Journal: Circ Heart Fail

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Abstract

Clinical Characteristics and Predictors of In-Hospital Mortality in Patients With Cardiogenic Shock: Results From the RESCUE Registry.

Yang JH, Choi KH, Ko YG, Ahn CM, ... Choi SH, Gwon HC
Background
In the current era of mechanical circulatory support, limited data are available on prognosis of cardiogenic shock (CS) caused by various diseases. We investigated the characteristics and predictors of in-hospital mortality in Korean patients with CS.
Methods
The RESCUE study (Retrospective and Prospective Observational Study to Investigate Clinical Outcomes and Efficacy of Left Ventricular Assist Device for Korean Patients With CS) is a multicenter, retrospective, and prospective registry of patients that presented with CS. Between January 2014 and December 2018, 1247 patients with CS were enrolled from 12 major centers in Korea. The primary outcome was in-hospital mortality.
Results
In-hospital mortality rate was 33.6%. The main causes of shock were ischemic heart disease (80.7%), dilated cardiomyopathy (6.1%), myocarditis (3.2%), and nonischemic ventricular arrhythmia (2.5%). Vasopressors were used in 1081 patients (86.7%). The most frequently used vasopressor was dopamine (63.4%) followed by norepinephrine (57.3%). An intraaortic balloon pump was used in 314 patients (25.2%) and extracorporeal membrane oxygenator in 496 patients (39.8%). In multivariable analysis, age ≥70years (odds ratio [OR], 2.73 [95% CI, 1.89-3.94], P<0.001), body mass index <25 kg/m2 (OR, 1.52 [95% CI, 1.08-2.16], P=0.017), cardiac arrest at presentation (OR, 2.16 [95% CI, 1.44-3.23], P<0.001), vasoactive-inotrope score >80 (OR, 3.55 [95% CI, 2.54-4.95], P<0.001), requiring continuous renal replacement therapy (OR, 4.14 [95% CI, 2.88-5.95], P<0.001), mechanical ventilator (OR, 3.17 [95% CI, 2.16-4.63], P<0.001), intraaortic balloon pump (OR, 1.55 [95% CI, 1.07-2.24], P=0.020), and extracorporeal membrane oxygenator (OR, 1.85 [95% CI, 1.25-2.76], P=0.002) were independent predictors for in-hospital mortality.
Conclusions
The in-hospital mortality of patients with CS remains high despite the high utilization of mechanical circulatory support. Age, low body mass index, cardiac arrest at presentation, amount of vasopressor, and advanced organ failure requiring various support devices were poor prognostic factors for in-hospital mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02985008.



Circ Heart Fail: 30 May 2021; 14:e008141
Yang JH, Choi KH, Ko YG, Ahn CM, ... Choi SH, Gwon HC
Circ Heart Fail: 30 May 2021; 14:e008141 | PMID: 34129366
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Abstract

Impact of Insulin Treatment on the Effect of Eplerenone: Insights From the EMPHASIS-HF Trial.

Ferreira JP, Lamiral Z, McMurray JJV, Swedberg K, ... Pitt B, Zannad F
Background
Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms).
Methods
The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used.
Results
The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulin-treated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.50-0.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes.
Conclusions
Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00232180.



Circ Heart Fail: 30 May 2021; 14:e008075
Ferreira JP, Lamiral Z, McMurray JJV, Swedberg K, ... Pitt B, Zannad F
Circ Heart Fail: 30 May 2021; 14:e008075 | PMID: 34129365
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Abstract

Potential Role of Natriuretic Response to Furosemide Stress Test During Acute Heart Failure.

Caravaca Pérez P, Nuche J, Morán Fernández L, Lora D, ... Arribas Ynsaurriaga F, Delgado JF
Background
Poor natriuresis has been associated with a poorer response to diuretic treatment and worse prognosis in acute heart failure. Recommendations on how and when to measure urinary sodium (UNa) are lacking. We aim to evaluate UNa quantification after a furosemide stress test (FST) capacity to predict appropriate decongestion during acute heart failure hospitalization.
Methods
Patients underwent an FST on day-1 of admission, and UNa was measured 2 hours after, dividing patients into low or high UNa based on the sample median value. A semiquantitative composite congestive score (CCS; 0-9) and NT pro-BNP (N-terminal pro-B-type natriuretic peptide) quantification were assessed before the FST and at day 5 after the FST.
Results
Median UNa after FST in the 65 patients included was 113 (97-122) mmol/L. At day 5, a lower proportion of patients with a low UNa reached a 30% decrease in NT-proBNP levels (21 [66%] for low UNa versus 31 [94%] for high UNa; P=0.005) and an appropriate grade of decongestion (CCS<3) (20 [62%] for low UNa versus 32 [97%] for high UNa; P<0.001). A UNa>83 mmol/L 2 hours after FST had a 96% sensitivity to predict an NT-proBNP reduction ≥30% and 95% to predict a CCS<3 at day 5. Low UNa patients presented a lower cumulative diuresis and weight loss and presented more often with prolonged hospitalization, worsening heart failure, and readmission because of acute heart failure or death at 6 months.
Conclusions
Low natriuresis after an FST identified patients at a higher risk of an inadequate diuretic response and an inappropriate decongestion. FST-guided diuretic treatment might help to improve decongestion, shorten hospitalizations, and to reduce adverse outcomes.



Circ Heart Fail: 30 May 2021; 14:e008166
Caravaca Pérez P, Nuche J, Morán Fernández L, Lora D, ... Arribas Ynsaurriaga F, Delgado JF
Circ Heart Fail: 30 May 2021; 14:e008166 | PMID: 34129364
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Abstract

Remote Hemodynamic Monitoring Equally Reduces Heart Failure Hospitalizations in Women and Men in Clinical Practice: A Sex-Specific Analysis of the CardioMEMS Post-Approval Study.

DeFilippis EM, Henderson J, Axsom KM, Costanzo MR, ... Brett ME, Givertz MM
Background
Response to pharmacological and device-based therapy for heart failure (HF) may vary by sex. We examined sex differences in response to ambulatory hemodynamic monitoring in clinical practice using the CardioMEMS PAS (Post-Approval Study).
Methods
The CardioMEMS PAS was a prospective, single-arm, multicenter, open-label study of 1200 adults with New York Heart Association class III HF and at least 1 HF hospitalization (HFH) within 12 months who underwent pulmonary artery pressure sensor implantation between 2014 and 2017. Changes in pulmonary artery pressure over time were stratified by ejection fraction <40% and sex. Clinical outcomes including HFH rate at 12 months, 1-year mortality, and quality of life were examined in women and men.
Results
Four hundred fifty-two women (38% of total) enrolled in the PAS were less likely to be White (78% versus 86%) and more likely to have nonischemic cardiomyopathy (44% versus 34%) and had significantly higher SBP (132 versus 124 mm Hg), mean ejection fraction (44% versus 36%), and pulmonary vascular resistance (3.2 versus 2.6 WU) than men (P<0.001 for all). There were similar reductions in pulmonary artery pressure from baseline to 12 months in both men and women for the whole cohort and for subgroups with HF with reduced ejection fraction and HF with preserved ejection fraction. Both sexes experienced significant decreases in HFH over 12 months (men: HR, 0.46 [95% CI, 0.40-0.52]; women: HR, 0.39 [95% CI, 0.33-0.46]). In adjusted models, there were no significant differences in change in HFH between men and women (interaction P=0.13) or all-cause mortality at 1 year (adjusted HR, 1.25 [95% CI, 0.88-1.77]).
Conclusions
Women and men enrolled in the CardioMEMS PAS had similar reductions from baseline in pulmonary artery pressure over 1 year and experienced similar reductions in HFH. Hemodynamic monitoring provides similar benefit with regard to HF events in both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02279888.



Circ Heart Fail: 30 May 2021; 14:e007892
DeFilippis EM, Henderson J, Axsom KM, Costanzo MR, ... Brett ME, Givertz MM
Circ Heart Fail: 30 May 2021; 14:e007892 | PMID: 34129363
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Abstract

Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.

Zhu S, Chen Z, Zhu M, Shen Y, ... Kunfu O, Fang X
Background
Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking.
Methods
We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).
Results
Taz cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity.
Conclusions
Our mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.



Circ Heart Fail: 30 May 2021; 14:e008289
Zhu S, Chen Z, Zhu M, Shen Y, ... Kunfu O, Fang X
Circ Heart Fail: 30 May 2021; 14:e008289 | PMID: 34129362
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Abstract

Levels of Trimethylamine N-Oxide Remain Elevated Long Term After Left Ventricular Assist Device and Heart Transplantation and Are Independent From Measures of Inflammation and Gut Dysbiosis.

