HF should be included in virtuous networks with a dialogue between all the physician involved, with commitment by all these physicians for appropriate decision-making on application of pharmacological and device treatments according to available evidence, as well as commitment for drug titration before and after device implant, taking advantage from remote monitoring, and with the safety of back up device therapy when indicated. There are potential synergistic effects of drug therapy, with all the therapies acting on neuro-hormonal and sympathetic activation, but specifically with sacubitril/valsartan, and device therapy, in particular cardiac resynchronization therapy, with added incremental benefits on positive cardiac remodelling, prevention of HF progression, and prevention of ventricular tachyarrhythmias.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur J Prev Cardiol: 22 Mar 2021; 28:110-123
Boriani G, De Ponti R, Guerra F, Palmisano P, ... D'Onofrio A, Ricci RP
Eur J Prev Cardiol: 22 Mar 2021; 28:110-123 | PMID: 33624080
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Abstract

Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure.

Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, ... Sunagawa K, Burkhoff D
Objectives
The authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF).
Background
The splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB.
Methods
We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight.
Results
Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p < 0.001) at peak exercise. The resting estimated SBV was lower in ambulatory patients with HFrEF than in decompensated HFrEF (p = 0.019). In ambulatory patients with HFrEF, post-SNB, the resting estimated SBV decreased by 532 ± 264 ml/70 kg (p < 0.001). Post-SNB, with exercise, there was no decrease of estimated SBV out of proportion to baseline effects (p = 0.661).
Conclusions
The estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151).

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

JACC Heart Fail: 30 Mar 2021; 9:293-300
Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, ... Sunagawa K, Burkhoff D
JACC Heart Fail: 30 Mar 2021; 9:293-300 | PMID: 33714749
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Abstract

Thromboembolism in Heart Failure Patients in Sinus Rhythm: Epidemiology, Pathophysiology, Clinical Trials, and Future Direction.

Lin AY, Dinatolo E, Metra M, Sbolli M, ... Butler J, Greenberg BH
Despite advances in medical and device therapy, patients with heart failure remain at high risk for morbidity and mortality. Experimental and clinical studies have shown an association between heart failure and a hypercoagulable state, and that patients with heart failure experience an increased incidence of stroke and other thromboembolic events, regardless of whether they are in atrial fibrillation. Although oral anticoagulation is recommended when atrial fibrillation is present, the benefits of this therapy in patients with heart failure in sinus rhythm are uncertain. Older randomized controlled trials comparing warfarin with antiplatelet therapy were, for the most part, underpowered and failed to show convincing benefits of warfarin therapy in this population. Several recent studies that assessed the effects of low-dose direct-acting oral anticoagulant therapy in patients with coronary artery disease in sinus rhythm either included or specifically targeted patients with heart failure. Post hoc analysis of their results showed that this treatment strategy was associated with improved outcomes in patients with acute coronary syndrome or stable coronary artery disease and also a significant reduction in thromboembolic events, including ischemic stroke. This review presents the rationale for anticoagulant therapy in patients with heart failure in sinus rhythm, discusses gaps in our knowledge base, offers suggestions for when anticoagulation might be considered, and identifies potential directions for future research.

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

JACC Heart Fail: 30 Mar 2021; 9:243-253
Lin AY, Dinatolo E, Metra M, Sbolli M, ... Butler J, Greenberg BH
JACC Heart Fail: 30 Mar 2021; 9:243-253 | PMID: 33714744
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Abstract

ECMO as a Bridge to Left Ventricular Assist Device or Heart Transplantation.

