Serum Markers of Neurodegeneration Are Strongly Linked to Heart Failure Severity and Outcome.

BACKGROUND: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. OBJECTIVES: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aß40), and amyloid beta 42 (Aß42) in a large, well-characterized cohort. METHODS: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters. RESULTS: All markers, but not the Aß42:Aß40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aß40: 3.90 [95% CI: 2.27-6.72], and Aß42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aß40: 3.13 [95% CI: 1.84-5.34], and Aß42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aß40, Aß42, and the Aß42:Aß40 ratio were significantly lower (P < 0.05 for all). CONCLUSIONS: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function.

The best of both worlds? General principles of psychopathology in personalized assessment.

A complex systems approach to psychopathology proposes that general principles lie in the dynamic patterns of psychopathology, which are not restricted to specific psychological processes like symptoms or affect. Hence, it must be possible to find general change profiles in time series data of fully personalized questionnaires. In the current study, we examined general change profiles in personalized self-ratings and related these to four measures of treatment outcome (International Symptom Rating, 21-item Depression Anxiety and Stress Scale, daily symptom severity, and self-reflective capacity). We analyzed data of 404 patients with mood and/or anxiety disorders who completed daily self-ratings on personalized questionnaires during psychotherapy. For each patient, a principal component analysis was applied to the multivariate time series in order to retrieve an univariate person-specific time series. Then, using classification and regression methods, we examined these time series for the presence of general change profiles. The change profile classification yielded the following distribution of patients: no-shift (n = 55; 14%), gradual-change (n = 52; 13%), one-shift (n = 233; 58%), reversed-shift (n = 39; 10%) and multiple-shifts (n = 25; 6%). The multiple-shift group had better treatment outcome than the no-shift group on all outcome measures. The one-shift and gradual-change groups had better treatment outcome than the no-shift group on two and three outcome measures, respectively. Overall, this study illustrates that person-specific (idiographic) and general (nomothetic) aspects of psychopathology can be integrated in a complex systems approach to psychopathology, which may combine "the best of both worlds." (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Obesity in heart failure with preserved ejection fraction with and without diabetes: risk factor or innocent bystander?

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a condition that commonly coexists with type 2 diabetes mellitus (T2DM) and obesity. Whether the obesity-related survival benefit generally observed in HFpEF extends to individuals with concomitant T2DM is unclear. This study sought to examine the prognostic role of overweight and obesity in a large cohort of HFpEF with and without T2DM. METHODS AND RESULTS: This large-scale cohort study included patients with HFpEF enrolled between 2010 and 2020. The relationship between body mass index (BMI), T2DM, and survival was assessed. A total of 6744 individuals with HFpEF were included, of which 1702 (25%) had T2DM. Patients with T2DM had higher BMI values (29.4 kg/m2 vs. 27.1 kg/m2, P < 0.001), higher N-terminal pro-brain natriuretic peptide values (864 mg/dL vs. 724 mg/dL, P < 0.001), and a higher prevalence of numerous risk factors/comorbidities than those without T2DM. During a median follow-up time of 47 months (Q1-Q3: 20-80), 2014 (30%) patients died. Patients with T2DM had a higher incidence of fatal events compared with those without T2DM, with a mortality rate of 39.2% and 26.7%, respectively (P < 0.001). In the overall cohort, using the BMI category 22.5-24.9 kg/m2 as the reference group, the unadjusted hazard ratio (HR) for all-cause death was increased in patients with BMI <22.5 kg/m2 [HR: 1.27 (confidence interval 1.09-1.48), P = 0.003] and decreased in BMI categories ≥25 kg/m2. After multivariate adjustment, BMI remained significantly inversely associated with survival in non-T2DM, whereas survival was unaltered at a wide range of BMI in patients with T2DM. CONCLUSION: Among the various phenotypes of HFpEF, the T2DM phenotype is specifically associated with a greater disease burden. Higher BMI is linked to improved survival in HFpEF overall, while this effect neutralises in patients with concomitant T2DM. Advising BMI-based weight targets and weight loss may be pursued with different intensity in the management of HFpEF, particularly in the presence of T2DM.

Individuals with HFpEF and concomitant diabetes show a distinct phenotype particularly associated with a higher disease burden and worse outcome. The obesity paradox observed in individuals with heart failure may not be generalized to HFpEF patients with concomitant diabetes.

