Journal: JACC Heart Fail

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Abstract

Rehabilitation Intervention in Older Patients With Acute Heart Failure With Preserved Versus Reduced Ejection Fraction.

Mentz RJ, Whellan DJ, Reeves GR, Pastva AM, ... O\'Connor CM, Kitzman DW
Objectives
This study assessed for treatment interactions by ejection fraction (EF) subgroup (≥45% [heart failure with preserved ejection fraction (HFpEF); vs <45% [heart failure with reduced ejection fraction (HFrEF)]).
Background
The REHAB-HF trial showed that an early multidomain rehabilitation intervention improved physical function, frailty, quality-of-life, and depression in older patients hospitalized with acute decompensated heart failure (ADHF).
Methods
Three-month outcomes were: Short Physical Performance Battery (SPPB), 6-min walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire (KCCQ). Six-month end points included all-cause rehospitalization and death and a global rank of death, all-cause rehospitalization, and SPPB. Prespecified significance level for interaction was P ≤ 0.1.
Results
Among 349 total participants, 185 (53%) had HFpEF and 164 (47%) had HFrEF. Compared with HFrEF, HFpEF participants were more often women (61% vs 43%) and had significantly worse baseline physical function, frailty, quality of life, and depression. Although interaction P values for 3-month outcomes were not significant, effect sizes were larger for HFpEF vs HFrEF: SPPB +1.9 (95% CI: 1.1-2.6) vs +1.1 (95% CI: 0.3-1.9); 6MWD +40 meters (95% CI: 9 meters-72 meters) vs +27 (95% CI: -6 meters to 59 meters); KCCQ +9 (2-16) vs +6 (-2 to 14). All-cause rehospitalization rate was nominally lower with intervention in HFpEF but not HFrEF [effect size 0.83 (95% CI: 0.64-1.09) vs 0.99 (95% CI: 0.74-1.33); interaction P = 0.40]. There were significantly greater treatment benefits in HFpEF vs HFrEF for all-cause death [interaction P = 0.08; intervention rate ratio 0.63 (95% CI: 0.25-1.61) vs 2.21 (95% CI: 0.78-6.25)], and the global rank end point (interaction P = 0.098) with benefit seen in HFpEF [probability index 0.59 (95% CI: 0.50-0.68)] but not HFrEF.
Conclusions
Among older patients hospitalized with ADHF, compared with HFrEF those with HFpEF had significantly worse impairments at baseline and may derive greater benefit from the intervention. (A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

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

JACC Heart Fail: 29 Sep 2021; 9:747-757
Mentz RJ, Whellan DJ, Reeves GR, Pastva AM, ... O'Connor CM, Kitzman DW
JACC Heart Fail: 29 Sep 2021; 9:747-757 | PMID: 34246602
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Abstract

Prognostic Value of Peak Oxygen Uptake in Patients Supported With Left Ventricular Assist Devices (PRO-VAD).

Mirza KK, Szymanski MK, Schmidt T, de Jonge N, ... Gustafsson F, PRO-VAD Investigators
Objectives
The purpose of this study was to examine whether peak oxygen uptake (pVO2) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients.
Background
pVO2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown.
Methods
We collected data for pVO2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO2 ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO2 ≤12 ml/kg/min if the patient was taking BB therapy.
Results
Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO2 in ml/kg/min, pVO2 ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO2 values (P ≤ 0.001 for all). For patients with pVO2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO2) slope <35, the 1-year survival was 100%.
Conclusions
Even after LVAD implantation, pVO2 has prognostic value, similar to HF patients not supported by mechanical circulatory support devices. (PROgnostic Value of Exercise Capacity Measured as Peak Oxygen Uptake [pVO2] in Recipients of Left Ventricular Assist Devices [PRO-VAD]; NCT04423562).

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

JACC Heart Fail: 29 Sep 2021; 9:758-767
Mirza KK, Szymanski MK, Schmidt T, de Jonge N, ... Gustafsson F, PRO-VAD Investigators
JACC Heart Fail: 29 Sep 2021; 9:758-767 | PMID: 34391745
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Abstract

Advanced Cardiovascular Imaging in Clinical Heart Failure.

Argulian E, Narula J
Cardiovascular imaging is the cornerstone of the assessment of patients with heart failure. Although noninvasive volumetric estimation of the cardiac function is an essential and indisputably useful clinical tool, cardiac imaging has evolved and matured to offer detailed functional, hemodynamic, and tissue characterization. The adoption of a new framework to diagnose and phenotype heart failure that incorporates comprehensive imaging assessment has been lacking in clinical trials. The present review offers a general overview of available imaging strategies for patients with heart failure.

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

JACC Heart Fail: 29 Sep 2021; 9:699-709
Argulian E, Narula J
JACC Heart Fail: 29 Sep 2021; 9:699-709 | PMID: 34391742
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Abstract

Forgone Medical Care Associated With Increased Health Care Costs Among the U.S. Heart Failure Population.

Thomas A, Valero-Elizondo J, Khera R, Warraich HJ, ... Nasir K, Desai NR
Objectives
The objective of this study was to describe the prevalence of patients with forgone/delayed care for heart failure (HF) and examine the associated demographic characteristics, health care utilization, and costs.
Background
HF is a leading cause of morbidity and mortality, with health care expenditures projected to increase 3-fold from 2012 to 2030. The proportion of HF patients with forgone/delayed medical care and the association with health care expenditures and utilization remain unknown.
Methods
Data on patients with HF were obtained from the Medical Expenditure Panel Survey to assess expenditures and health care utilization in the United States from 2004 to 2015. Patients with HF who reported forgone/delayed care, any missed or delayed medical treatment, were compared with those without care lapses.
Results
Overall, 16% of patients with HF reported forgone/delayed care, including 10% among the elderly (aged ≥65 years) and 27% among the nonelderly (aged <65 years). Patients with HF who reported forgone/delayed care had annual health care expenses $8,027 (95% CI: $1,181-$14,872) higher than those who did not. Among the elderly, those reporting forgone/delayed care had more emergency department visits (43% vs 58%; P < 0.05), and had higher annual inpatient costs (+$7,548; 95% CI: $1,109-$13,988) and total health care costs (+$10,581; 95% CI: $1,754-$19,409). Sixty percent of nonelderly and 46% of elderly patients with HF reported deferring care due to financial barriers.
Conclusions
Nearly 1 in 6 patients with HF in the United States reported forgone/delayed medical care, with one-half attributing it to financial reasons, and this was associated with higher overall health care spending.

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

JACC Heart Fail: 29 Sep 2021; 9:710-719
Thomas A, Valero-Elizondo J, Khera R, Warraich HJ, ... Nasir K, Desai NR
JACC Heart Fail: 29 Sep 2021; 9:710-719 | PMID: 34391737
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Abstract

Advanced Heart Failure Epidemiology and Outcomes: A Population-Based Study.