DeFilippis EM, Clerkin K, Truby LK, Francke M, ... Uriel N, Topkara VK
Objectives
The purpose of this study was to compare outcomes between patients on extracorporeal membrane oxygenation (ECMO) bridged to left ventricular assist device (LVAD) versus heart transplantation (HT) using registry data.
Background
Patients with heart failure supported with ECMO represent the highest priority in the new HT allocation system. For patients on ECMO, bridging to LVAD may be non-inferior compared with bridging to HT.
Methods
Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2017 and United Network for Organ Sharing (UNOS) database from 2006 to June 2019 requiring ECMO were included. Cause-specific hazard models were created and cumulative incidence functions were calculated with mortality, transplantation, and re-transplantation as competing events.
Results
A total of 906 patients received ECMO as bridge to VAD (n = 587, 64.8%) or as bridge to HT (n = 319, 35.2%). Patients bridged directly to HT were younger (age 46.3 ± 15.4 years vs. 52.1 ± 13.2 years; p < 0.001) and more likely to be female (93 [29.2%] vs. 139 [23.7%]; p = 0.022). Patients bridged directly to HT were more likely to have a nonischemic cardiomyopathy, restrictive physiologies, and allograft failure; (p < 0.05 for all). ECMO use increased over time in both UNOS and INTERMACS. There was no significant difference in mortality between groups (Gray\'s p = 0.581). This remained true even when the analysis was restricted to transplant-listed or eligible patients as well as patients with dilated phenotypes (excluding patients with congenital heart disease, restrictive phenotypes, and allograft failure).
Conclusions
There was no difference in mortality on pump support compared with posttransplant mortality among those bridged from ECMO to LVAD or HT.

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

JACC Heart Fail: 30 Mar 2021; 9:281-289
DeFilippis EM, Clerkin K, Truby LK, Francke M, ... Uriel N, Topkara VK
JACC Heart Fail: 30 Mar 2021; 9:281-289 | PMID: 33714743
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Abstract

Socioeconomic Status and Outcomes in Heart Failure With Reduced Ejection Fraction From Asia.

Teng TK, Tay WT, Richards AM, Chew TSM, ... Lam CSP, ASIAN-HF investigators
Background
Little is known regarding the impact of socioeconomic factors on the use of evidence-based therapies and outcomes in patients with heart failure with reduced ejection fraction across Asia.
Methods
We investigated the association of both patient-level (household income, education levels) and country-level (regional income level by World Bank classification, income disparity by Gini index) socioeconomic indicators on use of guideline-directed therapy and clinical outcomes (composite of 1-year mortality or HF hospitalization, quality of life) in the prospective multinational ASIAN-HF study (Asian Sudden Cardiac Death in Heart Failure).
Results
Among 4540 patients (mean age: 60±13 years, 23% women) with heart failure with reduced ejection fraction, 39% lived in low-income regions; 34% in regions with high-income disparity (Gini ≥42.8%); 64.4% had low monthly household income (<US$1000); and 29.5% had no/only primary education. The largest disparity in treatment across regional income levels pertained to β-blocker and device therapies, with patients from low-income regions being less likely to receive these treatments compared with those from high-income regions and even greater disparity among patients with lower education status and lower household income within each regional income strata. Higher country- and patient-level socioeconomic indicators related to higher quality of life scores and lower risk of the primary composite outcome. Notably, we found a significant interaction between regional income level and both household income and education status (Pinteraction <0.001 for both), where the association of low household income and low education status with poor outcomes was more pronounced in high-income compared with lower income regions.
Conclusions
These findings highlight the importance of socioeconomic determinants among patients with heart failure in Asia and suggest that attention should be paid to address disparities in access to care among the poor and less educated, including those from wealthy regions.
Registration
URL: https://clinicaltrials.gov; Unique Identifier: NCT01633398.



Circ Cardiovasc Qual Outcomes: 23 Mar 2021:CIRCOUTCOMES120006962; epub ahead of print
Teng TK, Tay WT, Richards AM, Chew TSM, ... Lam CSP, ASIAN-HF investigators
Circ Cardiovasc Qual Outcomes: 23 Mar 2021:CIRCOUTCOMES120006962; epub ahead of print | PMID: 33757307
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Abstract

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study).

Anthony C, Imran M, Pouliopoulos J, Emmanuel S, ... Macdonald P, Jabbour A
Objectives
This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT).
Background
Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs.
Methods
In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection.
Results
Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = -13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = -2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = -32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups.
Conclusions
The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

JACC Heart Fail: 30 Mar 2021; 9:301-313
Anthony C, Imran M, Pouliopoulos J, Emmanuel S, ... Macdonald P, Jabbour A
JACC Heart Fail: 30 Mar 2021; 9:301-313 | PMID: 33795116
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