Malnutrition outweighs the effect of the obesity paradox.

BACKGROUND: High body mass index (BMI) is paradoxically associated with better outcome in patients with heart failure (HF). The effects of malnutrition on this phenomenon across the whole spectrum of HF have not yet been studied. METHODS: In this observational study, patients were classified by guideline diagnostic criteria to one of three heart failure subtypes: reduced (HFrEF), mildy reduced (HFmrEF), and preserved ejection fraction (HFpEF). Data were retrieved from the Viennese-community healthcare provider network between 2010 and 2020. The relationship between BMI, nutritional status reflected by the prognostic nutritional index (PNI), and survival was assessed. Patients were classified by the presence (PNI < 45) or absence (PNI ≥ 45) of malnutrition. RESULTS: Of the 11 995 patients enrolled, 6916 (58%) were classified as HFpEF, 2809 (23%) HFmrEF, and 2270 HFrEF (19%). Median age was 70 years (IQR 61-77), and 67% of patients were men. During a median follow-up time of 44 months (IQR 19-76), 3718 (31%) of patients died. After adjustment for potential confounders, BMI per IQR increase was independently associated with better survival (adj. hazard ratio [HR]: 0.91 [CI 0.86-0.97], P = 0.005), this association remained significant after additional adjustment for HF type (adj. HR: 0.92 [CI 0.86-0.98], P = 0.011). PNI was available in 10 005 patients and lowest in HFrEF patients. PNI was independently associated with improved survival (adj. HR: 0.96 [CI 0.95-0.97], P < 0.001); additional adjustment for HF type yielded similar results (adj. HR: 0.96 [CI 0.96-0.97], P < 0.001). Although obese patients experienced a 30% risk reduction, malnutrition at least doubled the risk for death with 1.8- to 2.5-fold higher hazards for patients with poor nutritional status compared with normal weight well-nourished patients. CONCLUSIONS: The obesity paradox seems to be an inherent characteristic of HF regardless of phenotype and nutritional status. Yet malnutrition significantly changes trajectory of outcome with regard to BMI alone: obese patients with malnutrition have a considerably worse outcome compared with their well-nourished counterparts, outweighing protective effects of high BMI alone. In this context, routine recommendation towards weight loss in patients with obesity and HF should generally be made with caution and focus should be shifted on nutritional status.

Relevance of Neutrophil Neprilysin in Heart Failure.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls (p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity (p = 0.031) and correlated with neutrophil mNEP (p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both (p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (p interaction = 0.013) or PLR (p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.

Principal Morphomic and Functional Components of Secondary Mitral Regurgitation.

OBJECTIVES: The aim of this work was to identify the key morphological and functional features in secondary mitral regurgitation (sMR) and their prognostic impact on outcome. BACKGROUND: Secondary sMR in patients with heart failure and reduced ejection fraction typically results from distortion of the underlying cardiac architecture. The morphological components which may account for the clinical impact of sMR have not been systematically assessed or correlated with clinical outcomes. METHODS: Morphomic and functional network profiling were performed on a cohort of patients with stable heart failure optimized on guideline-based medical therapy. Principal component (PC) analysis and subsequent cluster analysis were used to condense the morphomic and functional data first into PCs with varimax rotation (PCVmax) and second into homogeneous clusters. Clusters and PCs were tested for their correlations with clinical outcomes. RESULTS: Morphomic and functional data from 383 patients were profiled and subsequently condensed into PCs. PCVmax 1 describes high loadings of left atrial morphological information, and PCVmax 2 describes high loadings of left ventricular (LV) topology. Based on these components, 4 homogeneous clusters were derived. sMR was most prominent in clusters 3 and 4, with the morphological difference being left ventricular size (median end-diastolic volume 188 mL [interquartile range: 160 mL-224 mL] vs 315 mL [264 mL-408 mL]; P < 0.001). Clusters were associated with mortality (P < 0.001), but sMR remained independently associated with mortality after adjusting for the clusters (adjusted HR: 1.42; 95% CI: 1.14-1.77; P < 0.01). The detrimental association of sMR with mortality was mainly driven by cluster 3 (HR: 2.18; 95% CI: 1.32-3.60; P = 0.002), the "small LV cavity" phenotype. CONCLUSIONS: These results challenge the current perceptions that sMR in heart failure with reduced ejection fraction results exclusively from global or local LV remodeling and are suggestive of a potential role of the left atrial component. The association of sMR with mortality cannot be purely attributed to cardiac morphology alone, supporting other complementary key aspects of mitral valve closure consistent with the force balance theory. Unsupervised clustering supports the association of sMR with mortality predominantly driven by the small LV cavity phenotype, as previously suggested by a conceptional framework and termed disproportionate sMR.