Dunlay SM, Roger VL, Killian JM, Weston SA, ... Blecker SB, Redfield MM
Objectives
The goal of this study was to evaluate the prevalence, characteristics, and outcomes of patients with advanced heart failure (HF) in a geographically defined population.
Background
Some patients with HF progress to advanced HF, characterized by debilitating HF symptoms refractory to therapy. Limited data are available on the epidemiology and outcomes of patients with advanced HF.
Methods
This was a population-based cohort study of all Olmsted County, Minnesota, adults with and without HF from 2007 to 2017. The 2018 European Society of Cardiology advanced HF diagnostic criteria were operationalized and applied to all patients with HF. Hospitalization and mortality in advanced HF, overall and according to ejection fraction (EF) type (reduced EF <40% [HFrEF], mid-range EF 40%-49% [HFmrEF], and preserved EF ≥50% [HFpEF]) were examined using Andersen-Gill and Cox models.
Results
Of 6,836 adults with HF, 936 (13.7%) met criteria for advanced HF. The prevalence of advanced HF increased with age and was higher in men. At advanced HF diagnosis, 396 (42.3%) patients had HFrEF, 134 (14.3%) had HFmrEF, and 406 (43.4%) had HFpEF. The median (interquartile range) time from advanced HF diagnosis to death was 12.2 months (3.7-29.9 months). The mean rate of hospitalization was 2.91 (95% CI: 2.78-3.06) per person-year in the first year after advanced HF diagnosis. There were no differences in risks of all-cause mortality or hospitalization by EF. Patients with advanced HFpEF were at lower risk for cardiovascular mortality compared with advanced HFrEF (HR: 0.79; 95% CI: 0.65-0.97).
Conclusions
In this population-based study, more than one-half of patients with advanced HF had mid-range or preserved EF, and survival was poor regardless of EF.

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

JACC Heart Fail: 29 Sep 2021; 9:722-732
Dunlay SM, Roger VL, Killian JM, Weston SA, ... Blecker SB, Redfield MM
JACC Heart Fail: 29 Sep 2021; 9:722-732 | PMID: 34391736
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Abstract

Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS.

Caponetti AG, Rapezzi C, Gagliardi C, Milandri A, ... Amass L, THAOS Investigators
Objectives
Because patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis.
Background
Transthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium.
Methods
The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy.
Results
There were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro-B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height).
Conclusions
In this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.

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

JACC Heart Fail: 29 Sep 2021; 9:736-746
Caponetti AG, Rapezzi C, Gagliardi C, Milandri A, ... Amass L, THAOS Investigators
JACC Heart Fail: 29 Sep 2021; 9:736-746 | PMID: 34391735
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Abstract

Drug Layering in Heart Failure: Phenotype-Guided Initiation.

Rosano GMC, Allen LA, Abdin A, Lindenfeld J, ... Wintrich J, Böhm M
Medications with proven benefit in patients with heart failure with reduced ejection fraction are recommended, according to prospective large clinical trials, in the stable patient after careful up-titration in a strict sequential order. Although the relevance of careful clinical up-titration is unproven, there is evidence that after recompensation and shortly after hospital discharge, the rate of cardiovascular death and hospitalization is high. Clinical studies provided evidence that the onset of treatment effects is rapid, occurring within 28 days with most of these drugs used, and in in some trials, early treatment after discharge or already started in the hospital has provided benefits. Therefore, early treatment without deferring it to the stable outpatient may be useful to reduce cardiac-related events further. This expert opinion proposes treatment layering according to individual patient phenotypes involving heart rate, blood pressure, impaired renal function, and electrolyte disturbances, as well as dedicated subgroups of patients with specific requirements for treatment initiation. This complements other approaches that suggest starting sequential treatment according to the size of treatment effects of drugs, specific cardiac diseases, and patient wishes. Patient phenotyping may guide personalized drug layering in heart failure with reduced ejection fraction that provides the best outcomes, whereas pragmatic clinical trials are warranted to scrutinize the effectiveness of these approaches.

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

JACC Heart Fail: 29 Sep 2021; epub ahead of print
Rosano GMC, Allen LA, Abdin A, Lindenfeld J, ... Wintrich J, Böhm M
JACC Heart Fail: 29 Sep 2021; epub ahead of print | PMID: 34627725
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Abstract

Association of Early Blood Pressure Decrease and Renal Function With Prognosis in Acute Heart Failure.

Matsue Y, Sama IE, Postmus D, Metra M, ... Voors AA, Teerlink JR
Objectives
The aim of this study was to investigate the association between systolic blood pressure (SBP) drop, worsening renal function (WRF), and prognosis in patients with acute heart failure (AHF).
Background
A large drop in SBP early after hospital admission for AHF might be associated with increased risk for WRF and prognosis. However, there is a paucity of data regarding the interaction between WRF and a drop in SBP on clinical outcomes.
Methods
A post hoc analysis among 6,544 patients with AHF enrolled in the RELAX-AHF-2 (Relaxin in Acute Heart Failure-2) trial was performed. Blood pressure was uniformly and repetitively measured. Peak SBP drop was defined as the difference between baseline SBP and lowest SBP documented during the first 48 hours. WRF was defined by an increase in serum creatinine of ≥0.3 mg/dL from baseline to day 5.
Results
Peak SBP drop was independently associated with a higher risk for WRF (HR: 1.11 per 10 mm Hg SBP drop; P < 0.001), 5-day worsening heart failure (HR: 1.12 per 10 mm Hg SBP drop; P = 0.006), and 180-day cardiovascular death (HR: 1.09 per 10 mm Hg SBP drop; P = 0.026) after adjustment for potential confounders including baseline SBP. There was no interaction between the prognostic value of early SBP drop according to the presence or absence of WRF.
Conclusions
In patients hospitalized for AHF, a greater early drop in SBP was associated with a higher incidence of WRF, worsening heart failure, and an increased risk for 180-day cardiovascular death. However, the association between SBP drop and prognosis was not influenced by WRF. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

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

JACC Heart Fail: 29 Sep 2021; epub ahead of print
Matsue Y, Sama IE, Postmus D, Metra M, ... Voors AA, Teerlink JR
JACC Heart Fail: 29 Sep 2021; epub ahead of print | PMID: 34627724
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Abstract

Pulmonary Artery Pressure Monitoring Effectively Guides Management to Reduce Heart Failure Hospitalizations in Obesity.

