Journal: Circ Heart Fail

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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: 04 May 2021:CIRCHEARTFAILURE120007991; epub ahead of print
Shah P, Psotka M, Taleb I, Alharethi R, ... Kfoury AG, Drakos SG
Circ Heart Fail: 04 May 2021:CIRCHEARTFAILURE120007991; epub ahead of print | PMID: 33947201
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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 cardiogenic shock. We sought to define clinical, hemodynamic, metabolic, and treatment parameters associated with clinical outcomes among HF-CS patients, using data from the Cardiogenic Shock Working Group (CSWG) Registry. Methods : Patients with HF-CS were identified from the multi-center CSWG registry and divided into 3 outcome categories assessed at hospital discharge: mortality, heart replacement therapy (HRT: durable ventricular assist device [VAD] or orthotopic heart transplant [OHT]), or native heart survival (NHS). Clinical characteristics, hemodynamic, laboratory parameters, drug therapies, acute mechanical circulatory support device (AMCS) utilization, and Society of Cardiovascular Angiography and Intervention (SCAI) stages were compared across the 3 outcome cohorts. Results : Of the 712 HF-CS patients identified, 180 (25.3%) died during their index admission, 277 (38.9%) underwent HRT (durable VAD or OHT), and 255 (35.8%) experienced NHS 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 HF-CS patients experiencing in-hospital death. Intra-aortic balloon pump (IABP) was the most commonly used AMCS device in the overall cohort and among patients receiving HRT. Patients receiving more than one AMCS device had the highest in-hospital mortality rate irrespective of the number of vasoactive drugs used. Mortality decreased with deteriorating SCAI 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 IABP being the most common device used and high rates of in-hospital mortality after exposure to more than one AMCS device.



Circ Heart Fail: 26 Apr 2021; epub ahead of print
Hernandez-Montfort J, Sinha SS, Thayer KL, Whitehead EH, ... Burkhoff D, Kapur NK
Circ Heart Fail: 26 Apr 2021; epub ahead of print | PMID: 33905259
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Abstract

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

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



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

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

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



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

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

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



Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007871; epub ahead of print
Blumer V, Mentz RJ, Sun JL, Butler J, ... O'Connor CM, Greene SJ
Circ Heart Fail: 28 Mar 2021:CIRCHEARTFAILURE120007871; epub ahead of print | PMID: 33775110
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Abstract

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

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



Circ Heart Fail: 24 Mar 2021:CIRCHEARTFAILURE120008113; epub ahead of print
Sinha A, Ning H, Carnethon MR, Allen NB, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 24 Mar 2021:CIRCHEARTFAILURE120008113; epub ahead of print | PMID: 33761754
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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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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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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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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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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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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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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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This program is still in alpha version.