Contemporary insights into the epidemiology, impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum.

AIM: Tricuspid regurgitation secondary to heart failure (HF) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of secondary tricuspid regurgitation (sTR) across the entire HF spectrum are lacking, yet are necessary for healthcare decision-making. METHODS AND RESULTS: This population-based study included data from 13 469 patients with HF and sTR from the Viennese community over a 10-year period. The primary outcome was long-term mortality. Overall, HF with preserved ejection fraction was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with HF with reduced ejection fraction (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex- and age-matched community and independent of HF subtype (moderate sTR: hazard ratio [HR] 6.32, 95% confidence interval [CI] 5.88-6.80, p < 0.001; severe sTR: HR 9.04; 95% CI 8.27-9.87, p < 0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95% CI 1.48-1.69, p < 0.001) and for severe sTR (HR 2.19, 95% CI 2.01-2.38, p < 0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis, severe sTR mortality risk was more pronounced in younger patients (<70 years). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state-of-the-art facilities and universal health care. CONCLUSION: Secondary tricuspid regurgitation is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing, the data suggest a major burden for healthcare systems that needs to be adequately addressed. Low-risk transcatheter treatment options may provide a suitable alternative.

A streamlined, machine learning-derived approach to risk-stratification in heart failure patients with secondary tricuspid regurgitation.

AIMS: Secondary tricuspid regurgitation (sTR) is the most frequent valvular heart disease and has a significant impact on mortality. A high burden of comorbidities often worsens the already dismal prognosis of sTR, while tricuspid interventions remain underused and initiated too late. The aim was to examine the most powerful predictors of all-cause mortality in moderate and severe sTR using machine learning techniques and to provide a streamlined approach to risk-stratification using readily available clinical, echocardiographic and laboratory parameters. METHODS AND RESULTS: This large-scale, long-term observational study included 3359 moderate and 1509 severe sTR patients encompassing the entire heart failure spectrum (preserved, mid-range and reduced ejection fraction). A random survival forest was applied to investigate the most important predictors and group patients according to their number of adverse features.The identified predictors and thresholds, that were associated with significantly worse mortality were lower glomerular filtration rate (<60 mL/min/1.73m2), higher NT-proBNP, increased high sensitivity C-reactive protein, serum albumin < 40 g/L and hemoglobin < 13 g/dL. Additionally, grouping patients according to the number of adverse features yielded important prognostic information, as patients with 4 or 5 adverse features had a fourfold risk increase in moderate sTR [4.81(3.56-6.50) HR 95%CI, P < 0.001] and fivefold risk increase in severe sTR [5.33 (3.28-8.66) HR 95%CI, P < 0.001]. CONCLUSION: This study presents a streamlined, machine learning-derived and internally validated approach to risk-stratification in patients with moderate and severe sTR, that adds important prognostic information to aid clinical-decision-making.

Measuring patient centeredness with German language Patient-Reported Experience Measures (PREM)-A systematic review and qualitative analysis according to COSMIN.

BACKGROUND: Patient centeredness is an integral part of the quality of care. Patient-reported experience measures (PREMs) are assumed to be an appropriate tool to assess patient-centredness. An evaluation of German-speaking PREMs is lacking. OBJECTIVE: To perform a systematic review and qualitative analysis of psychometric measurement qualities of German-language PREMs using for the first time a comprehensive framework of patient centredness. METHODS: A systematic literature search was performed in Medline, PsycInfo, CINHAL, Embase, Cochrane database (last search 9th November 2021) for studies describing generic, surgery- or cancer care-specific PREMs. All questionnaires that were developed in or translated into German were included. The content of the included PREMs was evaluated using a comprehensive framework of patient centredness covering 16 domains. Baseline data of all PREM studies were extracted by two independent reviewers. Psychometric measurement qualities of the PREMs were assessed using current COSMIN guidelines. RESULTS: After removal of duplicates 3,457 abstracts were screened, of which 3,345 were excluded. The remaining 112 articles contained 51 PREMs, of which 12 were either developed in (4 PREMs) or translated into German (8 PREMs). Eight PREMs were generic (NORPEQ, PPE-15, PEACS, HCAHPS, QPPS, DUQUE, PEQ-G, Schoenfelder et al.), 4 cancer care-specific (EORTC IN-PATSAT32, PSCC-G, Danish National Cancer Questionnaire, SCCC) and none was surgery-specific. None of the PREMs covered all domains of patient-centeredness. Overall rating of structural validity was adequate only for PEACS and HCAHPS. High ratings for internal consistency were given for NORPEQ, Schoenfelder et al., PSCC-G and the SCCC. Cross-cultural validity for translated questionnaires was adequate only for the PSCC-G, while reliability was adequately assessed only for the EORTC IN-PATSAT32. Due to a lack of measurement gold standard and minimal important change, criterion validity and measurement invariance could not be assessed for any of the PREMs. CONCLUSION: This is the first systematic review using a comprehensive framework of patient centredness and shows that none of the included PREMs, even those translated from other languages into German, cover all aspects of patient centredness. Furthermore, all included PREMS show deficits in the results or evaluation of psychometric measurement properties. Nonetheless, based on the results, the EORTC IN-PATSAT32 and PSCC-G can be recommended for use in cancer patients in the German-language region, while the German versions of the HCAHPS, NORPEQ, PPE-15 and PEACS can be recommended as generic PREMs. TRIAL REGISTRATION: Registration. PROSPERO CRD42021276827.