Neprilysin inhibition does not alter dynamic of proenkephalin-A 119-159 and pro-substance P in heart failure.

AIMS: As NEP degrades many substrates, the specific therapeutic mechanism of NEP inhibition with angiotensin receptor neprilysin inhibitor (ARNi) in heart failure with reduced ejection fraction (HFrEF) is not entirely evident. The aim of this study was to investigate the response of two substrates of NEP-the tachykinin and enkephalin systems-to the initiation of ARNi therapy in HFrEF. METHODS AND RESULTS: Between 2016 and 2018, 141 consecutive patients with stable HFrEF [74 with initiation of ARNi and 67 controls on continuous angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapy] were prospectively enrolled. Plasma proenkephalin-A 119-159 (PENK) and pro-substance P (pro-SP) were serially determined. Proenkephalin-A 119-159 and pro-SP correlated strongly with each other (rs  = 0.67, P < 0.001) and kidney function (rs  = -0.66, P < 0.001 and rs  = -0.54, P < 0.001) and modestly with NT-proBNP (rs  = 0.32, P < 0.001 and rs  = 0.24, P = 0.006, respectively). Concentrations of circulating PENK were slightly elevated after 1 and 2 year follow-up compared with baseline (BL) [BL median: 67.4 pmol/L (IQR: 57.3-89.8), 1 year: 83.5 pmol/L (IQR: 62.4-111.6), 2 years: 92.3 pmol/L (IQR: 63.1-101.9); BL vs. 1 year: P = 0.017 and BL vs. 2 years: P = 0.019] in the overall analysis, but lost significance at 2 year follow-up when assessed in paired subanalysis (P = 0.116). Plasma pro-SP levels remained comparable during the entire follow-up [BL median: 78.3 pmol/L (IQR: 67.9-90.6), 1 year: 75.9 pmol/L (IQR: 58.6-96.3), 2 years: 79.7 pmol/L (IQR: 59.9-105.3); P = ns for both timepoints]. Biomarker patterns of ARNi patients were independent from baseline therapy, that is, ACEi or ARB (P > 0.05 between groups). CONCLUSIONS: Although enkephalins and SP are known substrates of NEP, NEP inhibition by ARNi does not clearly affect the circulating precursors PENK and pro-SP in HFrEF.

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin-receptor/neprilysin-inhibitor treatment in chronic systolic heart failure.

AIMS: The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. METHODS: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. RESULTS: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition. CONCLUSION: The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.

Natural Course of Nonsevere Secondary Tricuspid Regurgitation.

BACKGROUND: Secondary tricuspid regurgitation (sTR) is frequent in patients with heart failure with reduced ejection fraction and is associated with adverse outcomes despite guideline-directed therapy. However, little is known about the natural course of nonsevere sTR and its relation to cardiac remodeling and outcomes. The aims of this study were therefore to investigate the natural course of sTR progression using quantitative measurements, to assess the prognostic impact on long-term mortality, and to identify risk factors associated with progressive sTR. METHODS: A total of 216 patients with heart failure with reduced ejection fraction receiving guideline-directed therapy were included in this long-term observational study. Progression of sTR was quantitatively defined as an increase of 0.2 cm2 in effective regurgitant orifice area or 15 mL in regurgitant volume, with transition to at least moderate sTR. Kaplan-Meier and Cox regression analyses were applied to assess survival during a 5-year follow-up period. RESULTS: Among patients with nonsevere sTR at baseline, 62 (29%) experienced sTR progression. Progressive sTR was accompanied by larger left and right atrial volumes (P = .02 and P < .02, respectively) and a higher prevalence of atrial fibrillation (P < .04). During a median follow-up period of 60 months (interquartile range, 37-60 months), 82 patients died. Progression of sTR conveyed a higher risk for long-term mortality (hazard ratio, 1.77; 95% CI, 1.1-2.83; P < .02), even after multivariate adjustment for bootstrap-selected (adjusted hazard ratio, 1.70; 95% CI, 1.06-2.74; P < .03) and clinical confounder (adjusted hazard ratio, 1.80; 95% CI, 1.07-3.05; P < .03) models. CONCLUSIONS: The incidence of progressive sTR despite guideline-directed therapy is associated with adverse cardiac and valvular remodeling as well as a significantly higher long-term mortality. Biatrial enlargement as well as atrial fibrillation are associated with the development of subsequent progressive sTR and may help identify patients at risk for sTR progression, potentially creating a window of opportunity for closer follow-up and newly arising minimally invasive transcatheter repair therapies.