Yuzefpolskaya M, Bohn B, Javaid A, Mondellini GM, ... Colombo PC, Demmer RT
Background
Trimethylamine N-oxide (TMAO)-a gut-derived metabolite-is elevated in heart failure (HF) and linked to poor prognosis. We investigated variations in TMAO in HF, left ventricular assist device (LVAD), and heart transplant (HT) and assessed its relation with inflammation, endotoxemia, oxidative stress, and gut dysbiosis.
Methods
We enrolled 341 patients. TMAO, CRP (C-reactive protein), IL (interleukin)-6, TNF-α (tumor necrosis factor alpha), ET-1 (endothelin-1), adiponectin, lipopolysaccharide, soluble CD14, and isoprostane were measured in 611 blood samples in HF (New York Heart Association class I-IV) and at multiple time points post-LVAD and post-HT. Gut microbiota were assessed via 16S rRNA sequencing among 327 stool samples. Multivariable regression models were used to assess the relationship between TMAO and (1) New York Heart Association class; (2) pre- versus post-LVAD or post-HT; (3) biomarkers of inflammation, endotoxemia, oxidative stress, and microbial diversity.
Results
ln-TMAO was lower among HF New York Heart Association class I (1.23 [95% CI, 0.52-1.94] µM) versus either class II, III, or IV (1.99 [95% CI, 1.68-2.30], 1.97 [95% CI, 1.71-2.24], and 2.09 [95% CI, 1.83-2.34] µM, respectively; all P<0.05). In comparison to class II-IV, ln-TMAO was lower 1 month post-LVAD (1.58 [95% CI, 1.32-1.83] µM) and 1 week and 1 month post-HT (0.97 [95% CI, 0.60-1.35] and 1.36 [95% CI, 1.01-1.70] µM). ln-TMAO levels in long-term LVAD (>6 months: 1.99 [95% CI, 1.76-2.22] µM) and HT (>6 months: 1.86 [95% CI, 1.66-2.05] µM) were not different from symptomatic HF. After multivariable adjustments, TMAO was not associated with biomarkers of inflammation, endotoxemia, oxidative stress, or microbial diversity.
Conclusions
TMAO levels are increased in symptomatic HF patients and remain elevated long term after LVAD and HT. TMAO levels were independent from measures of inflammation, endotoxemia, oxidative stress, and gut dysbiosis.



Circ Heart Fail: 30 May 2021; 14:e007909
Yuzefpolskaya M, Bohn B, Javaid A, Mondellini GM, ... Colombo PC, Demmer RT
Circ Heart Fail: 30 May 2021; 14:e007909 | PMID: 34129361
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Abstract

Exception Status Listing in the New Adult Heart Allocation System: A New Solution to an Old Problem?

Topkara VK, Clerkin KJ, Fried JA, Griffin J, ... Sayer G, Uriel N
Background
One of the goals of the revised 6-tiered US adult heart allocation policy was to improve risk stratification of patients to lower exception status utilization for transplant listing. We sought to define the characteristics and outcomes of waitlisted patients using exception status and to examine region- and center-level differences in utilization of exception status in the new heart allocation system.
Methods
This retrospective cohort analysis of the United Network for Organ Sharing database included adult waitlisted patients for heart transplant between October 18, 2018, and June 30, 2020, in the United States, stratified by use of exception status versus standard criteria.
Results
Out of 6351 patients, 1907 (30.0%) were waitlisted under exception status. Patients using exception status were more likely to have a nonischemic cause of heart failure, blood type O, United Network for Organ Sharing status 2 at listing and were less likely to have a durable left ventricular assist device at listing. Exception status utilization varied significantly between and within United Network for Organ Sharing regions. Listing by exception criteria was associated with a significantly higher incidence of heart transplantation compared with listing by standard criteria (hazard ratio, 1.25 [1.15-1.38], P<0.001), without increased risk of death or delisting for worsening clinical status (hazard ratio, 0.83 [0.65-1.05], P=0.12) after multivariable adjustment.
Conclusions
The status tiers of the new heart allocation system may not fully capture medical urgency and complexity of waitlisted patients as assessed by transplant physicians and review committees and may limit the ability to develop a heart allocation score.



Circ Heart Fail: 27 May 2021:CIRCHEARTFAILURE120007916; epub ahead of print
Topkara VK, Clerkin KJ, Fried JA, Griffin J, ... Sayer G, Uriel N
Circ Heart Fail: 27 May 2021:CIRCHEARTFAILURE120007916; epub ahead of print | PMID: 34044577
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Abstract

Association Between Angiotensin Receptor-Neprilysin Inhibition, Cardiovascular Biomarkers, and Cardiac Remodeling in Heart Failure with Reduced Ejection Fraction.

Murphy SP, Prescott MF, Maisel AS, Butler J, ... Solomon SD, Januzzi JL
Background : Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and soluble suppressor of tumorigenicity-2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF) treated with S/V is uncertain. Methods : In a prospective study of S/V in patients with HFrEF, this pre-specified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate Latent Growth Curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction (LVEF) and left atrial volume index (LAVi). Results : 715 out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline LVEF and LAVi were 29% and 40 ml/m2, respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/ml, hs-cTnT of 15.9 ng/L and sST2 of 24.7 ng/ml. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged -27.9% (95% CI: -35.1% to -20.7%; p<.001) for NT-proBNP; -6.7% (95% CI: -8.8% to -4.7%; p<.001) for hs-cTnT; and -1.6% (95% CI: -2.9% to -0.4%; p<.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in LVEF and LAVi. There was no association between changes in sST2 and changes in other measures. Conclusions : Following initiation of S/V, NT-proBNP, hs-cTnT and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with LA and LV reverse remodeling. Registration : URL: ClinicalTrials.gov; Unique Identifier: NCT02887183.



Circ Heart Fail: 14 May 2021; epub ahead of print
Murphy SP, Prescott MF, Maisel AS, Butler J, ... Solomon SD, Januzzi JL
Circ Heart Fail: 14 May 2021; epub ahead of print | PMID: 33998243
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Abstract

Clinical Outcomes Associated With Acute Mechanical Circulatory Support Utilization in Heart Failure Related Cardiogenic Shock.

Hernandez-Montfort J, Sinha SS, Thayer KL, Whitehead EH, ... Burkhoff D, Kapur NK
Background
Cardiogenic shock occurring in the setting of advanced heart failure (HF-CS) is increasingly common. However, recent studies have focused almost exclusively on acute myocardial infarction-related CS. We sought to define clinical, hemodynamic, metabolic, and treatment parameters associated with clinical outcomes among patients with HF-CS, using data from the Cardiogenic Shock Working Group registry.
Methods
Patients with HF-CS were identified from the multicenter Cardiogenic Shock Working Group registry and divided into 3 outcome categories assessed at hospital discharge: mortality, heart replacement therapy (HRT: durable ventricular assist device or orthotopic heart transplant), or native heart survival. Clinical characteristics, hemodynamic, laboratory parameters, drug therapies, acute mechanical circulatory support device (AMCS) utilization, and Society of Cardiovascular Angiography and Intervention stages were compared across the 3 outcome cohorts.
Results
Of the 712 patients with HF-CS identified, 180 (25.3%) died during their index admission, 277 (38.9%) underwent HRT (durable ventricular assist device or orthotopic heart transplant), and 255 (35.8%) experienced native heart survival without HRT. Patients who died had the highest right atrial pressure and heart rate and the lowest mean arterial pressure of the 3 outcome groups (P<0.01 for all). Biventricular and isolated left ventricular congestion were common among patients who died or underwent HRT, respectively. Lactate, blood urea nitrogen, serum creatinine, and aspartate aminotransferase were highest in patients with HF-CS experiencing in-hospital death. Intraaortic balloon pump was the most commonly used AMCS device in the overall cohort and among patients receiving HRT. Patients receiving >1 AMCS device had the highest in-hospital mortality rate irrespective of the number of vasoactive drugs used. Mortality increased with deteriorating Society of Cardiovascular Angiography and Intervention stages (stage B: 0%, stage C: 10.7%, stage D: 29.4%, stage E: 54.5%, 1-way ANOVA=<0.001).
Conclusions
Patients with HF-CS experiencing in-hospital mortality had a high prevalence of biventricular congestion and markers of end-organ hypoperfusion. Substantial heterogeneity exists with use of AMCS in HF-CS with intraaortic balloon pump being the most common device used and high rates of in-hospital mortality after exposure to >1 AMCS device.



Circ Heart Fail: 29 Apr 2021; 14:e007924
Hernandez-Montfort J, Sinha SS, Thayer KL, Whitehead EH, ... Burkhoff D, Kapur NK
Circ Heart Fail: 29 Apr 2021; 14:e007924 | PMID: 33905259
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Abstract

Framework to Classify Reverse Cardiac Remodeling With Mechanical Circulatory Support: The Utah-Inova Stages.

