Perspectives on weight control in diabetes - Tirzepatide.

Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist (GIP/GLP-1 RA) improves glycemic control. Besides improvement of glycemic control, tirzepatide treatment is associated with significantly more weight loss as compared to potent selective GLP-1 receptor agonists as well as other beneficial changes in cardio-metabolic parameters, such as reduced fat mass, blood pressure, improved insulin sensitivity, lipoprotein concentrations, and circulating metabolic profile in individuals with type 2 diabetes (T2D). Some of these changes are partially associated with weight reduction. We review here the putative mechanisms of GIP receptor agonism contributing to GLP-1 receptor agonism-induced weight loss and respective findings with GIP/GLP-1 RAs, including tirzepatide in T2D preclinical models and clinical studies. Subsequently, we summarize the clinical data on weight loss and related non-glycemic metabolic changes of tirzepatide in T2D. These findings suggest that the robust weight loss and associated changes are important contributors to the clinical profile of tirzepatide for the treatment of T2D diabetes and serve as the basis for further investigations including clinical outcomes.

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.

Soluble neprilysin and survival in critically ill patients.

BACKGROUND: Critically ill patients admitted to an intensive care unit (ICU) exhibit a high mortality rate irrespective of the initial cause of hospitalization. Neprilysin, a neutral endopeptidase degrading an array of vasoactive peptides became a drug target within the treatment of heart failure with reduced ejection fraction. The aim of this study was to analyse whether circulating levels of neprilysin at ICU admission are associated with 30 day mortality. METHODS AND RESULTS: In this single-centre prospective observational study, 222 consecutive patients admitted to a tertiary ICU at a university hospital were included. Blood was drawn at admission and soluble neprilysin levels were measured using ELISA. In the total cohort, soluble neprilysin levels did not differ according to survival status after 30 days as well as type of admission. However, in patients after surgery or heart valve intervention, 30 day survivors exhibited significantly lower circulating neprilysin levels as compared to those who died within 30 days (660.2, IQR: 156.4-2512.5 pg/mL vs. 6532.6, IQR: 1840.1-10 000.0 pg/mL; P = 0.02). Soluble neprilysin predicted mortality independently from age, gender, and commonly used scores of risk-prediction (EuroSCORE II, STS-score, and SAPS II score). Additionally, soluble neprilysin was markedly elevated in patients with sepsis and septic shock (P < 0.05). CONCLUSION: At the time of ICU admission, circulating levels of neprilysin independently predicted 30 day mortality in patients following cardiac surgery or heart valve intervention, but not in critically ill medical patients. Furthermore, patients suffering from sepsis and septic shock displayed significantly increased circulating neprilysin levels.

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.

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.

Sacubitril/valsartan is well tolerated in patients with longstanding heart failure and history of cancer and improves ventricular function: real-world data.

BACKGROUND: Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in patients with reduced ejection fraction (HFrEF) when compared to enalapril. Data about sacubitril/valsartan in patients with a history of cancer are scarce, as these patients were excluded from the pivotal trial, PARADIGM-HF. The aim of the current study was to assess tolerability of sacubitril/valsartan in patients with a history of cancer. METHODS: We identified 225 patients at our heart failure out-patient unit who fulfilled the indication criteria to receive sacubitril/valsartan. Out of these, 9.3% (n = 21) had a history of histologically confirmed cancer. Oncologic surgery was performed in 16 (76.2%) patients, 11 (52.4%) patients received previous antineoplastic therapy and 9 patients (42.9%) radiation. RESULTS: Sacubitril/valsartan was withdrawn in 3 of 21 patients (14.3%) because of dizziness (n = 2) or pruritus (n = 1). After a median follow-up of 12 months (range 1-34 months), NYHA functional class improved significantly from NYHA 3 to NYHA 2 (mean -0.6, p = 0.006) and left ventricular ejection fraction as assessed by echocardiography increased significantly from 26.8 ± 5.4% to 39.2 ± 10% (mean + 12%, CI 95% [8.4-16.4], p = 0.0004). NT-proBNP was significantly reduced (baseline median 2774 pg/ml, range 1441 - 12,982 vs follow-up 1266 pg/ml, range 199-6324, p = 0.009). There was no significant change in creatinine levels (1.18 ± 0.4 vs 1.22 ± 0.4 mg/dl; mean + 0.005 mg/dl, CI 95% [-0.21- 0.12], p = 0.566). CONCLUSIONS: In our pilot study we show that sacubitril/valsartan is generally well tolerated in patients with HFrEF and history of cancer. Importantly, even patients with long-standing cardiotoxicity induced heart failure can be treated and up-titrated with sacubitril/valsartan to usual target dosages, leading to improvement in LV function and biomarkers. Larger studies are needed to confirm these findings in cancer patients with cardiotoxicity.

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.

The clinical relevance of laboratory prognostic scores for patients with radiosurgically treated brain metastases of non-pulmonary primary tumor.

PURPOSE: To investigate the clinical value of the inflammation based prognostic scores for patients with radiosurgically treated brain metastases (BM) originating from non-pulmonary primary tumor (PT). METHODS: A retrospective analysis of 340 BM patients of different PT origin (melanoma, breast, gastrointestinal, or genitourinary cancer) was performed. Pre-radiosurgical laboratory prognostic scores, such as the Neutrophil-to-Lymphocyte Ratio (NLR), the Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), and the modified Glasgow Prognostic Score (mGPS), were investigated within 14 days before the first Gamma Knife radiosurgical treatment (GKRS1). RESULTS: In our study cohort, the estimated survival was significantly longer in patients with NLR < 5 (p < 0.001), LMR > 4 (p = 0.001) and in patients with a mGPS score of 0 (p < 0.001). Furthermore, univariate and multivariate Cox regression models revealed NLR ≥ 5, LMR < 4 and mGPS score ≥ 1 as independent prognostic factors for an increased risk of death even after adjusting for age, sex, KPS, extracranial metastases status, presence of neurological symptoms and treatment with immunotherapy (IT) or targeted therapy (TT). CONCLUSIONS: Summarizing previously published and present data, pre-radiosurgical mGPS and NLR groups seem to be the most effective and simple independent prognostic factors to predict clinical outcome in radiosurgically treated BM patients.

