Borlaug, Barry A.

Background: The FIGHT (Functional Impact of GLP-1 [glucagon-like peptide-1] for Heart Failure Treatment) trial randomized 300 patients with heart failure with reduced ejection fraction (HFrEF) and a recent hospitalization for heart failure to liraglutide versus placebo. While there was no difference in the primary outcome (rank score of time to death, time to rehospitalization for heart failure, and change in NT-proBNP [N-terminal pro-B-type natriuretic peptide]), there was a significant increase in cystatin C among patients randomized to liraglutide raising concern of adverse renal outcomes. We performed a post hoc analysis of FIGHT to investigate whether liraglutide was associated with worsening renal function (WRF). Methods: The relationship between randomization to liraglutide and WRF was evaluated using logistic regression models. Two hundred seventy-four patients (91%) had complete data to assess for WRF defined as: increase in SCr ≥0.3 mg/dL, or ≥25% decrease in estimated glomerular filtration rate, or an increase in cystatin C ≥0.3 mg/L from baseline to 180-days. Results: Patients with WRF (n=113, 41%), compared with those without, were older, had more comorbidities, and lower utilization of guideline-directed medical treatment. Logistic regression models showed that age and baseline cystatin C levels were associated with WRF. In adjusted models, liraglutide was not associated with excess risk of WRF compared with placebo (odds ratio, 1.02 [95% CI, 0.62–1.67]). There was also no difference in the rank score when WRF was added as a fourth-tier outcome. Conclusions: Liraglutide was not associated with WRF among patients with HFrEF and a recent hospitalization for heart failure. These data support the relative renal safety profile of liraglutide among patients with HFrEF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01800968.

Abstract Aims Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF. Methods and results In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DLCO) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DLCO (placebo: −0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: −0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events. Conclusion In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF.

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.

Abstract Aims Patient-reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures. Methods and results This is a secondary analysis of the National Heart, Lung, and Blood Institute-sponsored RELAX, NEAT-HFpEF and INDIE-HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6-min walk distance), volume of daily activity (accelerometry), physician-estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOLworst, QOLintermediate, QOLbest. The QOLworst HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6-min walk distance and actigraphy, but was not associated with NT-proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization. Conclusions Quality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT-proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF. Clinical Trial Registration: RELAX, NCT00763867; NEAT-HFpEF, NCT02053493; INDIE-HFpEF, NCT02742129.

Background: Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension. Methods: Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise. Conclusions: When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02980887.

Background: Patients with vascular stiffening may display increased arterial afterload that is out of proportion to systolic blood pressure (SBP). Since vascular and endothelial dysfunction develop in patients with coarctation of aorta (COA), we hypothesized that for any SBP, patients with mild COA (COA peak velocity <2 m/s) will have a higher arterial afterload and increased left ventricular mass index (LVMI) compared with controls, and that Doppler-derived arterial load indices would be a better predictor of LVMI compared with SBP alone. Methods: We studied 204 COA patients (age 35±12 y) and 204 matched controls. Doppler-derived arterial afterload was assessed using effective arterial elastance index and total arterial compliance index. Results: Despite similar SBP, the mild COA group displayed higher arterial afterload as evidenced by a higher elastance index (3.3±0.9 versus 2.9±0.7 mm Hg/mL·m 2 ; P <0.001) and lower total arterial compliance index (0.8±0.3 versus 1.2±0.5 mL/mm Hg·m 2 ; P <0.001). This was associated with higher LVMI in COA (109±35 versus 93±32, g/m 2 ; P <0.001). Compared with SBP (β=0.24 [95% CI, 0.02–0.45]), elastance index (β=20.2 [95% CI, 15.8–44.1]) and total arterial compliance index (β=−32.5 [95% CI, −43.8 to −123.6]) were better predictors of LVMI. Elastance index (but not SBP) was predictive of longitudinal increases in LVMI ( r =0.43, P <0.001). Conclusions: COA patients had higher arterial afterload compared with controls with similar SBP. In comparison to SBP, Doppler-derived arterial load indices correlate more strongly with LV hypertrophy. These data suggest that SBP may underestimate LV afterload in this population. This has important clinical implications since titration of antihypertensive therapy is currently based on SBP.