Brinkley DM, Guglin ME, Bennett MK, Redfield MM, ... Adamson PB, Stevenson LW
Objective
This study sought to determine the impact of therapy guided by pulmonary artery (PA) pressure monitoring in patients with heart failure (HF) and obesity.
Background
Obesity is prevalent in HF and associated with volume retention, but it complicates clinical assessment of congestion.
Methods
The CardioMEMS Post Approval Study was a prospective, multicenter, open-label trial in 1,200 patients with New York Heart Association functional class III HF and prior HF hospitalization (HFH) within 12 months. Patients with a body mass index (BMI) >35 kg/m2 were required to have a chest circumference <65 inches. Therapy was guided by PA pressure monitoring at sites, and HFHs were adjudicated 1 year before implantation and throughout follow-up. This analysis stratified patients according to ejection fraction (EF) <40% or ≥40% and by BMI <35 kg/m2 or ≥35 kg/m2.
Results
Baseline PA diastolic pressure was higher in patients with BMI ≥35 kg/m2 regardless of EF, but all PA pressures were reduced at 12 months in each cohort (P < 0.0001). HFH rate was reduced by >50% in both cohorts for EF <40% (BMI <35 kg/m2 [HR: 0.48; 95% CI: 0.41-0.55] and ≥35 kg/m2 [HR: 0.40; 95% CI: 0.31-0.53]) and EF ≥40% (BMI <35 kg/m2 [HR: 0.42; 95% CI: 0.35-0.52] and ≥35 kg/m2 [HR: 0.34; 95% CI: 0.25-0.45]; P < 0.0001). There was a nonsignificant trend toward greater reduction with more obesity. The all-cause hospitalization rate was also significantly reduced during monitoring (P < 0.01).
Conclusions
Management guided by PA pressure monitoring effectively reduced pressures, HFH, and all-cause hospitalization in patients with obesity regardless of EF. (CardioMEMS HF System Post Approval Study; NCT02279888).

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 01 Sep 2021; epub ahead of print
Brinkley DM, Guglin ME, Bennett MK, Redfield MM, ... Adamson PB, Stevenson LW
JACC Heart Fail: 01 Sep 2021; epub ahead of print | PMID: 34509410
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Abstract

Hemodynamic Determinants of Activity Measured by Accelerometer in Patients With Stable Heart Failure.

Omar M, Jensen J, Frederiksen PH, Videbæk L, ... Schou M, Møller JE
Objectives
This study examined the link between accelerometer recordings and cardiac pathophysiology measured with right heart cauterization at rest and with exercise in patients with HFrEF.
Background
Patient-worn accelerometers are increasingly being used in patients with heart failure with reduced ejection fraction (HFrEF) to assess activity and serve as surrogate endpoints in heart failure trials.
Methods
Physical average daily activity (PADA) and total average daily activity according to accelerometer units were assessed in 63 patients (mean age 58 ± 10 years; mean ejection fraction 26% ± 4%). Patients underwent hemodynamic exercise testing and accelerometry. Patients were divided according to PADA in PADALow and PADAHigh activity level groups based on median counts per minute of physical activity. Results Patients in the PADALow group were older and more frequently treated with diuretics. At rest, the PADALow group was characterized by a lower cardiac index (2.2 ± 0.4 L/min/m2 vs 2.4 ± 0.4 L/min/m2; P = 0.01) and stroke volume (70 ± 19 mL vs 81 ± 17 mL; P = 0.02) but not pulmonary capillary wedge pressure (12 ± 5 mm Hg vs 11 ± 5 mm Hg; P = 0.3). The PADALow group reached a lower cardiac index (4.8 ± 1.7 L/min/m2 vs 6.6 ± 1.7 L/min/m2; P < 0.001) but not in pulmonary capillary wedge pressure (31 ± 12 mm Hg vs 27 ± 8 mm Hg; P = 0.2) at peak exercise. The attenuated increase was associated with an attenuated increase in stroke volume (94 ± 32 mL vs 121 ± 29 mL; P < 0.001) rather than a reduced increase in heart rate (42 ± 23 beats/min vs 52 ± 21 beats/min; P = 0.07). PADA and total average daily accelerometer units were associated with patient-reported functional impairment according to the Kansas City Cardiomyopathy Questionnaire but not with New York Heart Association functional class.
Conclusions
Among stable ambulatory patients with HFrEF, lower daily activity is associated with poorer cardiac index reserve and reduced cardiac index during exercise. (Empagliflozin in Heart Failure Patients With Reduced Ejection Fraction; NCT03198585).

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

JACC Heart Fail: 31 Aug 2021; epub ahead of print
Omar M, Jensen J, Frederiksen PH, Videbæk L, ... Schou M, Møller JE
JACC Heart Fail: 31 Aug 2021; epub ahead of print | PMID: 34509409
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Abstract

Sacubitril/Valsartan Adherence and Postdischarge Outcomes Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Carnicelli AP, Li Z, Greiner MA, Lippmann SJ, ... Fonarow GC, O\'Brien EC
Objectives
The authors sought to investigate associations between sacubitril/valsartan adherence and clinical outcomes after hospitalization for heart failure with reduced ejection fraction (HFrEF).
Background
Sacubitril/valsartan improves outcomes in HFrEF, though the extent to which medication adherence is associated with outcomes in routine care is less well characterized.
Methods
The authors analyzed patients aged ≥65 years hospitalized for HFrEF within the Get With the Guidelines-Heart Failure registry linked with Medicare claims between October 2015 and September 2018 who were discharged with sacubitril/valsartan. Sacubitril/valsartan adherence was assessed using medication fills to calculate proportion of days covered (PDC) through 90 days postdischarge. Associations between postdischarge adherence (PDC < or ≥80%) and risk of readmission and death within 1 year were examined by comparing cumulative incidences and adjusted event rates.
Results
Among 897 patients prescribed sacubitril/valsartan at discharge, 295 (32.9%) had PDC ≥80% and 602 (67.1%) had PDC <80%. Baseline characteristics were balanced between groups. Compared with patients with PDC <80%, patients with PDC ≥80% had a significantly lower adjusted hazard of all-cause re-hospitalization (HR: 0.66; [95% CI: 0.48-0.89]) and death (HR: 0.42; [0.22-0.79]) at 90 days and at 1 year (HR: 0.69; [0.56-0.86] and HR: 0.53; [0.38-0.74], respectively). For every 5 percentage point increase in PDC, patients experienced a significant reduction in rehospitalization (HR: 0.98; [0.97-0.99]) and death (HR: 0.96; [0.94-0.97]) at 1 year.
Conclusions
In patients hospitalized for HFrEF and discharged on sacubitril/valsartan, high adherence to sacubitril/valsartan within 90 days after discharge was associated with substantially lower rates of readmission and death. Additional efforts to improve adherence with sacubitril/valsartan and other guideline-directed medical therapies in HFrEF are warranted.

Copyright © 2021. Published by Elsevier Inc.

