Distinguishing heart failure with reduced ejection fraction from heart failure with preserved ejection fraction: A phenomics approach.

AIM: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. METHODS AND RESULTS: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60-71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function. CONCLUSION: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.

Clinical characteristics and prognosis of patients with heart failure and high concentrations of interleukin-17D.

AIMS: Heart failure (HF) is associated with cytokine activation and inflammation. Experimental evidence suggests that plasma interleukin-17 (IL-17) is associated with myocardial fibrosis and cardiac dysfunction in HF. IL-17D, a subtype of IL-17 originates from particular tissues such as the heart. However, there is very limited data on the IL-17 cytokine family in patients with HF. Therefore, we investigated the association between circulating IL-17D levels, clinical characteristics and outcome in a large cohort of patients with heart failure. METHODS AND RESULTS: Plasma IL-17D was measured in 2032 patients with HF from 11 European countries using a proximity extension assay. The primary outcome was a composite of HF hospitalization or all-cause mortality. Patients with higher plasma IL-17D concentrations were more likely to have atrial fibrillation (AF), renal dysfunction and heart failure with preserved ejection fraction (HFpEF) and had higher plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations (all p < 0.001). IL-17D was not associated with interleukin-6 (IL-6) or C-reactive protein (CRP) concentrations. After adjustment for confounders in a multivariable Cox regression analysis, patients in the highest quartile of plasma IL-17D had a significantly increased risk of the composite outcome of HF hospitalization or all-cause mortality compared to patients in the lowest quartile [Hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.05-1.57]. CONCLUSION: In patients with HF, elevated plasma IL-17D concentrations are associated with higher plasma NT-proBNP concentrations and a higher prevalence of AF and renal dysfunction. High IL-17D concentrations are independently associated with worse outcome.

Biomarker signature and pathophysiological pathways in patients with chronic heart failure and metabolic syndrome.

AIM: The comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure. METHODS AND RESULTS: In 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468 [42%]) and without (n = 635 [58%]) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of three or more of five criteria, including central obesity, elevated serum triglycerides, reduced high-density lipoprotein cholesterol, insulin resistance and hypertension. The most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92, p = 5.85 × 10-21 ), fatty acid-binding protein 4 (log2 fold change 0.61, p = 1.21 × 10-11 ), interleukin-1 receptor antagonist (log2 fold change 0.47, p = 1.95 × 10-13 ), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35, p = 4.16 × 10-9 ), and proto-oncogene tyrosine-protein kinase receptor Ret (log2 fold change 0.31, p = 4.87 × 10-9 ). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohorts was up-regulation of the natural killer cell-mediated cytotoxicity pathway. CONCLUSION: Metabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation.

Albuminuria as a marker of systemic congestion in patients with heart failure.

AIMS: Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated. METHODS AND RESULTS: Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumincreatinine ratio (UACR) 30 mg/gCr and 300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4 and 10.0, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95 confidence interval 0.350.53, P 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings. CONCLUSION: In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.

Characteristics and clinical outcomes of patients with acute heart failure with a supranormal left ventricular ejection fraction.

AIM: Recent data suggest that guideline-directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a left ventricular ejection fraction (LVEF) of 55-65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U-shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients. METHODS AND RESULTS: RELAX-AHF-2 was a multicentre, placebo-controlled trial on the effects of serelaxin on 180-day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50-65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non-ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta-blockers and had higher blood urea nitrogen plasma levels. All-cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180-day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non-CV causes. No treatment effect of serelaxin was observed in any of the subgroups. CONCLUSIONS: In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non-CV death.

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence.

AIMS: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. METHODS AND RESULTS: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25-2.46; HR 1.71, 95% CI 1.39-2.11; and HR 1.44, 95% CI 1.23-1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. CONCLUSIONS: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

Heart failure with normal LVEF in BIOSTAT-CHF.

AIMS: Several studies have shown that heart failure (HF) drug treatment seems to benefit patients with preserved ejection fraction (HFpEF) and a left ventricular ejection fraction (LVEF) up to 55-60% but not with higher LVEF. Certain HF drugs are now indicated in patients with HFpEF and a LVEF below normal. However, not much is known about patients with a normal LVEF. Therefore, we investigated the prevalence, clinical characteristics and outcome of patients with HF and a normal LVEF. METHODS AND RESULTS: Normal LVEF was defined according to the Recommendations for Cardiac Chamber Quantification from the American Society of Echocardiography as a LVEF ≥62% for men and ≥ 64% for women. Preserved ejection fraction was defined as a LVEF ≥50% and reduced ejection fraction as a LVEF <50%. In the total cohort of 1568 studied patients with heart failure (mean age 73 years; 33.6% female) 57 patients (3.6%) had a normal LVEF. These patients least likely had a previous myocardial infarction (p < 0.001) or diabetes (p = 0.045), had the lowest Left Ventricular End Diastolic Diameter (p < 0.001), the highest rate of previous HF hospitalization in the last year (p = 0.015), the highest cardiac output (p < 0.001) and were most frequently women (p < 0.001). Patients with a normal LVEF had the lowest risk for the primary combined outcome of all-cause mortality and HF hospitalization. CONCLUSION: Only 3.6% of patients with HF had a sex-adjusted normal LVEF. Despite the sex-adjusted cut-offs they were more frequently female with less ischemic heart disease, higher cardiac output and better clinical outcomes.