Shah P, Psotka M, Taleb I, Alharethi R, ... Kfoury AG, Drakos SG
Background
Variable definitions and an incomplete understanding of the gradient of reverse cardiac remodeling following continuous flow left ventricular assist device (LVAD) implantation has limited the field of myocardial plasticity. We evaluated the continuum of LV remodeling by serial echocardiographic imaging to define 3 stages of reverse cardiac remodeling following LVAD.
Methods
The study enrolled consecutive LVAD patients across 4 study sites. A blinded echocardiographer evaluated the degree of structural (LV internal dimension at end-diastole [LVIDd]) and functional (LV ejection fraction [LVEF]) change after LVAD. Patients experiencing an improvement in LVEF ≥40% and LVIDd ≤6.0 cm were termed responders, absolute change in LVEF of ≥5% and LVEF <40% were termed partial responders, and the remaining patients with no significant improvement in LVEF were termed nonresponders.
Results
Among 358 LVAD patients, 34 (10%) were responders, 112 (31%) partial responders, and the remaining 212 (59%) were nonresponders. The use of guideline-directed medical therapy for heart failure was higher in partial responders and responders. Structural changes (LVIDd) followed a different pattern with significant improvements even in patients who had minimal LVEF improvement. With mechanical unloading, the median reduction in LVIDd was -0.6 cm (interquartile range [IQR], -1.1 to -0.1 cm; nonresponders), -1.1 cm (IQR, -1.8 to -0.4 cm; partial responders), and -1.9 cm (IQR, -2.9 to -1.1 cm; responders). Similarly, the median change in LVEF was -2% (IQR, -6% to 1%), 9% (IQR, 6%-14%), and 27% (IQR, 23%-33%), respectively.
Conclusions
Reverse cardiac remodeling associated with durable LVAD support is not an all-or-none phenomenon and manifests in a continuous spectrum. Defining 3 stages across this continuum can inform clinical management, facilitate the field of myocardial plasticity, and improve the design of future investigations.



Circ Heart Fail: 29 Apr 2021; 14:e007991
Shah P, Psotka M, Taleb I, Alharethi R, ... Kfoury AG, Drakos SG
Circ Heart Fail: 29 Apr 2021; 14:e007991 | PMID: 33947201
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Abstract

Current Limitations of Invasive Exercise Hemodynamics for the Diagnosis of Heart Failure With Preserved Ejection Fraction.

Baratto C, Caravita S, Soranna D, Faini A, ... Parati G, Vachiéry JL
Background
Exercise hemodynamics can differentiate heart failure with preserved ejection fraction (HFpEF) from noncardiac dyspnea. However, respiratory pressure swings may impact hemodynamic measurements, potentially leading to misdiagnosis of HFpEF. Moreover, threshold values for abnormal hemodynamic response indicative of HFpEF are not universally accepted. Thus, we sought to evaluate the impact of respiratory pressure swings on hemodynamic data interpretation as well as the concordance among 3 proposed exercise hemodynamic criteria for HFpEF: (1) end-expiratory pulmonary artery wedge pressure (PAWPexp) ≥25 mm Hg; (2) PAWPexp/cardiac output slope >2 mm Hg/L per minute; and (3) respiratory-averaged (avg) mean pulmonary artery pressure >30 mm Hg, total pulmonary resistanceavg >3 WU, PAWPavg ≥20 mm Hg.
Methods
Fifty-seven patients with unexplained dyspnea (70% women, 70±9 years) underwent exercise cardiac catheterization. The difference between end-expiratory and averaged hemodynamic values, as well as the concordance among the 3 hemodynamic definitions of HFpEF, were assessed.
Results
End-expiratory hemodynamics measurements were higher than values averaged across the respiratory cycle. During exercise, a larger proportion of patients exceeded the threshold of 25 mm Hg for PAWPexp rather than for PAWPavg (70% versus 53%, P<0.01). The concordance of 3/3 HFpEF exercise hemodynamic criteria was recorded in 70% of patients. PAWPexp/cardiac output slope identified HFpEF more frequently than the other 2 criteria (81% versus 64% to 69%), incorporating over 97% of abnormal responses to the latter. Patients with 3/3 positive criteria had worse clinical, gas-exchange, and hemodynamic profiles.
Conclusions
Respiratory pressure swings impact on the exercise hemodynamic definitions of HFpEF that provide discordant results in 30% of patients. Equivocal diagnoses of HFpEF might be limited by adopting the most sensitive and inclusive criterion alone (ie, PAWPexp/cardiac output slope).



Circ Heart Fail: 29 Apr 2021; 14:e007555
Baratto C, Caravita S, Soranna D, Faini A, ... Parati G, Vachiéry JL
Circ Heart Fail: 29 Apr 2021; 14:e007555 | PMID: 33951935
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Abstract

Bridging With Extracorporeal Membrane Oxygenation Under the New Heart Allocation System: A United Network for Organ Sharing Database Analysis.

Nordan T, Critsinelis AC, Mahrokhian SH, Kapur NK, ... Couper GS, Kawabori M
Background
The effect of the new donor heart allocation system on survival following bridging to transplantation with venous-arterial extracorporeal membrane oxygenation remains unknown. The new allocation system places extracorporeal membrane oxygenation-supported candidates at the highest status.
Methods
The United Network for Organ Sharing database was queried for adults bridged to single-organ heart transplantation with extracorporeal membrane oxygenation from October 2006 to February 2020. Association between implementation of the new system and recipient survival was analyzed using Kaplan-Meier estimates, Cox proportional hazards models, and propensity score matching.
Results
Of 364 recipients included, 173 and 191 were transplanted under new and old systems, respectively. Compared with the old system, waitlist time was halved under the new system (5 versus 10 days, P<0.01); recipients also demonstrated lower rates of prior cardiac surgery (32.9% versus 44.5%, P=0.03) and preoperative ventilation (30.6% versus 42.4%, P=0.02). Unadjusted 180-day survival was 90.2% (95% CI, 84.7%-94.2%) and 69.6% (95% CI, 62.6%-76.1%) under the new and old systems, respectively. Cox proportional hazards analysis demonstrated listing and transplantation under the new system to be an independent predictor of post-transplant survival (adjusted hazard ratio, 0.34 [95% CI 0.20-0.59]). Propensity score matching demonstrated a similar trend (hazard ratio, 0.36 [95% CI, 0.19-0.66]). Candidates listed under the new system were significantly less likely to experience waitlist mortality or deterioration (subhazard ratio, 0.38 [95% CI, 0.25-0.58]) and more likely to survive to transplant (subhazard ratio, 4.29 [95% CI, 3.32-5.54]).
Conclusions
Recipients transplanted following extracorporeal membrane oxygenation bridging to transplantation under the new system achieve greater 180-day survival compared with the old and demonstrate less preoperative comorbidity. Waitlist outcomes have also improved significantly under the new allocation system.



Circ Heart Fail: 29 Apr 2021; 14:e007966
Nordan T, Critsinelis AC, Mahrokhian SH, Kapur NK, ... Couper GS, Kawabori M
Circ Heart Fail: 29 Apr 2021; 14:e007966 | PMID: 33951934
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Abstract

Estimated Health Care Utilization and Expenditures in Individuals With Heart Failure From the Medical Expenditure Panel Survey.

Klein S, Jiang S, Morey JR, Pai A, ... Lala A, Ferket BS
Background
Heart failure (HF) constitutes a growing burden for public health and the US health care system. While the prevalence of HF is increasing, differences in health care utilization and expenditures within various sociodemographic groups remain poorly defined.
Methods
We used the Medical Expenditure Panel Survey to assess annual health care utilization and expenditures from 2012 to 2017. Health care utilization was based on the annual frequency of various health care encounters. Annual total and out-of-pocket expenditures were evaluated for hospital inpatient stays, emergency room visits, outpatient visits, office-based medical provider visits, prescribed medicines, dental visits, home health aid visits, and other medical expenses. We performed univariable and multivariable regression analysis based on patient characteristics including sociodemographic and comorbidity variables.
Results
Our results showed that total health care expenditures among patients with HF were $21 177 (95% CI, $18 819-$24 736) per year as compared with $5652 (95% CI, $5469-$5837) in those without HF (P<0.001). Total expenditures within the population with HF were primarily being driven by expenditures associated with inpatient hospitalizations. Increasing number of comorbid conditions was associated with significant increases in total health care expenditures. Older age, female sex, earlier study years, number of comorbidities, higher level of education, and increasing family income brackets independently raised out-of-pocket expenditures.
Conclusions
Our findings of increased health care utilization and expenditures based on sex, age, increasing number of comorbidities, wealthier income status, and increased education attainment level may be used for efforts aimed at better distributing health care resources to improve health outcomes in HF.



Circ Heart Fail: 29 Apr 2021; 14:e007763
Klein S, Jiang S, Morey JR, Pai A, ... Lala A, Ferket BS
Circ Heart Fail: 29 Apr 2021; 14:e007763 | PMID: 33980040
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Abstract

Intersection of Heart Failure and Pregnancy: Beyond Peripartum Cardiomyopathy.

DeFilippis EM, Haythe JH, Walsh MN, Kittleson MM
Heart failure (HF) is a leading cause of morbidity and mortality in pregnant women in the United States. Although peripartum cardiomyopathy is the most common diagnosis for pregnant women with HF, women with preexisting cardiomyopathies and systolic dysfunction are also at risk as the hemodynamic demands of pregnancy can lead to decompensation, arrhythmia, and rarely death. The differential diagnosis of HF in pregnancy is broad and includes Takotsubo or stress cardiomyopathy, exacerbation of a preexisting cardiomyopathy, such as familial cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or left ventricular noncompaction. This review will explore the implications of pregnancy in women with preexisting cardiomyopathies and de novo HF, risk assessment and preconception planning, decisions about contraception, the safety of HF medications and implantable cardioverter-defibrillators during pregnancy, pregnancy in women with left ventricular assist devices and following heart transplantation.



