Heart Failure Risk Assessment Research Articles

Defining and Refining Heart Failure Risk Stratification to Optimize Patient Selection for Cardiac Transplantation

VO2, BNP, GFR, RAP, CI, LVEDP, EF, Na, BUN, MR, LVEDD, PCWP, PVCs, VT, QRS, LBBB, COPD, DM, TpnI, alb, CAD, OSA, Hct, RDW, CRT, ICD, HRV—the complex alphabet soup of heart failure risk assessment used to inform clinical decision making, select patient cohorts for trials, and ensure that expensive and supply-limited treatments are utilized in the most effective and equitable manner. Despite the seeming complexity of this task, heart failure clinicians have become facile at integrating multiple distinct variables into a cohesive understanding of risk using baseline patient characteristics, measures of cardiac structure and function, biomarkers, and assessment of functional capacity. The prognostic significance of many risk-associated parameters, such as ejection fraction, ventricular size, and the pathogenesis of heart failure are firmly established. However, recognition of the importance of common comorbidities and the rapidly evolving field of novel biomarkers that represent perturbation of normal biological pathways or markers of early organ damage have reshaped and refined contemporary risk assessment. More recently, larger datasets have facilitated the derivation and validation of multivariable risk-prediction models, such as the Heart Failure Survival Score, the Seattle Heart Failure Model, and the ESCAPE Risk Score.1–3 Article see p 6 In this issue of Circulation: Heart Failure , Kato et al4 re-examine the pivotal role of cardiopulmonary exercise testing in heart failure risk assessment and extend the sentinel work by Mancini that validated VO2 as a potent predictor of short- and intermediate-term mortality.5 Mancini’s original observation that a peak VO2 <14 mL/kg per min was associated with excessive morality led to its …

Abstract 18278: The Prognostic Value Of WFDC2, a New Biomarker for Heart Failure

Aim s: Identification of plasma biomarkers that help to stratify heart failure (HF) patients may help to improve treatment. We investigated the prognostic value of WAP four-disulfide core domain protein 2 (WFDC2, also termed HE4), a biomarker not previously described in HF. Methods: Data of 567 patients participating in the Coordinating study evaluating outcomes of Advising and Counselling in Heart failure (COACH) study were analysed. Patients had been hospitalized for HF and were followed for 18 months. Several plasma biomarker levels were determined using an ELISA platform. The primary endpoint of this study was a composite of all-cause mortality and HF hospitalization. Results: Mean age was 71±11 years, 62% were males, mean LVEF was 33±14%, and mean eGFR was 54±20 mL/minute. WFDC2 was identified as a biomarker that showed strong correlation with HF severity, according to NYHA functional class and BNP levels ( P &lt; 0.001). WFDC2 also showed a strong positive correlation with GDF15 ( P &lt;0.001). In addition, WFDC2 levels correlated with kidney function (BUN, creatinine, and eGFR; all P &lt;0.001). Cox regression analysis revealed that a doubling of WFDC2 levels was associated with a hazard ratio (HR) of 1.73 (1.53-1.95) for the primary outcome ( P &lt;0.001). After correction for age, gender, BNP and eGFR the HR was 1.46 (1.23-1.72) ( P &lt;0.001) and after additional adjustment for GDF15 the HR lowered to 1.30 (1.07-1.59) ( P =0.009). The AUC in the ROC curve analysis increased from 0.7123 to 0.7375 when WFDC2 was included to the clinical model ( P =0.068). The IDI and NRI metrics for reclassification showed highly significant improvements when WFDC2 was added to the clinical model (NRI=0.12, P &lt;0.001) and this remained significant after inclusion of BNP to this model. Conclusion: WFDC2 plasma levels are correlated with markers of HF severity, show prognostic value, and improve risk assessment in HF.

Cardiopulmonary exercise testing and prognosis in heart failure due to systolic left ventricular dysfunction: a validation study of the European Society of Cardiology Guidelines and Recommendations (2008) and further developments