Plasma Neprilysin Displays No Relevant Association With Neurohumoral Activation in Chronic HFrEF.

Background Neprilysin is a transmembrane endopeptidase involved in the breakdown of a variety of vasoactive peptides and serves as a therapeutic target in heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate the relationship of circulating neprilysin with neurohumoral activation and the impact of plasma neprilysin activity on prognosis in HFrEF. Methods and Results A total of 369 chronic HFrEF patients were enrolled prospectively. Plasma neprilysin concentration and activity were determined by a specific ELISA and a fluorometric method. The association between plasma neprilysin and heart failure (HF) severity, neurohumoral activation, ie norepinephrine and absolute renin concentration, as well as all-cause mortality was assessed. Median plasma neprilysin concentrations and activity levels were 413 pg/mL (interquartile range 0-4111) and 2.36 nmol/mL per minute (interquartile range 1.16-4.59). No correlation could be shown between plasma neprilysin concentrations and activity (rs=0.09, P=0.088). Plasma neprilysin activity correlated with HF severity reflected by New York Heart Association stage (P=0.003) and tertiles of N-terminal pro-B-type natriuretic peptide (P<0.001), whereas neprilysin concentrations did not (P=0.220; P=0.849). There was no relevant relationship between plasma neprilysin concentrations and activity, with neurohumoral activation reflected by absolute renin concentration (rs=-0.02, P=0.648; rs=0.03, P=0.574) or norepinephrine levels (rs=-0.06, P=0.248; rs=0.20, P<0.001). Neither circulating neprilysin concentrations nor activity were associated with outcome. Conclusions Plasma neprilysin concentrations and activity are not directly related to neurohumoral activation, indicating that neprilysin regulation is either more complex or not correctly mirrored by circulating neprilysin as a biomarker. Circulating neprilysin concentrations and activity were not associated with overall survival, implicating limited prognostic value of plasma neprilysin measurements in HFrEF patients.

Increased resting heart rate and prognosis in treatment-naïve unselected cancer patients: results from a prospective observational study.

AIMS: Cancer patients suffer from impaired cardiovascular function. Elevated resting heart rate (RHR) has been identified as a marker for increased long-term mortality in cancer patients prior to the receipt of anticancer treatment. We aimed to establish whether RHR is associated with survival in treatment-naïve cancer patients. METHODS AND RESULTS: This prospective study enrolled 548 unselected treatment-naïve cancer patients between 2011 and 2013. The median age of the cohort was 62 years; 40.9% were male and 32.7% had metastatic disease. Median RHR was 72 b.p.m. Most patients were in sinus rhythm (n = 507, 92.5%). Clinical heart failure was noted in 37 (6.8%) patients. RHR was not related to cancer stage (P = 0.504). Patients in the highest RHR tertile had higher levels of high-sensitivity troponin (P = 0.003) and N-terminal pro-B-type natriuretic peptide (P = 0.039). During a median follow-up of 25 months (interquartile range: 16-32 months; range: 0-40 months), 185 (33.8%) patients died from any cause [1-year-mortality: 17%, 95% confidence interval (CI) 13-20%]. In univariate survival analysis, RHR predicted all-cause mortality [crude hazard ratio (HR) for a 5 b.p.m. increase in RHR: 1.09, 95% CI 1.04-1.15; P < 0.001], and remained significantly associated with outcome after adjustment for age, gender, tumour entity, tumour stage, cardiac status and haemoglobin (adjusted HR for a 5 b.p.m. increase in RHR: 1.10, 95% CI 1.04-1.16; P < 0.001). There was no significant impact of metastatic/non-metastatic disease state on the predictive value of RHR (P = 0.433 for interaction). In subgroup analyses, the strongest associations for RHR with mortality were observed in lung (crude HR 1.14; P = 0.007) and gastrointestinal (crude HR 1.31; P < 0.001) cancer. CONCLUSIONS: Treatment-naïve cancer patients with higher RHRs display higher levels of cardiovascular biomarkers. RHR was independently associated with all-cause mortality, especially in lung and gastrointestinal cancers. Elevated RHR and cardiovascular biomarkers may represent early signs of incipient cardiac dysfunction.