Circ Heart Fail: 29 Apr 2021; 14:e008223
DeFilippis EM, Haythe JH, Walsh MN, Kittleson MM
Circ Heart Fail: 29 Apr 2021; 14:e008223 | PMID: 33980039
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Abstract

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

Mentz RJ, Ambrosy AP, Ezekowitz JA, Lewis GD, ... Hernandez AF, HEART-FID Trial Investigators
Background
Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited.
Methods
The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance.
Conclusions
The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.



Circ Heart Fail: 29 Apr 2021; 14:e008100
Mentz RJ, Ambrosy AP, Ezekowitz JA, Lewis GD, ... Hernandez AF, HEART-FID Trial Investigators
Circ Heart Fail: 29 Apr 2021; 14:e008100 | PMID: 34003690
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Abstract

Association of Health Insurance Payer Type and Outcomes After Durable Left Ventricular Assist Device Implantation: An Analysis of the STS-INTERMACS Registry.

Khatana SAM, Hanff TC, Nathan AS, Dayoub EJ, ... Giri J, Groeneveld PW
Background
Due to the high cost of left ventricular assist device (LVAD) therapy, payer type may be an important factor in determining eligibility. How payer type influences outcomes after LVAD implantation is unclear. We, therefore, aimed to study the association of health insurance payer type with outcomes after durable LVAD implantation.
Methods
Using STS-INTERMACS (Society of Thoracic Surgeons-Interagency Registry for Mechanically Assisted Circulatory Support), we studied nonelderly adults receiving a durable LVAD from 2016 to 2018 and compared all-cause mortality and postindex hospitalization adverse event episode rate by payer type. Multivariable Fine-Gray and generalized linear models were used to compare the outcomes.
Results
Of the 3251 patients included, 26.0% had Medicaid, 24.9% had Medicare alone, and 49.1% had commercial insurance. Compared with commercially insured patients, mortality did not differ for patients with Medicaid (subdistribution hazard ratio, 1.00 [95% CI, 0.75-1.34], P=0.99) or Medicare (subdistribution hazard ratio, 1.09 [95% CI, 0.84-1.41], P=0.52). Medicaid was associated with a significantly lower adjusted incidence rate (incidence rate ratio, 0.88 [95% CI, 0.78-0.99], P=0.041), and Medicare was associated with a significantly higher adjusted incidence rate (incidence rate ratio, 1.16 [95% CI, 1.03-1.30], P=0.011) of adverse event episodes compared with commercially insured patients.
Conclusions
All-cause mortality after durable LVAD implantation did not differ significantly by payer type. Payer type was associated with the rate of adverse events, with Medicaid associated with a significantly lower rate, and Medicare with a significantly higher rate of adverse event episodes compared with commercially insured patients.



Circ Heart Fail: 29 Apr 2021; 14:e008277
Khatana SAM, Hanff TC, Nathan AS, Dayoub EJ, ... Giri J, Groeneveld PW
Circ Heart Fail: 29 Apr 2021; 14:e008277 | PMID: 33993721
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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% [95% CI, 18.7%-36.7%]) and women (25.8% [95% CI, 16.3%-34.2%]). In contrast, PAF associated with obesity was the highest in White men (21.0% [95% CI, 14.6%-27.0%]) and women (17.9% [95% CI, 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% [95% CI, 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: 30 Mar 2021; 14:e008113
Sinha A, Ning H, Carnethon MR, Allen NB, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 30 Mar 2021; 14:e008113 | PMID: 33761754
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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, 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: 30 Mar 2021; 14:e007297
Cordola Hsu AR, Xie B, Peterson DV, LaMonte MJ, ... Wong ND, WHI Investigators
Circ Heart Fail: 30 Mar 2021; 14:e007297 | PMID: 33775111
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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: 30 Mar 2021; 14:e007871
Blumer V, Mentz RJ, Sun JL, Butler J, ... O'Connor CM, Greene SJ
Circ Heart Fail: 30 Mar 2021; 14:e007871 | PMID: 33775110
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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: 30 Mar 2021; 14:e007957
Birati EY, Najjar SS, Tedford RJ, Houston BA, ... Moss N, Genuardi MV
Circ Heart Fail: 30 Mar 2021; 14:e007957 | PMID: 33813838
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Impact:
Abstract

Two-Year Follow Up of the LATERAL Clinical Trial: A Focus on Adverse Events.

Wieselthaler GM, Klein L, Cheung AW, Danter MR, ... Maltais S, McGee EC
Background
The LATERAL trial validated the safety and efficacy of the thoracotomy approach for implantation of the HeartWare HVAD System, leading to Food and Drug Administration approval. We sought to analyze 24-month adverse event (AE) rates, including a temporal analysis of the risk profile, associated with the thoracotomy approach for the HVAD system.
Methods
AEs from the LATERAL trial were evaluated over 2 years postimplant. Data was obtained from the Interagency Registry for Mechanically Assisted Circulatory Support database for 144 enrolled United States and Canadian patients. Temporal AE profiles were expressed as events per patient year.
Results
During 162.5 patient years of support, there were 25 driveline infections (0.15 events per patient year), 50 gastrointestinal bleeds (0.31 events per patient year), and 21 strokes (0.13 events per patient year). Longitudinal AE analysis at follow-up intervals of <30 and 30 to 180 days, and 6 to 12 and 12 to 24 months revealed the highest AE rate at <30 days, with a decrease in total AEs within the first 6 months. After 6 months, most AE rates either stabilized or decreased through 2 years, including a 95% overall freedom from disabling stroke.
Conclusions
Two-year follow-up of the LATERAL trial revealed a favorable morbidity profile in patients supported with the HVAD system, as AE rates were more likely to occur in the first 30 days postimplant, and overall AE rates were significantly reduced after 6 months. Importantly, 2-year freedom from disabling stroke was 95%. These data further support the improving AE profile of patients on long-term HVAD support. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02268942.



Circ Heart Fail: 30 Mar 2021; 14:e006912
Wieselthaler GM, Klein L, Cheung AW, Danter MR, ... Maltais S, McGee EC
Circ Heart Fail: 30 Mar 2021; 14:e006912 | PMID: 33866829
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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

Hemodynamic Effects of Sacubitril-Valsartan Versus Enalapril in Patients With Heart Failure in the EVALUATE-HF Study: Effect Modification by Left Ventricular Ejection Fraction and Sex.

Mitchell GF, Solomon SD, Shah AM, Claggett BL, ... Desai AS, EVALUATE-HF Investigators*
Background
Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction.
Methods
EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Zc) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12.
Results
In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, -3.0±0.8 mm Hg, P<0.001) and pulse pressure (-3.0±0.8 mm Hg, P<0.001). Postdose reductions in Zc were greater in the sacubitril-valsartan group (-16±6 dyne×second/cm5, P=0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction P=0.036). With LVEF<0.40, postdose reductions in Zc were greater in the sacubitril-valsartan group (trough, -3±8 dyne×second/cm5 versus post-dose, -17±8 dyne×second/cm5; interaction P=0.024) with no sex difference (treatment×sex interaction, P=0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Zc in women (women, -80±21 dyne×second/cm5 versus men, -20±13 dyne×second/cm5; interaction P=0.019).
Conclusions
In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Zc. In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Zc in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02874794.



Circ Heart Fail: 27 Feb 2021; 14:e007891
Mitchell GF, Solomon SD, Shah AM, Claggett BL, ... Desai AS, EVALUATE-HF Investigators*
Circ Heart Fail: 27 Feb 2021; 14:e007891 | PMID: 33663237
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Impact:
Abstract

In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure.

Gargalovic P, Wong P, Onorato J, Finlay H, ... Wexler R, Gordon D
Background
New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin\'s short half-life limits its therapeutic utility. Here, we describe the preclinical characterization of a novel, orally bioavailable APJ agonist, BMS-986224.
Methods
BMS-986224 pharmacology was compared with (Pyr1) apelin-13 using radio ligand binding and signaling pathway assays downstream of APJ (cAMP, phosphorylated ERK [extracellular signal-regulated kinase], bioluminescence resonance energy transfer-based G-protein assays, β-arrestin recruitment, and receptor internalization). Acute effects on cardiac function were studied in anesthetized instrumented rats. Chronic effects of BMS-986224 were assessed echocardiographically in the RHR (renal hypertensive rat) model of cardiac hypertrophy and decreased cardiac output.
Results
BMS-986224 was a potent (Kd=0.3 nmol/L) and selective APJ agonist, exhibiting similar receptor binding and signaling profile to (Pyr1) apelin-13. G-protein signaling assays in human embryonic kidney 293 cells and human cardiomyocytes confirmed this and demonstrated a lack of signaling bias relative to (Pyr1) apelin-13. In anesthetized instrumented rats, short-term BMS-986224 infusion increased cardiac output (10%-15%) without affecting heart rate, which was similar to (Pyr1) apelin-13 but differentiated from dobutamine. Subcutaneous and oral BMS-986224 administration in the RHR model increased stroke volume and cardiac output to levels seen in healthy animals but without preventing cardiac hypertrophy and fibrosis, effects differentiated from enalapril.
Conclusions
We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr1) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure.