The study aims were to validate the cardiopulmonary exercise testing (CPET) parameters recommended by the European Society of Cardiology 2008 Guidelines for risk assessment in heart failure (HF) (ESC-predictors) and to verify the predictive role of 11 supplementary CPET (S-predictors) parameters. We followed 749 HF patients for cardiovascular death and urgent heart transplantation for 3 years: 139 (19%) patients had cardiac events. ESC-predictors - peak oxygen consumption (VO(2)), slope of minute ventilation vs carbon dioxide production (VE/VCO(2)) and exertional oscillatory ventilation - were all related to outcome at univariate and multivariable analysis. The ESC/2008 prototype based on ESC-predictors presented a Harrell's C concordance index of 0.725, with a likely χ2 of 98.31. S-predictors - predicted peak VO(2), peak oxygen pulse, peak respiratory exchange ratio, peak circulatory power, peak VE/VCO(2), VE/VCO(2) slope normalized by peak VO(2), VO(2) efficiency slope, ventilatory anaerobic threshold detection, peak end-tidal CO(2) partial pressure, peak heart rate, and peak systolic arterial blood pressure (SBP) - were all linked to outcome at univariate analysis. When individually added to the ESC/2008 prototype, only peak SBP and peak O(2) pulse significantly improved the model discrimination ability: the ESC + peak SBP prototype had a Harrell's C index 0.750 and reached the highest likely χ2 (127.16, p < 0.0001). We evaluated the longest list of CPET prognostic parameters yet studied in HF: ESC-predictors were independent predictors of cardiovascular events, and the ESC prototype showed a convincing predictive capacity, whereas none of 11 S-predictors enhanced the prognostic performance, except peak SBP.

Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure: Results From the A-HeFT Trial

Background Genetic heterogeneity at the endothelial nitric oxide synthase (NOS3) locus influences heart failure outcomes. The prevalence of NOS3 variants differs in black and white cohorts, but the impact of these differences is unknown. Methods and Results Subjects (n = 352) in the Genetic Risk Assessment of Heart Failure (GRAHF) substudy of the African-American Heart Failure Trial were genotyped for NOS3 polymorphisms: –786 T/C promoter, intron 4a/4b, and Glu298Asp and allele frequencies and compared with a white heart failure cohort. The effect of treatment with fixed-dose combination of isosorbide dinitrates and hydralazine (FDC I/H) on event-free survival and composite score (CS) of survival, hospitalization, and quality of life (QoL) was analyzed within genotype subsets. In GRAHF, NOS3 genotype frequencies differed from the white cohort ( P < .001). The –786 T allele was associated with lower left ventricular ejection fraction (LVEF) ( P = .01), whereas the intron 4a allele was linked to lower diastolic blood pressure and higher LVEF ( P = .03). Only the Glu298Asp polymorphism influenced treatment outcome; therapy with FDC I/H improved CS ( P = .046) and QoL ( P = .03) in the Glu298Glu subset only. Conclusions In black subjects with heart failure, NOS3 genotype influences blood pressure and left ventricular remodeling. The impact of genetic heterogeneity on treatment with FDC I/H requires further study.

Prognostic Import of the Corin I555(P568) Allele in African-Americans with Moderate to Severe Heart Failure: Results from the A-HefT Trial

Background: Corin processes pro-ANP/BNP into biologically active peptides. The corin gene contains two SNPs in complete linkage disequilibrium (T555I and Q568P) defining the minor corin I555(P568) allele. This allele is exclusive to African-Americans and associated with risk for hypertension and LVH. This study determined the prognostic import of the corin I555(P568) allele in African-Americans with systolic heart failure. Methods: We studied 354 subjects in the African-America Heart Failure Trial (A-HeFT) enrolled in GRAHF, the Genetic Risk Assessment in Heart Failure.

Aldosterone Synthase Promoter Polymorphism Predicts Outcome in African Americans With Heart Failure: Results From the A-HeFT Trial

We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT). Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however, little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele, associated with higher aldosterone synthase activity, has been linked to hypertension; however, its impact on outcomes in HF is unknown. A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively, and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype. Of the cohort, 218 patients were TT, 114 CT, and 22 patients were CC. Baseline etiology, blood pressure, and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects, intermediate for heterozygotes, and the poorest for CC homozygotes (p = 0.018), and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2, p = 0.001). The TT genotype, more prevalent in blacks, was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01). The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.

P.6.053 Prevalence of depression in diabetic adultswith metabolic syndrome

The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins (G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial).GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans.A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were assessed in GNB3 genotype subsets.The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 ± 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 ± 0.06. For GNB3 genotype, 184 subjects were TT (53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H = 0.50 ± 1.6; placebo = −0.11 ± 1.8, p = 0.02), QoL (FDC I/H = 0.69 ± 1.4; placebo = 0.24 ± 1.5, p = 0.04), and event-free survival (hazard ratio: 0.51, p = 0.047), but not in subjects with the C allele (for CS, FDC I/H = −0.05 ± 1.7; placebo = −0.09 ± 1.7, p = 0.87; for QoL, FDC I/H = 0.28 ± 1.5; placebo = 0.14 ± 1.5, p = 0.56; and for event-free survival, p = 0.35).The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role of the GNB3 genotype for targeting therapy with FDC I/H deserves further study.