JACC Heart Fail: 31 Aug 2021; epub ahead of print
Carnicelli AP, Li Z, Greiner MA, Lippmann SJ, ... Fonarow GC, O'Brien EC
JACC Heart Fail: 31 Aug 2021; epub ahead of print | PMID: 34509408
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Abstract

Health Status Predicts Short- and Long-Term Risk of Composite Clinical Outcomes in Acute Heart Failure.

Hu D, Liu J, Zhang L, Bai X, ... He G, Li J
Objectives
This study aims to examine the association between the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score and the 30-day and 1-year rates of composite events of cardiovascular death and heart failure (HF) rehospitalization in patients with acute HF.
Background
Few studies reported the prognostic effects of KCCQ in acute HF.
Methods
This study prospectively enrolled adult patients hospitalized for HF from 52 hospitals in China and collected the KCCQ-12 score within 48 hour of index admission. The study used multivariable Cox regression to examine the association between KCCQ-12 score and 30-day and 1-year composite events and was further stratified by new-onset HF and acutely decompensated chronic heart failure (ADCHF). Subgroup analyses were performed to explore the potential heterogeneity. The study evaluated the incremental prognostic value of KCCQ-12 score over N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and established risk scores by C-statistics, net reclassification improvement, and integrated discrimination improvement.
Results
Among 4,898 patients, 29.4% had new-onset HF. After adjustment, each 10-point decrease in the KCCQ-12 score was associated with a 13% increase in 30-day risk and a 7% increase in 1-year risk. The associations were consistent regardless of new-onset HF or ADCHF, age, sex, left ventricular ejection fraction, New York Heart Association functional class, NT-proBNP level, comorbidities, and renal function. Adding KCCQ-12 score to NT-proBNP and established risk scores significantly improved prognostic capabilities measured by C-statistics, net reclassification improvement, and integrated discrimination improvement.
Conclusions
In acute HF, a poor KCCQ-12 score predicted short- and long-term risks of cardiovascular death and HF rehospitalization. KCCQ-12 could serve as a convenient tool for rapid initial risk stratification and provide additional prognostic value over NT-proBNP and established risk scores.

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

JACC Heart Fail: 31 Aug 2021; epub ahead of print
Hu D, Liu J, Zhang L, Bai X, ... He G, Li J
JACC Heart Fail: 31 Aug 2021; epub ahead of print | PMID: 34509406
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Abstract

Spironolactone in Patients With an Echocardiographic HFpEF Phenotype Suggestive of Cardiac Amyloidosis: Results From TOPCAT.

Sperry BW, Hanna M, Shah SJ, Jaber WA, Spertus JA
Objectives
This study investigated an enriched cohort of patients with heart failure and preserved ejection fraction (HFpEF) in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with an echocardiographic phenotype of cardiac amyloidosis.
Background
There is a high prevalence of increased interventricular septal (IVS) thickness and decreased mitral annular systolic (s\') velocity in cardiac amyloidosis. In addition, clinical trials of neurohormonal blockade are missing in this population.
Methods
TOPCAT randomized patients with HFpEF to spironolactone or placebo therapy with a primary endpoint of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Patients with IVS and s\' velocity measurements were included, and adjusted Cox models assessed the effect of echocardiographic variables and spironolactone on the primary endpoint.
Results
Among 590 patients, mean s\' velocity was 6.4 ± 2.1 cm/s and IVS thickness was 1.2 ± 0.2 cm. The enriched cohort with characteristics of cardiac amyloidosis (s\' velocity ≤6 cm/s and IVS thickness ≥1.2 cm) included 135 patients (23% of the cohort). After a median follow-up of 2.6 years (1.5 years-3.9 years), these patients had the worst prognosis (adjusted HR: 2.10; 95% CI: 1.26 to 3.50; P = 0.004). Both s\' velocity and IVS thickness were individually associated with the primary endpoint, and abnormalities in these parameters were additive as lower s\' velocity was particularly prognostic in those with greater IVS thickness (interaction: P = 0.013). Spironolactone was associated with improved outcomes in the overall cohort (P = 0.024), and patients in the enriched cohort had a benefit similar to that in other groups (interaction: P = 0.382).
Conclusions
An enriched subset of patients with structural and functional echocardiographic features of cardiac amyloidosis had the worst prognosis in the TOPCAT study, but they benefitted similarly from spironolactone therapy. Future studies of mineralocorticoid receptor antagonists in patients with cardiac amyloidosis are warranted.

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

JACC Heart Fail: 31 Aug 2021; epub ahead of print
Sperry BW, Hanna M, Shah SJ, Jaber WA, Spertus JA
JACC Heart Fail: 31 Aug 2021; epub ahead of print | PMID: 34509404
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Abstract

Long-Term Neurocognitive Outcome in Patients With Continuous Flow Left Ventricular Assist Device.

Cho SM, Floden D, Wallace K, Hiivala N, ... Mahr C, Uchino K
Objectives
The authors sought to examine the long-term cognitive outcome of patients with continuous flow left ventricular assist device (CF-LVAD).
Background
Data on long-term neurocognitive outcome in LVAD are limited. We examined the neurocognitive outcome of patients who received a CF-LVAD as destination therapy.
Methods
Patients with HeartWare (HVAD) and HeartMate II who were enrolled in the ENDURANCE and ENDURANCE Supplemental trials were eligible. Cognition was evaluated with neuropsychological testing preoperatively and at 6, 12, and 24 months after implantation. General linear models identified demographic, disease, and treatment factors that predicted decline on each neurocognitive measure.
Results
Of 668 patients who completed baseline testing and at least 1 follow-up evaluation, 552 were impaired at baseline on at least 1 cognitive measure. At each follow-up, approximately 23% of tested patients declined and 20% improved relative to baseline on at least 1 cognitive measure. Of those who were intact at baseline, only 10%-12% declined in delayed memory and 11%-16% declined in executive function at all 3 follow-ups. For patients impaired at baseline, delayed memory decline was associated with the HVAD device and male sex, whereas executive function decline was associated with the HVAD device and stroke during CF-LVAD support. For patients intact at baseline, male sex and history of hypertension were associated with decline in immediate memory and executive function, respectively.
Conclusion
Neurocognitive function remained stable or improved for most patients (∼80%) with CF-LVAD at 6, 12, and 24 months after implantation. Male sex, hypertension, HVAD, and stroke were associated with cognitive decline.

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

JACC Heart Fail: 31 Aug 2021; epub ahead of print
Cho SM, Floden D, Wallace K, Hiivala N, ... Mahr C, Uchino K
JACC Heart Fail: 31 Aug 2021; epub ahead of print | PMID: 34509403
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Abstract

Lung Ultrasound-Guided Emergency Department Management of Acute Heart Failure (BLUSHED-AHF): A Randomized Controlled Pilot Trial.