Circ Heart Fail: 27 Feb 2021; 14:e007351
Gargalovic P, Wong P, Onorato J, Finlay H, ... Wexler R, Gordon D
Circ Heart Fail: 27 Feb 2021; 14:e007351 | PMID: 33663236
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Impact:
Abstract

Synergistic Impact of Systolic Blood Pressure and Perfusion Status on Mortality in Acute Heart Failure.

Rossello X, Bueno H, Gil V, Jacob J, ... Miró Ò, ICA-SEMES Research Group*
Background
Physical examination remains the cornerstone in the assessment of acute heart failure. There is a lack of adequately powered studies assessing the combined impact of both systolic blood pressure (SBP) and hypoperfusion on short-term mortality.
Methods
Patients with acute heart failure from 41 Spanish emergency departments were recruited consecutively in 3 time periods between 2011 and 2016. Logistic regression models were used to assess the association of 30-day mortality with SBP (<90, 90-109, 110-129, and ≥130 mm Hg) and with manifestations of hypoperfusion (cold skin, cutaneous pallor, delayed capillary refill, livedo reticularis, and mental confusion) at admission.
Results
Among 10 979 patients, 1143 died within the first 30 days (10.2%). There was an inverse association between 30-day mortality and initial SBP (35.4%, 18.9%, 12.4%, and 7.5% for SBP<90, SBP 90-109, SBP 110-129, and SBP≥130 mm Hg, respectively; P<0.001) and a positive association with hypoperfusion (8.0%, 14.8%, and 27.6% for those with none, 1, ≥2 signs/symptoms of hypoperfusion, respectively; P<0.001). After adjustment for 11 risk factors, the prognostic impact of hypoperfusion on 30-day mortality varied across SBP categories: SBP≥130 mm Hg (odds ratio [OR]=1.03 [95% CI, 0.77-1.36] and OR=1.18 [95% CI, 0.86-1.62] for 1 and ≥2 compared with 0 manifestations of hypoperfusion), SBP 110 to 129 mm Hg (OR=1.23 [95% CI, 0.86-1.77] and OR=2.18 [95% CI, 1.44-3.31], respectively), SBP 90 to 109 mm Hg (OR=1.29 [95% CI, 0.79-2.10] and OR=2.24 [95% CI, 1.36-3.66], respectively), and SBP<90 mm Hg (OR=1.34 [95% CI, 0.45-4.01] and OR=3.22 [95% CI, 1.30-7.97], respectively); P-for-interaction =0.043.
Conclusions
Hypoperfusion confers an incremental risk of 30-day all-cause mortality not only in patients with low SBP but also in normotensive patients. On admission, physical examination plays a major role in determining prognosis in patients with acute heart failure.



Circ Heart Fail: 27 Feb 2021; 14:e007347
Rossello X, Bueno H, Gil V, Jacob J, ... Miró Ò, ICA-SEMES Research Group*
Circ Heart Fail: 27 Feb 2021; 14:e007347 | PMID: 33677977
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Impact:
Abstract

Obesity and Outcomes Following Cardiogenic Shock Requiring Acute Mechanical Circulatory Support.

Sreenivasan J, Khan MS, Sharedalal P, Hooda U, ... Colombo PC, Rich JD
Background
The association of obesity on outcomes in patients with cardiogenic shock requiring acute mechanical circulatory support has not been thoroughly investigated.
Methods
We evaluated the National Readmission Database for adults with either acute myocardial infarction or heart failure complicated by cardiogenic shock requiring acute mechanical circulatory support between January 2016 and November 2017. Exposure was assessed using International Classification of Diseases, Tenth Revision codes for the degree of obesity with the reference being body mass index (BMI) of 20.0 to 29.9 group. Multiple logistic regression and Cox regression analysis were used to analyze in-hospital mortality and 30-day readmission, respectively.
Results
The survey-weighted sample included a total of 35 555 hospitalizations with a mean age of 65.4±0.2 years and 29.8% females. Obesity was associated with higher in-hospital mortality (no obesity, 26.4% [BMI, 20.0-29.9] versus class I obesity, 25.0% [BMI, 30.0-34.9] versus class II obesity, 28.7% [BMI, 35.0-39.9] versus class III obesity, 34.9% [BMI, ≥40]; P<0.001). On stratified analysis, compared with a nonobese phenotype, younger adults (age <60) with class II and class III obesity (odds ratio, 1.9 [95% CI, 1.1-3.5], P=0.02; odds ratio, 2.1 [95% CI, 1.2-3.7], P=0.01) and older adults (age ≥60) with class III obesity (odds ratio, 1.7 [95% CI, 1.2-2.4], P=0.005) had higher mortality. There was no association between the degree of obesity and 30-day readmission.
Conclusions
Among adults with acute myocardial infarction or acute heart failure resulting in cardiogenic shock requiring acute mechanical circulatory support, younger adults with class II and class III obesity and older patients with class III obesity have a higher risk of in-hospital mortality compared with nonobese patients.



Circ Heart Fail: 27 Feb 2021; 14:e007937
Sreenivasan J, Khan MS, Sharedalal P, Hooda U, ... Colombo PC, Rich JD
Circ Heart Fail: 27 Feb 2021; 14:e007937 | PMID: 33706552
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Impact:
Abstract

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

Rohde LE, Claggett BL, Wolsk E, Packer M, ... McMurray JJV, Solomon SD
Background
The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction.
Methods
We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality.
Results
Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes).
Conclusions
Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.



Circ Heart Fail: 27 Feb 2021; 14:e008052
Rohde LE, Claggett BL, Wolsk E, Packer M, ... McMurray JJV, Solomon SD
Circ Heart Fail: 27 Feb 2021; 14:e008052 | PMID: 33706551
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Impact:
Abstract

Renal Sympathetic Denervation in Patients With Heart Failure With Preserved Ejection Fraction.

Kresoja KP, Rommel KP, Fengler K, von Roeder M, ... Böhm M, Lurz P
Background
Arterial hypertension is the most common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) and mediates adverse hemodynamics through related aortic stiffness and increased pulsatile load. We aimed to investigate the clinical and hemodynamic implications of renal sympathetic denervation (RDN) in patients with HFpEF and uncontrolled arterial hypertension.
Methods
Patients undergoing RDN between 2011 and 2018 in a single-center were retrospectively analyzed and classified as HFpEF (n=99) or no HF (n=65). Stroke volume index and aortic distensibility were measured through cardiac magnetic resonance imaging, and left ventricular (LV) systolic and diastolic properties were assessed echocardiographically.
Results
At baseline, patients with HFpEF had higher stroke volume index (median 40 [interquartile range, 33-48] versus 33 [26-40] mL/m2, P=0.002), pulse pressure (69 [63-77] versus 61 [55-67] mm Hg, P<0.001), but lower LV-VPES100mm Hg (18 [10-28] versus 24 [15-40] mL, P=0.007) and aortic distensibility (1.5 [1.1-2.6] versus 2.7 [1.1-3.5] 10-3 mm Hg-1, P=0.013) as compared to no-HF patients. Systolic blood pressure decreased comparable in patients with HFpEF and no-HF patients following RDN (-9 [-16 to -2], P<0.001). After RDN stroke volume index (-3 [-9 to +3] mL/m2, P=0.011) decreased and aortic distensibility (0.2 [-0.1 to +1.1] 10-3 mm Hg-1, P=0.007) and systolic stiffness (P<0.001) increased in HFpEF patients. LV diastolic stiffness and LV filling pressures as well as NT-proBNP (N-terminal pro-B-type natriuretic peptide) decreased after RDN in patients with HFpEF (P=0.032, P=0.043, and P<0.001, respectively).
Conclusions
Patients with HFpEF undergoing RDN showed increased stroke volume index, vascular, and LV stiffness as compared to no-HF patients. Following RDN those hemodynamic alterations and reduced systolic and diastolic LV stiffness were partly normalized, implying RDN might be a potential therapeutic strategy for arterial hypertension and HFpEF.



Circ Heart Fail: 27 Feb 2021; 14:e007421
Kresoja KP, Rommel KP, Fengler K, von Roeder M, ... Böhm M, Lurz P
Circ Heart Fail: 27 Feb 2021; 14:e007421 | PMID: 33706547
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Impact:
Abstract

Clinical Profile and Health Disparities in a Multiethnic Cohort of Patients With Hypertrophic Cardiomyopathy.

Butters A, Semsarian CR, Bagnall RD, Yeates L, ... Semsarian C, Ingles J
Background
Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population.
Methods
We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed.
Results
Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m2, P<0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P=0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P<0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P=0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P<0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P=0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7, whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P<0.0001).
Conclusions
There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine-based care of individuals with hypertrophic cardiomyopathy.



Circ Heart Fail: 27 Feb 2021; 14:e007537
Butters A, Semsarian CR, Bagnall RD, Yeates L, ... Semsarian C, Ingles J
Circ Heart Fail: 27 Feb 2021; 14:e007537 | PMID: 33724884
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Impact:
Abstract

Exercise Ventricular Rates, Cardiopulmonary Exercise Performance, and Mortality in Patients With Heart Failure With Atrial Fibrillation.