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.

Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro.

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

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.

Large Animal Models of Cell-Free Cardiac Regeneration.

The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that can induce the heart to repair itself through cardiomyocyte proliferation, angiogenesis, and advantageous remodeling. Large animal models are an invaluable step toward translating basic research into clinical applications. In this review, we give an overview of the state-of-the-art in cell-free cardiac regeneration therapies that have been tested in large animal models, mainly pigs. Cell-free cardiac regeneration therapies involve stem cell secretome- and extracellular vesicles (including exosomes)-induced cardiac repair, RNA-based therapies, mainly regarding microRNAs, but also modified mRNA (modRNA) as well as other molecules including growth factors and extracellular matrix components. Various methods for the delivery of regenerative substances are used, including adenoviral vectors (AAVs), microencapsulation, and microparticles. Physical stimulation methods and direct cardiac reprogramming approaches are also discussed.

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.

The inflammation-based modified Glasgow prognostic score is associated with survival in stable heart failure patients.

AIMS: The progression of heart failure is presumably dependent on the individual inflammatory host response. The combination of the inflammatory markers, albumin, and C-reactive protein, termed modified Glasgow prognostic score (mGPS), has been derived from cancer patients and validated in multiple cohorts. This study aimed to investigate the impact of the easily available mGPS on survival of stable patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with stable HFrEF undergoing routine ambulatory care between January 2011 and November 2017 have been identified from a prospective registry at the Medical University of Vienna. Comorbidities, laboratory data as well as the nutritional risk index at baseline were assessed. All-cause mortality was defined as the primary study end point. The mGPS was calculated, and its association with heart failure severity and impact on overall survival were determined. Data were analysed for a total of 443 patients. The mGPS was 0 for 352 (80%), 1 for 76 (17%), and 2 for 14 (3%) patients, respectively. Elevation of mGPS was associated with worsening of routine laboratory parameters linked to prognosis, especially NT-proBNP [median 1830 pg/mL (IQR 764-3455) vs. 4484 pg/mL (IQR 1565-8003) vs. 6343 pg/mL (IQR 3750-15401) for mGPS 0, 1, and 2, respectively; P < 0.001] and nutritional risk index. In the Cox regression analysis, the increase of mGPS was associated with adverse outcome in the univariate analysis [crude hazard ratio 3.00 (95% CI 2.14-4.21), P < 0.001] and after adjustment for multiple covariates as age, gender, body mass index, and glomerular filtration rate as well as heart failure severity reflected by NT-proBNP and New York Heart Association class [adj. hazard ratio 1.87 (95% CI 1.19-2.93), P = 0.006]. CONCLUSIONS: Enhanced inflammation and nutritional depletion are more common in advanced heart failure. The inflammation-based score mGPS predicts survival in HFrEF patients independently of NT-proBNP emphasizing the significance of the individual pro-inflammatory response on prognosis.

Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance.

AIMS: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. METHODS AND RESULTS: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. CONCLUSIONS: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

A Unifying Concept for the Quantitative Assessment of Secondary Mitral Regurgitation.

BACKGROUND: Diverging guideline definitions for the quantitative assessment of severe secondary mitral regurgitation (sMR) reflect the lacking link of the sMR spectrum to mortality and has introduced a source of uncertainty and continuing debate. OBJECTIVES: The current study aimed to define improved risk-thresholds specifically tailored to the complex nature of sMR that provide a unifying solution to the ongoing guideline-controversy. METHODS: This study enrolled 423 heart failure patients under guideline-directed medical therapy and assessed sMR by effective regurgitant orifice area (EROA), regurgitant volume (RegVol), and regurgitant fraction (RegFrac). RESULTS: Measures of sMR severity were consistently associated with 5-year mortality with a hazard ratio of 1.42 for a 1-SD increase (95% confidence interval [CI]: 1.25 to 1.63; p < 0.001) for EROA, 1.37 (95% CI: 1.20 to 1.56; p < 0.001) for RegVol, and 1.50 (95% CI: 1.30 to 1.73; p < 0.001) for RegFrac. Results remained statistically significant after bootstrap- or clinical confounder-based adjustment. Spline-curve analyses showed a linearly increasing risk enabling the ability to stratify into low-risk (EROA <20 mm2 and RegVol <30 ml), intermediate-risk (EROA 20 to 29 mm2 and RegVol 30 to 44 ml), and high-risk (EROA ≥30 mm2 and RegVol ≥45 ml) groups. In the intermediate-risk group, a RegFrac ≥50% as indicator for hemodynamic severe sMR was associated with poor outcome (p = 0.017). A unifying concept based on combined assessment of the EROA, the RegVol, and the RegFrac showed a significantly better discrimination compared with the currently established algorithms. CONCLUSIONS: Risk-based thresholds tailored to the pathophysiological concept of sMR provide a unifying solution to the ongoing guideline controversy. An algorithm based on the combined assessment of the unifying cutoffs for EROA, RegVol, and RegFrac improves risk prediction compared with currently established grading.