Pang PS, Russell FM, Ehrman R, Ferre R, ... Li X, Collins SP
Objectives
The goal of this study was to determine whether a 6-hour lung ultrasound (LUS)-guided strategy-of-care improves pulmonary congestion over usual management in the emergency department (ED) setting. A secondary goal was to explore whether early targeted intervention leads to improved outcomes.
Background
Targeting pulmonary congestion in acute heart failure remains a key goal of care. LUS B-lines are a semi-quantitative assessment of pulmonary congestion. Whether B-lines decrease in patients with acute heart failure by targeting therapy is not well known.
Methods
A multicenter, single-blind, ED-based, pilot trial randomized 130 patients to receive a 6-hour LUS-guided treatment strategy versus structured usual care. Patients were followed up throughout hospitalization and 90 days\' postdischarge. B-lines ≤15 at 6 h was the primary outcome, and days alive and out of hospital (DAOOH) at 30 days was the main exploratory outcome.
Results
No significant difference in the proportion of patients with B-lines ≤15 at 6 hours (25.0% LUS vs 27.5% usual care; P = 0.83) or the number of B-lines at 6 hours (35.4 ± 26.8 LUS vs 34.3 ± 26.2 usual care; P = 0.82) was observed between groups. There were also no differences in DAOOH (21.3 ± 6.6 LUS vs 21.3 ± 7.1 usual care; P = 0.99). However, a significantly greater reduction in the number of B-lines was observed in LUS-guided patients compared with those receiving usual structured care during the first 48 hours (P = 0.04).
Conclusions
In this pilot trial, ED use of LUS to target pulmonary congestion conferred no benefit compared with usual care in reducing the number of B-lines at 6 hours or in 30 days DAOOH. However, LUS-guided patients had faster resolution of congestion during the initial 48 hours. (B-lines Lung Ultrasound-Guided ED Management of Acute Heart Failure Pilot Trial; NCT03136198).

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

JACC Heart Fail: 30 Aug 2021; 9:638-648
Pang PS, Russell FM, Ehrman R, Ferre R, ... Li X, Collins SP
JACC Heart Fail: 30 Aug 2021; 9:638-648 | PMID: 34246609
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Abstract

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

Vergaro G, Gentile F, Meems LMG, Aimo A, ... de Boer RA, Emdin M
Objectives
The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories.
Background
Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain.
Methods
Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death.
Results
The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = -0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men.
Conclusions
NT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.

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

JACC Heart Fail: 30 Aug 2021; 9:653-663
Vergaro G, Gentile F, Meems LMG, Aimo A, ... de Boer RA, Emdin M
JACC Heart Fail: 30 Aug 2021; 9:653-663 | PMID: 34246607
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Abstract

Prognostic Value of Urinary and Plasma C-Type Natriuretic Peptide in Acute Decompensated Heart Failure.

Ma X, Chen Y, Reginauld SH, Scott CG, ... Burnett JC, Sangaralingham SJ
Objectives
This study sought to characterize urinary and plasma C-type natriuretic peptide (CNP) in acute decompensated heart failure (ADHF) to define their relationship with clinical variables and to determine whether urinary and plasma CNP together add prognostic value.
Background
CNP is a protective hormone that is synthesized in the kidney and endothelium and possesses antiremodeling properties. Urinary and plasma CNP levels are elevated in pathophysiological conditions; however, their regulation and prognostic value in heart failure (HF) is unclear.
Methods
Urinary and plasma CNP were measured in 109 healthy subjects and 208 patients with ADHF; the 95th percentile of CNP values from healthy subjects established the normal contemporary cutoffs. Patients with ADHF were stratified based on urinary and plasma CNP levels for clinical characterization and the assessment of risk for adverse outcomes.
Results
There was no significant correlation between urinary and plasma CNP in both cohorts. Urinary and plasma CNP were significantly elevated in patients with ADHF, and both increased with disease severity and were positively correlated with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP). Of the patients with ADHF, 23% had elevations in both urinary and plasma CNP, whereas 24% had normal CNP levels. During a median follow-up of 3 years, patients with elevated urinary and plasma CNP had a significantly higher risk of rehospitalization and/or death (HR: 1.79; P = 0.03) and rehospitalization (HR: 2.16; P = 0.01) after adjusting for age, sex, left ventricular ejection fraction, renal function, and plasma NT-proBNP. The C-statistic and integrated discrimination analyses further supported that the addition of urinary and plasma CNP to established risk models improved the prediction of adverse outcomes in patients with ADHF.
Conclusions
Urinary and plasma CNP are differentially regulated in ADHF, and elevations in both provided independent prognostic value for predicting adverse outcomes.

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

JACC Heart Fail: 30 Aug 2021; 9:613-623
Ma X, Chen Y, Reginauld SH, Scott CG, ... Burnett JC, Sangaralingham SJ
JACC Heart Fail: 30 Aug 2021; 9:613-623 | PMID: 34246604
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Abstract

Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF: The PARAGON-HF Trial.

Gori M, Senni M, Claggett B, Liu J, ... McMurray JJV, Solomon SD
Objectives
This study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF).
Background
hs-TnT is a marker of myocardial injury in HF.
Methods
The PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT.
Results
hs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07).
Conclusions
Higher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

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

JACC Heart Fail: 30 Aug 2021; 9:627-635
Gori M, Senni M, Claggett B, Liu J, ... McMurray JJV, Solomon SD
JACC Heart Fail: 30 Aug 2021; 9:627-635 | PMID: 34246603
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Abstract

Sex-Specific Outcomes of Transcatheter Mitral-Valve Repair and Medical Therapy for Mitral Regurgitation in Heart Failure.

Kosmidou I, Lindenfeld J, Abraham WT, Rinaldi MJ, ... Mack MJ, Stone GW
Objectives
This study sought to assess the sex-specific outcomes in patients with heart failure (HF) with 3+ and 4+ secondary mitral regurgitation (SMR) treated with transcatheter mitral valve repair (TMVr) plus guideline-directed medical therapy (GDMT) versus GDMT alone in the COAPT trial.
Background
The impact of sex in patients with HF and severe SMR treated with TMVr with the MitraClip compared with GDMT alone is unknown.
Methods
Patients were randomized 1:1 to TMVr versus GDMT alone. Two-year outcomes were examined according to sex.
Results
Among 614 patients, 221 (36.0%) were women. Women were younger than men and had fewer comorbidities, but reduced quality of life and functional capacity at baseline. In a joint frailty model accounting for the competing risk of death, the 2-year cumulative incidence of the primary endpoint of all HF hospitalizations (HFH) was higher in men compared with women treated with GDMT alone. However, the relative reduction in HFHs with TMVr was greater in men (HR: 0.43; 95% CI: 0.34-0.54) than women (HR: 0.78; 95% CI: 0.57-1.05) (Pinteraction = 0.002). A significant interaction between TMVr versus GDMT alone treatment and time was present for all HFHs in women (HR: 0.57; 95% CI: 0.39-0.84, and HR: 1.39; 95% CI: 0.83-2.33 between 0-1 year and 1-2 years after randomization, respectively, Pinteraction = 0.007) but not in men (HR: 0.48; 95% CI: 0.36-0.64, and HR: 0.33; 95% CI: 0.21-0.51; Pinteraction = 0.16). Female sex was independently associated with a lower adjusted risk of death at 2 years (HR: 0.64; 95% CI: 0.46-0.90; P = 0.011). TMVr consistently reduced 2-year mortality compared with GDMT alone, irrespective of sex (Pinteraction = 0.99).
Conclusions
In the COAPT trial, TMVr with the MitraClip resulted in improved clinical outcomes compared with GDMT alone, irrespective of sex. However, the impact of TMVr in reducing HFH was less pronounced in women compared with men beyond the first year after treatment. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Tria] [COAPT]; NCT01626079).