Guideline directed medical therapy and reduction of secondary mitral regurgitation.

BACKGROUND: Guideline-directed medical therapy (GDMT) is the recommended initial treatment for secondary mitral regurgitation (SMR), however, supported by only little comprehensive evidence. This study, therefore, sought to assess the effect of GDMT titration on SMR and to identify specific substance combinations able to reduce SMR severity. METHODS AND RESULTS: We included 261 patients who completed two visits with an echocardiographic exam available within 1 month at each visit. After comprehensively defining GDMT titration as well as SMR reduction, logistic regression analysis was applied in order to assess the effects of overall GDMT titration and specific substance combinations on SMR severity. SMR severity improved by at least 1° in 39.3% of patients with subsequent titration of GDMT and was accompanied by reverse remodelling and clinical improvement. The effects of GDMT titration were significantly associated with SMR reduction (adj. odds ratio 2.91, 95% confidence interval 1.34-6.32, P = 0.007). Moreover, angiotensin receptor/neprilysin inhibitor (ARNi) as well as the combined dosage effects of (i) renin-angiotensin system inhibitors (RASi) and mineralocorticoid-receptor antagonists (MRA), (ii) beta-blockers (BB) and MRA, as well as (iii) RASi, BB, and MRA were all significantly associated with SMR improvement (P < 0.044 for all). CONCLUSION: The present study provides comprehensive evidence for the effectiveness of contemporary GDMT to specifically improve SMR. Our data indicate that GDMT titration conveys a three-fold increased chance of reducing SMR severity. Moreover, the dosage effects of ARNi, as well as the combination of RASi and MRA, BB and MRA, and all three substances in the aggregate are able to significantly improve SMR.

[Patient-centeredness]. / Patientenorientierung.

BACKGROUND: Patient-centeredness has developed into the guiding principle of healthcare policy over the last decade. However, its practical implementation is hindered by numerous problems and opposing interests. OBJECTIVE: To define and elucidate the term patient-centeredness, describe evidence-based measurement tools and outline recommendations for practical implementation. MATERIAL AND METHODS: A narrative literature review was carried out in Medline, Cochrane Library, PsyINfo and CINHAL. Based on the results the concept of Patient-Reported Experience Measures (PREM) is explained and a comprehensive PREM system is developed. RESULTS: Patient-centeredness is a not yet clearly defined theoretical construct. Patient-centeredness covers up to 16 different aspects ranging from patient involvement to the transition of care. Patient centeredness is most frequently measured via PREMs. Contrary to other countries, there are only a limited number of validated PREMs available in German and measurement qualities are frequently unclear or insufficient. No comprehensive PREM system has been developed for the German language so far. Important aspects of surgical care are not captured by currently available German language PREMs. CONCLUSION: Contrary to other countries no comprehensive PREM system is available in the German language. Currently available German PREMs do not enable the adequate assessment of surgical aspects of care. Important organizational, regulatory, methodological, and financial aspects must be addressed before patient-centeredness can be implemented into every clinical practice in German-speaking countries.

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.