Elshazly MB, Wilkoff BL, Tarakji K, Wu Y, ... Wazni O, Cho L
Background
In heart failure (HF) with sinus rhythm, resting and exercise heart rates correlate with exercise capacity and mortality. However, in HF with atrial fibrillation (AF), this correlation is unknown. Our aim is to investigate the association of resting and exercise ventricular rates (VRs) with exercise capacity and mortality in HF with AF.
Methods
We identified 903 patients with HF and AF referred for cardiopulmonary stress testing. AF was defined as history of AF and AF during cardiopulmonary stress testing. We constructed multivariable models to evaluate the association of resting VR, peak exercise VR, VR reserve (peak VR-resting VR), and chronotropic index with (1) peak oxygen consumption (PVO2) ≤18 mL/kg per minute, (2) continuous PVO2, and (3) 10-year all-cause mortality.
Results
Median (25th-75th percentile) age was 60 (52-67) years, left ventricular ejection fraction was 25 (15-50)%, and 76.1% were males. Patients with lower (quartile 1) compared with higher (quartile 4) peak VR, VR reserve, and chronotropic index were more likely to have PVO2 ≤18 mL/kg per min (adjusted odds ratio [95% CI]: 14.92 [8.07-27.58], 24.60 [12.36-48.98], and 22.31 [11.24-44.27], respectively), and higher all-cause mortality (adjusted hazard ratio [95% CI]: 2.56 [1.62-4.04], 2.29 [1.47-3.59], and 2.30 [1.51-3.49], respectively). For every 10 beats per minute increase in VR reserve, PVO2 increased by 1.05 mL/kg per minute (B-coefficient [95% CI]: 1.05 [0.94-1.15]) and mortality decreased by 12% (adjusted hazard ratio [95% CI]: 0.88 [0.83-0.94]). Resting VR was associated with PVO2 (B-coefficient [95% CI]: -0.46 [-0.70 to -0.23]) but not mortality (adjusted hazard ratio [95% CI]: 0.97 [0.88-1.06]).
Conclusions
In patients with HF and AF, higher resting VR and lower peak exercise VR, VR reserve, and chronotropic index were all associated with worse peak exercise capacity, but only lower exercise VR parameters were associated with higher mortality. Dedicated studies are needed to gauge whether modulating exercise VR enhances exercise performance and outcomes.



Circ Heart Fail: 30 Jan 2021; 14:e007451
Elshazly MB, Wilkoff BL, Tarakji K, Wu Y, ... Wazni O, Cho L
Circ Heart Fail: 30 Jan 2021; 14:e007451 | PMID: 33478244
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Impact:
Abstract

Sustained Improvement in Diastolic Reserve Following Percutaneous Pericardiotomy in a Porcine Model of Heart Failure With Preserved Ejection Fraction.

Jain CC, Pedrotty D, Araoz PA, Sugrue A, ... Asirvatham SJ, Borlaug BA
Background
Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown.
Methods
Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging.
Results
The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%-45%, P<0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, P=0.0003, 95% CI, -2.2 to -5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, P=0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction.
Conclusions
The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.



Circ Heart Fail: 30 Jan 2021; 14:e007530
Jain CC, Pedrotty D, Araoz PA, Sugrue A, ... Asirvatham SJ, Borlaug BA
Circ Heart Fail: 30 Jan 2021; 14:e007530 | PMID: 33478242
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Impact:
Abstract

Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload-Induced Heart Failure.

Kim SK, Biwer LA, Moss ME, Man JJ, ... Alcaide P, Jaffe IZ
Background
Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored.
Methods
Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry.
Results
Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction.
Conclusions
These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.



Circ Heart Fail: 30 Jan 2021; 14:e007279
Kim SK, Biwer LA, Moss ME, Man JJ, ... Alcaide P, Jaffe IZ
Circ Heart Fail: 30 Jan 2021; 14:e007279 | PMID: 33517669
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Impact:
Abstract

Better Understanding the Disparity Associated With Black Race in Heart Transplant Outcomes: A National Registry Analysis.

Maredia H, Bowring MG, Massie AB, Bae S, ... Segev DL, Bush EL
Background
Black heart transplant recipients have higher risk of mortality than White recipients. Better understanding of this disparity, including subgroups most affected and timing of the highest risk, is necessary to improve care of Black recipients. We hypothesize that this disparity may be most pronounced among young recipients, as barriers to care like socioeconomic factors may be particularly salient in a younger population and lead to higher early risk of mortality.
Methods
We studied 22 997 adult heart transplant recipients using the Scientific Registry of Transplant Recipients data from January 2005 to 2017 using Cox regression models adjusted for recipient, donor, and transplant characteristics.
Results
Among recipients aged 18 to 30 years, Black recipients had 2.05-fold (95% CI, 1.67-2.51) higher risk of mortality compared with non-Black recipients (P<0.001, interaction P<0.001); however, the risk was significant only in the first year post-transplant (first year: adjusted hazard ratio, 2.30 [95% CI, 1.60-3.31], P<0.001; after first year: adjusted hazard ratio, 0.84 [95% CI, 0.54-1.29]; P=0.4). This association was attenuated among recipients aged 31 to 40 and 41 to 60 years, in whom Black recipients had 1.53-fold ([95% CI, 1.25-1.89] P<0.001) and 1.20-fold ([95% CI, 1.09-1.33] P<0.001) higher risk of mortality. Among recipients aged 61 to 80 years, no significant association was seen with Black race (adjusted hazard ratio, 1.12 [95% CI, 0.97-1.29]; P=0.1).
Conclusions
Young Black recipients have a high risk of mortality in the first year after heart transplant, which has been masked in decades of research looking at disparities in aggregate. To reduce overall racial disparities, clinical research moving forward should focus on targeted interventions for young Black recipients during this period.



Circ Heart Fail: 30 Jan 2021; 14:e006107
Maredia H, Bowring MG, Massie AB, Bae S, ... Segev DL, Bush EL
Circ Heart Fail: 30 Jan 2021; 14:e006107 | PMID: 33525893
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Impact:
Abstract

Effect of Inotropes on Patient-Reported Health Status in End-Stage Heart Failure: A Review of Published Clinical Trials.

Clarke JD, Riello R, Allen LA, Psotka MA, ... Desai NR, Ahmad T
Background
A growing population of patients with end-stage heart failure (HF) with reduced ejection fraction has limited treatment options to improve their quality and quantity of life. Although positive inotropes have failed to show survival benefit, these agents may enhance patient-reported health status, that is, symptoms, functional status, and health-related quality of life. We sought to review the available clinical trial data on positive inotrope use in patients with end-stage HF and to summarize evidence supporting the use of these agents to improve health status of patients with end-stage HF.
Methods
A literature review of randomized controlled trials examining the use of positive inotropy in HF with reduced ejection fraction was conducted. We searched MEDLINE, SCOPUS, and Web of Science between January 1980 to December 2018 for randomized controlled trials that used as their main outcome measures the effects of inotrope therapy on (1) morbidity/mortality, (2) symptoms, (3) functional status, or (4) health-related quality of life. Inotropes of interest included adrenergic agents, phosphodiesterase inhibitors, calcium sensitizers, myosin activators, and SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) modulators.
Results
Twenty-two out of 26 inotrope randomized controlled trials measured the effect of inotropes on at least one patient-reported health status domain. Among the 22 studies with patient-related health status outcomes, 11 (50%) gauged symptom response, 15 (68%) reported functional capacity changes, and 12 (54%) reported health-related quality of life measures. Fourteen (64%) of these trials noted positive outcomes in at least one health status domain measured; 11 (79%) of these positive studies used agents that worked through phosphodiesterase inhibition.
Conclusions
There has been a lack of standardization surrounding measurement of patient-centered outcomes in studies of inotropes for end-stage HF with reduced ejection fraction. The degree to which positive inotropes can improve patient-reported health status and the adverse risk they pose remains unknown.



Circ Heart Fail: 30 Jan 2021; 14:e007759
Clarke JD, Riello R, Allen LA, Psotka MA, ... Desai NR, Ahmad T
Circ Heart Fail: 30 Jan 2021; 14:e007759 | PMID: 33530705
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Impact:
Abstract

Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial.

Berg DD, Samsky MD, Velazquez EJ, Duffy CI, ... Morrow DA, DeVore AD
Background
In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile.
Methods
PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219).
Results
The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each).
Conclusions
In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.



Circ Heart Fail: 30 Jan 2021; 14:e007034
Berg DD, Samsky MD, Velazquez EJ, Duffy CI, ... Morrow DA, DeVore AD
Circ Heart Fail: 30 Jan 2021; 14:e007034 | PMID: 33530704
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Impact:
Abstract

Risk-Based Approach for the Prediction and Prevention of Heart Failure.

