Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure.

BACKGROUND: We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF). RESULTS: Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73-4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11-2.79) for VEGFR1; and HR 4.04 (95% CI 2.19-7.44) for HGF). CONCLUSIONS: Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.

Comparison of Hydralazine/Nitrate and Angiotensin Receptor Neprilysin Inhibitor Use Among Black Versus Nonblack Americans With Heart Failure and Reduced Ejection Fraction (from CHAMP-HF).

Underuse of hydralazine/nitrate (HYD/NIT) in black patients with heart failure and reduced ejection fraction (HFrEF) has been previously described, but whether this important treatment gap persists in contemporary practice is unknown. Sacubitril/valsartan has become a part of guideline-directed medical therapy for HFrEF but data on utilization of this therapy in black patients is lacking. This study addressed these issues by assessing the frequency of HYD/NIT and sacubitril/valsartan use in black patients with HFrEF in the Change the Management of Patients with Heart Failure Registry, a multicenter cohort study. The association of race with utilization rates of these agents was also evaluated. Clinical and medication data at baseline and during 12 months of follow-up from black and nonblack registry patients without documented contraindications or intolerance to the medications of interest were analyzed. Data were available from December 2015 to October 2017, in 4,848 HFrEF patients, of whom 853 were black (18%) and 3995 were nonblack. Black patients were younger, more likely to be female, and had lower ejection fractions compared with nonblacks. Only 11% of black patients were receiving HYD/NIT therapy at baseline and 13% at 1 year. The percentage of black patients treated at baseline with sacubitril/valsartan was also low at 18% and remained unchanged at 1 year. After adjustment for covariates, race was independently associated with HYD/NIT use (odds ratio 8.32; 95% confidence interval 6.12 to 11.3; p < 0.0001), but not for sacubitril/valsartan. In conclusion, study findings demonstrate a marked persistent treatment gap for HYD/NIT and similar poor utilization of sacubitril/valsartan in black patients with HFrEF despite current guideline recommendations.

Biomarker-guided therapies in heart failure: a forum for unified strategies.

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and meta-analyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union.

Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes.

OBJECTIVES: The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. BACKGROUND: Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. METHODS: The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. RESULTS: Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. CONCLUSIONS: Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.

Prospective evaluation of the association between cardiac troponin T and markers of disturbed erythropoiesis in patients with heart failure.

BACKGROUND: Elevated cardiac troponin T is a well-documented marker of cardiomyocyte damage and poor prognosis in patients with heart failure. We prospectively evaluated the relationship between this marker and hematopoietic disturbances in heart failure. METHODS: Data were analyzed from 254 patients in the UNITE-HF Biomarker Registry, a prospective, observational, multicenter study of the clinical and biomarker correlates of anemia in heart failure. Logistic regression modeling assessed relationships between detectable troponin T and indices of hematologic function including anemia and red cell distribution width. RESULTS: Anemia (hemoglobin≤12 g/dL) was present in 65 of the 254 study patients, and detectable troponin T was found in 39. Anemia was a significant independent predictor of detectable troponin T in models that considered a number of clinical characteristics including renal function, functional class, heart rate, and systolic blood pressure (odds ratio 2.57, 95% CI 1.09-6.09, P=.032). Likewise, detectable troponin T was directly and independently related to red cell distribution width in similar multivariable analyses (odds ratio 1.36 per unit increase, 95% CI 1.08-1.71, P=.008). CONCLUSIONS: Anemia and increasing red cell distribution width were independently associated with elevated troponin T, a marker of cardiomyocyte injury or death in patients with heart failure.