Tailored Risk Stratification in Severe Mitral Regurgitation and Heart Failure Using Supervised Learning Techniques.

Background: Secondary mitral regurgitation (sMR) in the setting of heart failure (HF) has considerable impact on quality of life, HF rehospitalizations, and mortality. Identification of high-risk cohorts is essential to understand disease trajectories and for risk stratification. Objectives: This study aimed to provide a structured decision tree-like approach to risk stratification in patients with severe sMR and HF. Methods: This observational study included 1,317 patients with severe sMR from the entire HF spectrum. Clinical, echocardiographic, and laboratory data were extracted for all patients. The primary end point was all-cause mortality. Survival tree analysis, a supervised learning technique, was applied to identify patient subgroups at risk of mortality and further stratified by HF subtype (preserved, mildly reduced, and reduced ejection fraction). Results: Using supervised learning (survival tree method), 8 distinct subgroups were identified that differed significantly in long-term survival. Subgroup 7, characterized by younger age (≤66 years), higher hemoglobin (>12.7 g/dL), and higher albumin levels (>40.6 g/L) had the best survival. In contrast, subgroup 5 displayed a 20-fold risk of mortality (hazard ratio: 20.38 [95% CI: 10.78-38.52]); P < 0.001 and had older age (>68 years), low serum albumin (≤40.6 g/L), and higher NT-proBNP levels (≥9,750 pg/mL). Unique subgroups were further identified for each type of HF subtypes. Conclusions: Supervised machine learning reveals heterogeneity in the sMR risk spectrum, highlighting the clinical variability in the population. A decision tree-like model can help identify differences in outcomes among subgroups and can help provide tailored risk stratification.

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.

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.

Burden, treatment use, and outcome of secondary mitral regurgitation across the spectrum of heart failure: observational cohort study.

OBJECTIVES: To define prevalence, long term outcome, and treatment standards of secondary mitral regurgitation (sMR) across the heart failure spectrum. DESIGN: Large scale cohort study. SETTING: Observational cohort study with data from the Viennese community healthcare provider network between 2010 and 2020, Austria. PARTICIPANTS: 13 223 patients with sMR across all heart failure subtypes. MAIN OUTCOME MEASURES: Association between sMR and mortality in patients assigned by guideline diagnostic criteria to one of three heart failure subtypes: reduced, mid-range, and preserved ejection fraction, was assessed. RESULTS: Severe sMR was diagnosed in 1317 patients (10%), correlated with increasing age (P<0.001), occurred across the entire spectrum of heart failure, and was most common in 656 (25%) of 2619 patients with reduced ejection fraction. Mortality of patients with severe sMR was higher than expected for people of the same age and sex in the same community (hazard ratio 7.53; 95% confidence interval 6.83 to 8.30, P<0.001). In comparison with patients with heart failure and no/mild sMR, mortality increased stepwise with a hazard ratio of 1.29 (95% confidence interval 1.20 to 1.38, P<0.001) for moderate and 1.82 (1.64 to 2.02, P<0.001) for severe sMR. The association between severe sMR and excess mortality was consistent after multivariate adjustment and across all heart failure subgroups (mid-range ejection fraction: hazard ratio 2.53 (95% confidence interval 2.00 to 3.19, P<0.001), reduced ejection fraction: 1.70 (1.43 to 2.03, P<0.001), and preserved ejection fraction: 1.52 (1.25 to 1.85, P<0.001)). Despite available state-of-the-art healthcare, high volume heart failure, and valve disease programmes, severe sMR was rarely treated by surgical valve repair (7%) or replacement (5%); low risk transcatheter repair (4%) was similarly seldom used. CONCLUSION: Secondary mitral regurgitation is common overall, increasing with age and associated with excess mortality. The association with adverse outcome is significant across the entire heart failure spectrum but most pronounced in those with mid-range and reduced ejection fractions. Despite these poor outcomes, surgical valve repair or replacement are rarely performed; similarly, low risk transcatheter repair, specifically in the heart failure subsets with the highest expected benefit from treatment, is seldom used. The current data suggest an increasing demand for treatment, particularly in view of an expected increase in heart failure in an ageing population.

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

BACKGROUND: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy. OBJECTIVES: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy. METHODS: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients. RESULTS: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity. CONCLUSIONS: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

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.

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

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.

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.