Sinha A, Gupta DK, Yancy CW, Shah SJ, ... Lloyd-Jones DM, Khan SS
Targeted prevention of heart failure (HF) remains a critical need given the high prevalence of HF morbidity and mortality. Similar to risk-based prevention of atherosclerotic cardiovascular disease, optimal HF prevention strategies should include quantification of risk in the individual patient. In this review, we discuss incorporation of a quantitative risk-based approach into the existing HF staging landscape and the clinical opportunity that exists to translate available data on risk estimation to help guide personalized decision making. We first summarize the recent development of key HF risk prediction tools that can be applied broadly at a population level to estimate risk of incident HF. Next, we provide an in-depth description of the clinical utility of biomarkers to personalize risk estimation in select patients at the highest risk of developing HF. We also discuss integration of genomics-enhanced approaches (eg, Titin [TTN]) and other risk-enhancing features to reclassify risk with a precision medicine approach to HF prevention. Although sequential testing is very likely to identify low and high-risk individuals with excellent accuracy, whether or not interventions based on these risk models prevent HF in clinical practice requires prompt attention including randomized placebo-controlled trials of candidate therapies in risk-enriched populations. We conclude with a summary of unanswered questions and gaps in evidence that must be addressed to move the field of HF risk assessment forward.



Circ Heart Fail: 30 Jan 2021; 14:e007761
Sinha A, Gupta DK, Yancy CW, Shah SJ, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 30 Jan 2021; 14:e007761 | PMID: 33535771
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Impact:
Abstract

Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure.

Park JF, Clark VR, Banerjee S, Hong J, ... Saddic L, Umar S
Background
Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH.
Methods
We performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5).
Results
We identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated cellular communication network factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV.
Conclusions
Transcriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of cellular communication network factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure.



Circ Heart Fail: 30 Jan 2021; 14:e007058
Park JF, Clark VR, Banerjee S, Hong J, ... Saddic L, Umar S
Circ Heart Fail: 30 Jan 2021; 14:e007058 | PMID: 33541093
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Impact:
Abstract

Association Between Coffee Intake and Incident Heart Failure Risk: A Machine Learning Analysis of the FHS, the ARIC Study, and the CHS.

Stevens LM, Linstead E, Hall JL, Kao DP
Background
Coronary heart disease, heart failure (HF), and stroke are complex diseases with multiple phenotypes. While many risk factors for these diseases are well known, investigation of as-yet unidentified risk factors may improve risk assessment and patient adherence to prevention guidelines. We investigated the diet domain in FHS (Framingham Heart Study), CHS (Cardiovascular Heart Study), and the ARIC study (Atherosclerosis Risk in Communities) to identify potential lifestyle and behavioral factors associated with coronary heart disease, HF, and stroke.
Methods
We used machine learning feature selection based on random forest analysis to identify potential risk factors associated with coronary heart disease, stroke, and HF in FHS. We evaluated the significance of selected variables using univariable and multivariable Cox proportional hazards analysis adjusted for known cardiovascular risks. Findings from FHS were then validated using CHS and ARIC.
Results
We identified multiple dietary and behavioral risk factors for cardiovascular disease outcomes including marital status, red meat consumption, whole milk consumption, and coffee consumption. Among these dietary variables, increasing coffee consumption was associated with decreasing long-term risk of HF congruently in FHS, ARIC, and CHS.
Conclusions
Higher coffee intake was found to be associated with reduced risk of HF in all three studies. Further study is warranted to better define the role, possible causality, and potential mechanism of coffee consumption as a potential modifiable risk factor for HF.



Circ Heart Fail: 30 Jan 2021; 14:e006799
Stevens LM, Linstead E, Hall JL, Kao DP
Circ Heart Fail: 30 Jan 2021; 14:e006799 | PMID: 33557575
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Impact:
Abstract

Myocardial Tissue Reverse Remodeling After Guideline-Directed Medical Therapy in Idiopathic Dilated Cardiomyopathy.

Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y
Background
The prognosis of patients with idiopathic dilated cardiomyopathy (DCM) has improved remarkably in recent decades with guideline-directed medical therapy. Left ventricular (LV) reverse remodeling (LVRR) is one of the major therapeutic goals. Whether myocardial fibrosis or inflammation would reverse associated with LVRR remains unknown.
Methods
A total of 157 prospectively enrolled patients with DCM underwent baseline and follow-up cardiovascular magnetic resonance examinations with a median interval of 13.7 months (interquartile range, 12.2-18.5 months). LVRR was defined as an absolute increase in LV ejection fraction of >10% to the final value of ≥35% and a relative decrease in LV end-diastolic volume of >10%. Statistical analyses were performed using paired t test and student t test, logistic regression analysis, and linear regression analysis.
Results
Forty-eight (31%) patients reached LVRR. At baseline, younger age, worse New York Heart Association class, new-onset heart failure, lower LV ejection fraction, absence of late gadolinium enhancement, lower myocardial T2, and extracellular volume were significant predictors of LVRR. During the follow-up, patients with and without LVRR both showed a significant decrease of myocardial native T1 (LVRR: [baseline] 1303.0±43.6 ms; [follow-up] 1244.7±51.8 ms; without LVRR: [baseline] 1308.5±80.5 ms; [follow-up] 1287.6±74.9 ms, both P<0.001), matrix and cellular volumes while no significant difference was observed in T2 or extracellular volume values after treatment.
Conclusions
In patients with idiopathic DCM, the absence of late gadolinium enhancement, lower T2, and extracellular volume values at baseline are significant predictors of LVRR. The myocardial T1, matrix, and cell volume decrease significantly in patients with LVRR after guideline-directed medical therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ChiCTR1800017058.



Circ Heart Fail: 30 Dec 2020; 14:e007944
Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y
Circ Heart Fail: 30 Dec 2020; 14:e007944 | PMID: 33185117
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Impact:
Abstract

Brain-Derived Neurotrophic Factor Improves Impaired Fatty Acid Oxidation Via the Activation of Adenosine Monophosphate-Activated Protein Kinase-ɑ - Proliferator-Activated Receptor-r Coactivator-1ɑ Signaling in Skeletal Muscle of Mice With Heart Failure.

Matsumoto J, Takada S, Furihata T, Nambu H, ... Sabe H, Kinugawa S
Background
We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ-proliferator-activated receptor-r coactivator-1ɑ) axis.
Methods
MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK.
Results
The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside.
Conclusions
Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training.



Circ Heart Fail: 30 Dec 2020; 14:e005890
Matsumoto J, Takada S, Furihata T, Nambu H, ... Sabe H, Kinugawa S
Circ Heart Fail: 30 Dec 2020; 14:e005890 | PMID: 33356364
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Impact:
Abstract

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.

Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, ... Kelly DP, Westenbrink BD
Background
Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.
Methods
Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.
Results
The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.
Conclusions
Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.



Circ Heart Fail: 30 Dec 2020; 14:e007684
Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, ... Kelly DP, Westenbrink BD
Circ Heart Fail: 30 Dec 2020; 14:e007684 | PMID: 33356362
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Impact:
Abstract

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Schuldt M, Pei J, Harakalova M, Dorsch LM, ... van der Velden J, Kuster DWD
Background
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCMSMP), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCMSMN). Genotype-specific differences have been reported in cardiac function. Moreover, HCMSMN patients have later disease onset and a better prognosis than HCMSMP patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group.
Methods
A proteomics screen was performed in cardiac tissue from 39 HCMSMP patients, 11HCMSMN patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novel MYBPC32373insG mouse model was used to confirm functional relevance of our proteomic findings.
Results
In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCMSMP than in HCMSMN and controls. Higher tubulin detyrosination was also found in 2 unrelated MYBPC3 mouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes.
Conclusions
Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCMSMP. This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCMSMP, whereas a beneficial effect may be limited in patients with HCMSMN.



Circ Heart Fail: 30 Dec 2020; 14:e007022
Schuldt M, Pei J, Harakalova M, Dorsch LM, ... van der Velden J, Kuster DWD
Circ Heart Fail: 30 Dec 2020; 14:e007022 | PMID: 33430602
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Impact:
Abstract

Automated E-Counseling for Chronic Heart Failure: CHF-CePPORT Trial.

Nolan RP, Ross HJ, Farkouh ME, Huszti E, ... Wielgosz A, Mielniczuk LM
Background
International task force statements advocate telehealth programs to promote health-related quality of life for patients with chronic heart failure (CHF). To that end, we evaluated the efficacy and usability of an automated e-counseling program.
Methods
This Canadian multi-site double-blind randomized trial assessed whether usual care plus either internet-based e-counseling (motivational and cognitive-behavioral tools for CHF self-care) or e-based conventional CHF self-care education (e-UC) improved 12-month Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS). Secondary outcomes included program engagement (total logon weeks, logons, and logon hours), total CHF self-care behaviors, diet (fruit and vegetable servings), 6-minute walk test, and 4-day step count. The association between program engagement and health-related quality of life was assessed using KCCQ-OS tertiles.
Results
We enrolled 231 patients, median age =59.5 years, 22% female, and elevated median KCCQ-OS=83.0 (interquartile range, 68-93). KCCQ-OS increase ≥5 points was not more prevalent for e-counseling, n=29 (29.6%) versus e-UC, n=32 (34.0%), P=0.51. E-Counseling versus e-UC increased total logon weeks (P=0.02), logon hours (P=0.001), and logons (P<0.001). Only e-counseling showed a positive association between 12-month KCCQ-OS tertile and logon weeks (P=0.04) and logon hours (P=0.004). E-Counseling increased CHF self-care behavior and diet but not 6-minute walk test or 4-day step count.
Conclusions
The primary KCCQ-OS end point was negative for this trial. Only e-counseling showed a positive association between program engagement and 12-month KCCQ-OS tertile, and it improved CHF self-care behavior and diet. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01864369.