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

JACC Heart Fail: 30 Aug 2021; 9:674-683
Kosmidou I, Lindenfeld J, Abraham WT, Rinaldi MJ, ... Mack MJ, Stone GW
JACC Heart Fail: 30 Aug 2021; 9:674-683 | PMID: 34391744
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Abstract

A Pragmatic Approach to Weaning Temporary Mechanical Circulatory Support: A State-of-the-Art Review.

Randhawa VK, Al-Fares A, Tong MZY, Soltesz EG, ... Cremer P, Estep JD
Temporary mechanical circulatory support (TMCS) provides short-term support to patients with or at risk of refractory cardiogenic shock. Although indications, contraindications, and complications of TMCS may guide device selection, optimal strategies for device weaning and explant remain poorly defined. Under the revised adult heart allocation policy implemented by the United Nations for Organ Sharing in October 2018, rejustification of heart transplant listing status includes demonstrating TMCS dependency with attempted device wean trials. However, standardized device-specific weaning and explant protocols have not been proposed or evaluated. This review highlights when to use percutaneous TMCS in cardiogenic shock, with a focus on weaning and explant considerations. Terminology for important concepts that guide device escalation, de-escalation, and explantation have been defined. Clinical, hemodynamic, metabolic, and imaging features have been defined, which can guide a tailored approach to TMCS weaning and explant based on the approach used at the Cleveland Clinic. A narrative review of published studies that have reported TMCS weaning protocols and survey results of member centers from CS-MCS working group centers is also provided. Future research is needed to better understand optimal timing and implementation of standardized protocols to achieve successful TMCS weaning and explant.

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

JACC Heart Fail: 30 Aug 2021; 9:664-673
Randhawa VK, Al-Fares A, Tong MZY, Soltesz EG, ... Cremer P, Estep JD
JACC Heart Fail: 30 Aug 2021; 9:664-673 | PMID: 34391743
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Abstract

Prognostic Importance of Health Status Versus Functional Status in Heart Failure and Secondary Mitral Regurgitation.

Arnold SV, Stone GW, Jain SS, Mack MJ, ... Cohen DJ, COAPT Investigators
Objectives
This study sought to understand the extent to which health status and exercise capacity are independently associated with long-term outcomes in patients with heart failure (HF) and secondary mitral regurgitation (MR).
Background
Secondary MR in patients with HF leads to impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-minute walk distance [6MWD]), both of which improve after transcatheter mitral valve repair (TMVr).
Methods
The study used data from the COAPT trial (N = 604) to examine the association of baseline KCCQ-OS and 6MWD with 2-year mortality and HF hospitalization, adjusting for treatment arm and patient factors. We also examined the association of change in KCCQ-OS and 6MWD from baseline to 1 month with risk of outcomes from 1 month to 2 years. Interactions of KCCQ-OS and 6MWD with treatment assignment were explored.
Results
Mean baseline KCCQ-OS was 53 ± 23 points, and 6MWD was 240 ± 125 meters. In models including both measures, greater baseline 6MWD (but not KCCQ-OS) was associated with reduced 2-year mortality (HR per 125 meters: 0.75, 95% CI: 0.61-0.92). When stratified by treatment group, both baseline KCCQ-OS and 6MWD were independently associated with HF hospitalization in patients treated with medical therapy, whereas only KCCQ-OS was associated with HF hospitalization in patients treated with TMVr. In separate analyses, 1-month improvements in KCCQ-OS and 6MWD were each associated with lower subsequent risk of mortality and HF hospitalization, independent of treatment group.
Conclusions
Among patients with HF and severe secondary MR, assessment of both health status and exercise capacity provide complementary prognostic information for patients with HF and severe secondary MR-both before and after TMVr. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).

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

JACC Heart Fail: 30 Aug 2021; 9:684-692
Arnold SV, Stone GW, Jain SS, Mack MJ, ... Cohen DJ, COAPT Investigators
JACC Heart Fail: 30 Aug 2021; 9:684-692 | PMID: 34391740
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Abstract

Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure.

McMurray JJV, Wheeler DC, Stefánsson BV, Jongs N, ... Heerspink HJL, DAPA-CKD Trial Committees and Investigators
Objectives
The purpose of this paper was to investigate the effects of dapagliflozin in chronic kidney disease (CKD) patients, with and without heart failure (HF).
Background
Patients with CKD, with and without type 2 diabetes, were enrolled in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial. Some patients had HF at baseline.
Methods
A total of 4,304 participants were randomized to dapagliflozin 10 mg daily or placebo. The primary composite endpoint was ≥50% decline in estimated glomerular filtration rate, end-stage kidney disease, or kidney/cardiovascular death. Secondary endpoints were a kidney composite (primary endpoint minus cardiovascular death), the composite of cardiovascular death/HF hospitalization, and all-cause death. Analysis of outcomes according to HF history was prespecified.
Results
HF patients (n = 468; 11%) were older and had more coronary disease, atrial fibrillation, and type 2 diabetes. Mean estimated glomerular filtration rate was similar in patients with and without HF. Rates of HF hospitalization/cardiovascular death and death from any cause were higher in HF patients, but the secondary kidney failure outcome occurred at the same rate in people with and without HF. Dapagliflozin reduced the risk of the primary outcome equally in patients with HF (HR: 0.58 [95% CI: 0.37-0.91]) and without HF (HR: 0.62 [95% CI: 0.51-0.75]) (P interaction = 0.59). The proportional risk-reductions were similar in patients with and without HF for the cardiovascular death/HF hospitalization composite (HR: 0.68 [95% CI: 0.44-1.05] vs HR: 0.70 [95% CI: 0.51-0.97], respectively; P interaction = 0.90), and all-cause death (HR: 0.56 [95% CI: 0.34-0.93] vs HR: 0.73 [95% CI: 0.54-0.97], respectively; P interaction = 0.39), although absolute risk reductions were larger in HF patients. Adverse event rates were low and did not differ among patients with or without HF.
Conclusions
Dapagliflozin reduced the risk of kidney failure and cardiovascular death/HF hospitalization and prolonged survival in CKD patients with or without type 2 diabetes, independently of history of HF. (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease [DAPA-CKD]; NCT03036150).