Circ Heart Fail: 30 Dec 2020; 14:e007073
Nolan RP, Ross HJ, Farkouh ME, Huszti E, ... Wielgosz A, Mielniczuk LM
Circ Heart Fail: 30 Dec 2020; 14:e007073 | PMID: 33464959
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Impact:
Abstract

Metabolomic Profiles and Heart Failure Risk in Black Adults: Insights From the Jackson Heart Study.

Tahir UA, Katz DH, Zhao T, Ngo D, ... Wilson JG, Gerszten RE
Background
Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease.
Methods
We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction.
Results
Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P=1.2×10-3), diacetylspermine (hazard ratio, 1.34; P=3.4×10-3), and uridine (hazard ratio, 0.79; P, 3×10-4). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (N-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction.
Conclusions
The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.



Circ Heart Fail: 30 Dec 2020; 14:e007275
Tahir UA, Katz DH, Zhao T, Ngo D, ... Wilson JG, Gerszten RE
Circ Heart Fail: 30 Dec 2020; 14:e007275 | PMID: 33464957
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Impact:
Abstract

CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.

Richards DA, Aronovitz MJ, Liu P, Martin GL, ... Mendelsohn ME, Blanton RM
Background
Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.
Methods
Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days (P<0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10).
Results
CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (P<0.001), significantly improved LV ejection fraction (P=0.009), and attenuated left atrial dilation (P<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (P=0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle (P<0.001), alongside increased phosphorylation of Ser273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site.
Conclusions
The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.



Circ Heart Fail: 30 Dec 2020; 14:e007300
Richards DA, Aronovitz MJ, Liu P, Martin GL, ... Mendelsohn ME, Blanton RM
Circ Heart Fail: 30 Dec 2020; 14:e007300 | PMID: 33464954
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Impact:
Abstract

Impairments in Blood Pressure Regulation and Cardiac Baroreceptor Sensitivity Among Patients With Heart Failure Supported With Continuous-Flow Left Ventricular Assist Devices.

Sailer C, Edelmann H, Buchanan C, Giro P, ... Tarumi T, Cornwell WK
Background
Continuous-flow (CF) left ventricular assist devices (LVADs) improve outcomes for patients with advanced heart failure (HF). However, the lack of a physiological pulse predisposes to side-effects including uncontrolled blood pressure (BP), and there are little data regarding the impact of CF-LVADs on BP regulation.
Methods
Twelve patients (10 males, 60±11 years) with advanced heart failure completed hemodynamic assessment 2.7±4.1 months before, and 4.3±1.3 months following CF-LVAD implantation. Heart rate and systolic BP via arterial catheterization were monitored during Valsalva maneuver, spontaneous breathing, and a 0.05 Hz repetitive squat-stand maneuver to characterize cardiac baroreceptor sensitivity. Plasma norepinephrine levels were assessed during head-up tilt at supine, 30o and 60o. Heart rate and BP were monitored during cardiopulmonary exercise testing.
Results
Cardiac baroreceptor sensitivity, determined by Valsalva as well as Fourier transformation and transfer function gain of Heart rate and systolic BP during spontaneous breathing and squat-stand maneuver, was impaired before and following LVAD implantation. Norepinephrine levels were markedly elevated pre-LVAD and improved-but remained elevated post-LVAD (supine norepinephrine pre-LVAD versus post-LVAD: 654±437 versus 323±164 pg/mL). BP increased during cardiopulmonary exercise testing post-LVAD, but the magnitude of change was modest and comparable to the changes observed during the pre-LVAD cardiopulmonary exercise testing.
Conclusions
Among patients with advanced heart failure with reduced ejection fraction, CF-LVAD implantation is associated with modest improvements in autonomic tone, but persistent reductions in cardiac baroreceptor sensitivity. Exercise-induced increases in BP are blunted. These findings shed new light on mechanisms for adverse events such as stroke, and persistent reductions in functional capacity, among patients supported by CF-LVADs. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078972.



Circ Heart Fail: 30 Dec 2020; 14:e007448
Sailer C, Edelmann H, Buchanan C, Giro P, ... Tarumi T, Cornwell WK
Circ Heart Fail: 30 Dec 2020; 14:e007448 | PMID: 33464953
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Impact:
Abstract

Defining Shock and Preshock for Mortality Risk Stratification in Cardiac Intensive Care Unit Patients.

Jentzer JC, Burstein B, Van Diepen S, Murphy J, ... Naidu SS, Baran DA
Background
Previous studies have defined preshock as isolated hypotension or isolated hypoperfusion, whereas shock has been variably defined as hypoperfusion with or without hypotension. We aimed to evaluate the mortality risk associated with hypotension and hypoperfusion at the time of admission in a cardiac intensive care unit population.
Methods
We analyzed Mayo Clinic cardiac intensive care unit patients admitted between 2007 and 2015. Hypotension was defined as systolic blood pressure <90 mm Hg or mean arterial pressure <60 mm Hg, and hypoperfusion as admission lactate >2 mmol/L, oliguria, or rising creatinine. Associations between hypotension and hypoperfusion with hospital mortality were estimated using multivariable logistic regression.
Results
Among 10 004 patients with a median age of 69 years, 43.1% had acute coronary syndrome, and 46.1% had heart failure. Isolated hypotension was present in 16.7%, isolated hypoperfusion in 15.3%, and 8.7% had both hypotension and hypoperfusion. Stepwise increases in hospital mortality were observed with hypotension and hypoperfusion compared with neither hypotension nor hypoperfusion (3.3%; all P<0.001): isolated hypotension, 9.3% (adjusted odds ratio, 1.7 [95% CI, 1.4-2.2]); isolated hypoperfusion, 17.2% (adjusted odds ratio, 2.3 [95% CI, 1.9-3.0]); both hypotension and hypoperfusion, 33.8% (adjusted odds ratio, 2.8 [95% CI, 2.1-3.6]). Adjusted hospital mortality in patients with isolated hypoperfusion was higher than in patients with isolated hypotension (P=0.02) and not significant different from patients with both hypotension and hypoperfusion (P=0.18).
Conclusions
Hypotension and hypoperfusion are both associated with increased mortality in cardiac intensive care unit patients. Hospital mortality is higher with isolated hypoperfusion or concomitant hypotension and hypoperfusion (classic shock). We contend that preshock should refer to isolated hypotension without hypoperfusion, while patients with hypoperfusion can be considered to have shock, irrespective of blood pressure.



Circ Heart Fail: 30 Dec 2020; 14:e007678
Jentzer JC, Burstein B, Van Diepen S, Murphy J, ... Naidu SS, Baran DA
Circ Heart Fail: 30 Dec 2020; 14:e007678 | PMID: 33464952
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Impact:
Abstract

Cardiac Microvascular Endothelial Cells in Pressure Overload-Induced Heart Disease.

Trenson S, Hermans H, Craps S, Pokreisz P, ... Luttun A, Janssens S
Background
Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS).
Methods
In Tie2-Gfp mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac Gfp+-MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women).
Results
In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of Cartilage Intermediate Layer Protein (Cilp), Thrombospondin-4, Adamtsl-2, and Collagen1a1 were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS (P<0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%-474%; P=0.008) and procollagen secretion by 85% (mean [95% CI, 16%-154%]; P<0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting (P<0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS.
Conclusions
Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.



Circ Heart Fail: 30 Dec 2020; 14:e006979
Trenson S, Hermans H, Craps S, Pokreisz P, ... Luttun A, Janssens S
Circ Heart Fail: 30 Dec 2020; 14:e006979 | PMID: 33464950
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Impact:
Abstract

Extracardiac Abnormalities of Preload Reserve: Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease.

Fudim M, Sobotka PA, Dunlap ME
While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.



Circ Heart Fail: 30 Dec 2020; 14:e007308
Fudim M, Sobotka PA, Dunlap ME
Circ Heart Fail: 30 Dec 2020; 14:e007308 | PMID: 33464948
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Impact:
Abstract

Effect of Empagliflozin as an Add-On Therapy on Decongestion and Renal Function in Patients With Diabetes Hospitalized for Acute Decompensated Heart Failure: A Prospective Randomized Controlled Study.

Tamaki S, Yamada T, Watanabe T, Morita T, ... Shintani A, Fukunami M
Background
Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure.
Methods
The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula.
Results
There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups.
Conclusions
In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.



Circ Heart Fail: 30 Dec 2020; 14:e007048
Tamaki S, Yamada T, Watanabe T, Morita T, ... Shintani A, Fukunami M
Circ Heart Fail: 30 Dec 2020; 14:e007048 | PMID: 33663235
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Impact:
Abstract

Novel Trial Design: CHIEF-HF.

Spertus JA, Birmingham MC, Butler J, Lingvay I, ... Januzzi JL, Whang J
Background
The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms.
Methods
One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire.
Results
The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic.
Conclusions
CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04252287.



Circ Heart Fail: 30 Dec 2020; 14:e007767
Spertus JA, Birmingham MC, Butler J, Lingvay I, ... Januzzi JL, Whang J
Circ Heart Fail: 30 Dec 2020; 14:e007767 | PMID: 33724883
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Impact:

This program is still in alpha version.