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

JACC Heart Fail: 04 Aug 2021; epub ahead of print
McMurray JJV, Wheeler DC, Stefánsson BV, Jongs N, ... Heerspink HJL, DAPA-CKD Trial Committees and Investigators
JACC Heart Fail: 04 Aug 2021; epub ahead of print | PMID: 34446370
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Abstract

Duration of Diabetes and Incident Heart Failure: The ARIC (Atherosclerosis Risk In Communities) Study.

Echouffo-Tcheugui JB, Zhang S, Florido R, Hamo C, ... Selvin E, Ndumele CE
Objectives
This study assessed the association of diabetes duration with incident heart failure (HF).
Background
Diabetes increases HF risk. However, the independent effect of diabetes duration on incident HF is unknown.
Methods
We included 9,734 participants (mean age 63 years, 58% women, 22% Black) at ARIC (Atherosclerosis Risk In Communities) Visit 4 (1996-1998) without HF or coronary heart disease. We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first 4 ARIC visits spaced 3 years apart, and self-reported diagnosis date for those with diabetes diagnosed before Visit 1. We used Cox regression to estimate associations of diabetes duration with incident HF, accounting for intercurrent coronary heart disease and other risk factors. We performed analyses stratified by age (<65 years or ≥65 years), race, sex, and glycemic control (hemoglobin A1C [HbA1C] consistently <7%, vs HbA1C ≥7%), with tests for interaction.
Results
Over 22.5 years of follow-up, there were 1,968 HF events. Compared to those without diabetes, HF risk rose with longer diabetes duration, with the highest risk among those with ≥15 y diabetes duration (HR: 2.82; 95% CI: 2.25-3.63). Each 5-year increase in diabetes duration was associated with a 17% (95% CI: 11-22) relative increase in HF risk. Similar results were observed across HF subtypes. The HF and diabetes duration associations were stronger among those aged <65 years, those with HbA1C ≥7%, those with a body mass index ≥30 kg/m2, women, and Blacks (all P interactions <0.05).
Conclusions
Delaying diabetes onset may augment HF prevention efforts, and therapies to improve HF outcomes might target those with long diabetes duration.

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

JACC Heart Fail: 30 Jul 2021; 9:594-603
Echouffo-Tcheugui JB, Zhang S, Florido R, Hamo C, ... Selvin E, Ndumele CE
JACC Heart Fail: 30 Jul 2021; 9:594-603 | PMID: 34325890
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Abstract

Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study.

Requena-Ibáñez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, ... Fuster V, Badimon JJ
Objectives
The goal of this study was to evaluate the effect of empagliflozin, in addition to optimal medical treatment, on epicardial adipose tissue (EAT), interstitial myocardial fibrosis, and aortic stiffness in nondiabetic patients with heart failure with reduced ejection fraction (HFrEF).
Background
Several randomized clinical trials have established the benefits of the inhibitors of the sodium-glucose cotransporter-2 receptor (SGLT2-i) in HFrEF, independent of their hypoglycemic effects. The mechanisms of the benefits of SGLT2-i in HFrEF have not been well defined.
Methods
This study was a secondary analysis of patients enrolled in the EMPA-TROPISM [ATRU-4] (Are the cardiac benefits of Empagliflozin independent of its hypoglycemic activity?) clinical trial. It was a double-blind, placebo-controlled randomized clinical trial investigating the effect of empagliflozin in nondiabetic patients with HFrEF. Patients underwent cardiac magnetic resonance at baseline and after 6 months. Interstitial myocardial fibrosis was calculated by using T1 mapping (extracellular volume). Aortic stiffness was calculated by using pulsed wave velocity, and EAT was measured from the cine sequences.
Results
Empagliflozin is associated with significant reductions in EAT volume (-5.14 mL; 95% CI: -8.36 to -1.92) compared with placebo (-0.75 mL; 95% CI: -3.57 to 2.06; P < 0.05); this finding was paralleled by reductions in subcutaneous adipose tissue area (-5.33 cm2 [95% CI: -12.61 to 1.95] vs 9.13 cm2 [95% CI: -2.72 to 20.99]; P < 0.05). Empagliflozin-treated patients reported a reduction in extracellular volume (-1.25% [±0.56 95% CI] vs 0.24% [±0.57 95% CI]; (P < 0.01)]; specifically, empagliflozin reduced both matrix volume (-7.24 mL [95% CI: -11.59 to -2.91] vs 0.70 mL [95% CI: -0.89 to 2.29]; P < 0.001) and cardiomyocyte volume (-11.08 mL [95% CI: -19.62 to -2.55] vs 0.80 mL [95% CI: -1.96 to 3.55]; P < 0.05). Pulsed wave velocity was also significantly reduced in the empagliflozin group (-0.58 cm/s [95% CI: -0.92 to -0.25] vs 0.60 cm/s [95% CI: 0.14 to 1.06]; P < 0.01). Using proteomics, empagliflozin was associated with a significant reduction in inflammatory biomarkers.
Conclusions
Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness, and inflammatory markers in nondiabetic patients with HFrEF. These results shed new light on the mechanisms of action of the benefits of SGLT2-i. (Are the \"Cardiac Benefits\" of Empagliflozin Independent of Its Hypoglycemic Activity [ATRU-4] [EMPA-TROPISM]; NCT03485222).

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

JACC Heart Fail: 30 Jul 2021; 9:578-589
Requena-Ibáñez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, ... Fuster V, Badimon JJ
JACC Heart Fail: 30 Jul 2021; 9:578-589 | PMID: 34325888
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Impact:
Abstract

Patient Phenotypes and SGLT-2 Inhibition in Type 2 Diabetes: Insights From the EMPA-REG OUTCOME Trial.

Sharma A, Ofstad AP, Ahmad T, Zinman B, ... Desai N, Mentz RJ
Objectives
Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.
Background
In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.
Methods
Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).
Results
In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30).
Conclusions
Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).

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

JACC Heart Fail: 30 Jul 2021; 9:568-577
Sharma A, Ofstad AP, Ahmad T, Zinman B, ... Desai N, Mentz RJ
JACC Heart Fail: 30 Jul 2021; 9:568-577 | PMID: 34325887
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Impact:
Abstract

Impact of Diabetes on Outcomes After Transcatheter Mitral Valve Repair in Heart Failure: COAPT Trial.

Shahim B, Ben-Yehuda O, Chen S, Redfors B, ... Mack MJ, Stone GW
Objectives
This paper sought to determine whether diabetes influences the outcomes of transcatheter mitral valve repair (TMVr) in patients with heart failure (HF) and secondary mitral regurgitation (SMR).
Background
Diabetes is associated with worse outcomes in patients with HF.
Methods
The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With functional Mitral Regurgitation) trial randomized HF patients with 3+ or 4+ SMR to MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone. Two-year outcomes were evaluated in patients with versus without diabetes.
Results
Of 614 patients, 229 (37.3%) had diabetes. Diabetic patients had higher 2-year rates of death than those without diabetes (40.8% vs 32.3%, respectively; adjusted P = 0.04) and tended to have higher rates of HF hospitalization (HFH) (HFH: 50.1% vs 43.0%, respectively; adjusted P = 0.07). TMVr reduced the 2-year rate of death consistently in patients with (30.3% vs 49.9%, respectively; adjusted HR: 0.51; 95% CI: 0.32 to 0.81) and without (27.0% vs 38.3%, respectively; adjusted HR: 0.57; 95% CI: 0.39-0.84) diabetes (Pinteraction = 0.72). TMVr also consistently reduced the 2-year rates of HFH in patients with (32.2% vs 54.8%, respectively; adjusted HR: 0.41; 95% CI: 0.28-0.58) and without (41.5% vs 59.0%, respectively; adjusted HR: 0.54: 95% CI 0.35-0.82) diabetes (Pinteraction = 0.33). Greater movements in quality-of-life (QOL) and exercise capacity occurred with TMVr than with GDMT alone, regardless of diabetic status.
Conclusions
Among HF patients with severe SMR in the COAPT trial, those with diabetes had a worse prognosis. Nonetheless, diabetic and nondiabetic patients had consistent reductions in the 2-year rates of death and HFH and improvements in QOL and functional capacity following TMVr treatment using the MitraClip than with maintenance on GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).

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

JACC Heart Fail: 30 Jul 2021; 9:559-567
Shahim B, Ben-Yehuda O, Chen S, Redfors B, ... Mack MJ, Stone GW
JACC Heart Fail: 30 Jul 2021; 9:559-567 | PMID: 34325886
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Abstract

Mineralocorticoid Receptor Antagonist Improves Cardiac Structure in Type 2 Diabetes: Data From the MIRAD Trial.

Brandt-Jacobsen NH, Lav Madsen P, Johansen ML, Rasmussen JJ, ... Schou M, Kistorp C
Objectives
This study investigated the impact of the MR antagonist (MRA) eplerenone on LVM in type 2 diabetes patients at high risk for cardiovascular disease (CVD).
Background
MRA activation is associated with cardiac fibrosis and increased left ventricular mass (LVM), which is an independent predictor of adverse CVD, including heart failure in patients with type 2 diabetes.
Methods
A prespecified analysis of secondary endpoints in a randomized, double-blinded clinical trial of 140 patients with type 2 diabetes at high risk of or established CVD. Patients were randomized to receive high-dose eplerenone therapy (100 mg-200 mg) or placebo as an add-on to standard care for 26 weeks. Indexed LVM (LVMi) and T1 time were measured using cardiac magnetic resonance (CMR) imaging. Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), pro-collagen type I N-terminal propeptide (P1NP), and type III N-terminal propeptide (P3NP).
Results
Of 140 patients in the MIRAD trial, 104 patients were subject to CMR imaging (eplerenone: 54 patients; placebo: 50 patients). Mean LVMi at baseline was 74.2 ± 16 g/m2. The treatment effect (ie, between-group differences) was a decrease of 3.7 g/m2 following the eplerenone treatment (95% CI: -6.7 to -0.7; P = 0.017), with a corresponding decrease in absolute LVM. Plasma NT-proBNP concentrations decreased by 22% (P = 0.017) using eplerenone compared with placebo, and P1NP decreased 3.3 ng/mL (P = 0.019). No differences in T1 times or P3NP concentrations were observed between groups.
Conclusions
The addition of high-dose eplerenone in high-risk type 2 diabetes was associated with a clear reduction in LVMi and in NT-proBNP and P1NP levels, which may suggest a clinical benefit in heart failure prevention. (EU Clinical trials: Mineralocorticoid Receptor Antagonists in Type 2 Diabetes [MIRAD]; 2015-002519-14).

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

JACC Heart Fail: 30 Jul 2021; 9:550-558
Brandt-Jacobsen NH, Lav Madsen P, Johansen ML, Rasmussen JJ, ... Schou M, Kistorp C
JACC Heart Fail: 30 Jul 2021; 9:550-558 | PMID: 34325885
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Abstract

Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes.

Packer M
Diabetes promotes the development of both heart failure with a reduced ejection fraction and heart failure with a preserved ejection fraction through diverse mechanisms, which are likely mediated through hyperinsulinemia rather than hyperglycemia. Diabetes promotes nutrient surplus signaling (through Akt and mammalian target of rapamycin complex 1) and inhibits nutrient deprivation signaling (through sirtuin-1 and its downstream effectors); this suppresses autophagy and promotes endoplasmic reticulum and oxidative stress and mitochondrial dysfunction, thereby undermining the health of diabetic cardiomyocytes. The hyperinsulinemia of diabetes may also activate sodium-hydrogen exchangers in cardiomyocytes (leading to injury and loss) and in the proximal renal tubules (leading to sodium retention). Diabetes may cause epicardial adipose tissue expansion, and the resulting secretion of proinflammatory adipocytokines onto the adjoining myocardium can lead to coronary microcirculatory dysfunction and myocardial inflammation and fibrosis. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors-the only class of antidiabetic medication that reduces serious heart failure events-may act to mitigate each of these mechanisms. SGLT2 inhibitors up-regulate sirtuin-1 and its downstream effectors and autophagic flux, thus explaining the actions of these drugs to reduce oxidative stress, normalize mitochondrial structure and function, and mute proinflammatory pathways in the stressed myocardium. Inhibition of SGLT2 may also lead to a reduction in the activity of sodium-hydrogen exchangers in the kidney (leading to diuresis) and in the heart (attenuating the development of cardiac hypertrophy and systolic dysfunction). Finally, SGLT2 inhibitors reduce the mass and mute the adverse biology of epicardial adipose tissue (and reduce the secretion of leptin), thus explaining the capacity of these drugs to mitigate myocardial inflammation, microcirculatory dysfunction, and fibrosis, and improve ventricular filling dynamics. The pathophysiological mechanisms by which SGLT2 inhibitors may benefit heart failure likely differ depending on ejection fraction, but each represents interference with distinct pathways by which hyperinsulinemia may adversely affect cardiac structure and function.

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

JACC Heart Fail: 30 Jul 2021; 9:535-549
Packer M
JACC Heart Fail: 30 Jul 2021; 9:535-549 | PMID: 34325884
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This program is still in alpha version.