Coping styles as predictors for quality of life and prognosis in patients at risk for or with a diagnosis of heart failure: Results from the observational DIAST-CHF study.

OBJECTIVE: Patients with heart failure often experience impaired health-related quality of life (HRQOL) and have an increased risk of cardiovascular and cerebrovascular events. The aim of this study was to investigate the predictive role of different coping styles on outcome. METHODS: This longitudinal study included 1536 participants who either had cardiovascular risk factors or were diagnosed with heart failure. Follow-ups took place one, two, five and ten years after recruitment. Coping and HRQOL were investigated using self-assessment questionnaires (Freiburg Questionnaire for Coping with Illness, Short Form-36 Health Survey). Somatic outcome was quantified by incidence of major adverse cardiac and cerebrovascular events (MACCE) and 6-min-walking-distance. RESULTS: Pearson correlation and multiple linear regression analysis showed significant associations between the coping styles used at the first three time points and HRQOL after five years. After adjusting for baseline HRQOL, minimization and wishful thinking predicted worse mental HRQOL (ß = -0.106; p = 0.006), while depressive coping predicted worse mental (ß = -0.197; p < 0.001) and physical HRQOL (ß = -0.085; p = 0.03; n = 613). Active problem-oriented coping could not significantly predict HRQOL. Only minimization and wishful thinking was significantly associated with an increased 10-year-risk for MACCE (hazard ratio = 1.06; 95% confidence interval: 1.01-1.11; p = 0.02; n = 1444) and reduction in 6-min-walking-distance at 5 years (ß = -0.119; p = 0.004; n = 817) in adjusted analyses. CONCLUSIONS: Depressive coping and minimization and wishful thinking were associated with worse quality of life in patients at risk for or with diagnosed heart failure. Minimization and wishful thinking also predicted worse somatic outcome. Therefore, patients using those coping styles might benefit from early psychosocial interventions.

Biomarker profiles in heart failure with preserved vs. reduced ejection fraction: results from the DIAST-CHF study.

AIMS: Chronic heart failure (HF) is a common disease and one of the leading causes of death worldwide. Heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF) are different diseases with distinct as well as comparable pathophysiologies and diverse responses to therapeutic agents. We aimed to identify possible pathobiochemical signalling pathways and biomarkers in HFpEF and HFrEF by using a broad proteomic approach. METHODS AND RESULTS: A total of 180 biomarkers in the plasma of a representative subgroup (71 years old) of HFpEF (70% female) with a left ventricular ejection fraction (LVEF) ≥ 50% and HFrEF (18% female) with an LVEF ≤ 40% patients (n = 127) from the Prevalence and Clinical Course of Diastolic Dysfunction and Diastolic Heart Failure (DIAST-CHF) trial were examined and compared with a healthy control group (n = 40; 48% female). We were able to identify 35 proteins that were expressed significantly different in both HF groups compared with the control group. We determine 29 unique proteins expressed in HFpEF and 33 unique proteins in HFrEF. Significantly up-regulated trefoil factor 3 (TFF3) and down-regulated contactin-1 could be identified as previously unknown biomarkers for HF. However, TFF3 is also a predictive factor for the occurrence of a cardiovascular event in HFpEF patients. In HFpEF, serine protease 27 was found at reduced levels for the first time, which could offer a new therapeutic target. Additionally, network analyses showed a special role of platelet-derived growth factor subunit A, Dickkopf-related protein 1, and tumour necrosis factor receptor superfamily member 6 in HFpEF patients, whereas perlecan and junctional adhesion molecule A stood out in the HFrEF group. Overall, signalling pathways of metabolic processes, cellular stress, and iron metabolism seemed to be important for HFrEF, whereas for HFpEF, oxygen stress, haemostasis, cell renewal, cell migration, and cell proliferation are in the foreground. CONCLUSIONS: The identified proteins and signalling pathways offer new therapeutic and diagnostic approaches for patients with chronic HF.

Evaluation of the HFA-PEFF Score: results from the prospective DIAST-CHF cohort.

AIMS: Although the number of patients suffering from heart failure with preserved ejection fraction (HFpEF) increases, the routine diagnosis remains a challenge. In the absence of a pathognomonic sign for HFpEF or specific treatment strategies, a prognosis-based characterization of suspected patients remains promising for both the risk stratification of the patients and a disease definition. The Heart Failure Association (HFA) of the European Society of Cardiology has introduced an algorithm with different levels of likelihood regarding the diagnosis of HFpEF, the HFA-PEFF score. We aimed to evaluate the predictive value of this algorithm in a large cohort regarding mortality, symptom burden, and the functional status. METHODS AND RESULTS: DIAST-CHF is a multicentre, population-based, prospective, observational study in subjects with at least one risk factor for HFpEF between the age of 50 and 85. We calculated the HFA-PEFF score (n = 1668) and analysed the risk groups for overall mortality, cardiovascular hospitalization, and submaximal functional capacity (6-min walk distance) at baseline and after a follow-up period of 10 years. Patients with high HFA-PEFF score values 5&6 showed a higher mortality than those with an intermediate score (score values 2-4) and low score values (high 21.3% vs. intermediate 10.1% vs. low 4.3%, P < 0.001). Also, the burden of MACE (death, cardiovascular hospitalization, new myocardial infarction, first diagnosis of HF) was increased in the high score values group (high 40.7% vs. intermediate 25.9% vs. low 13.9%, P < 0.001). Similarly, patients with higher scores had higher cumulative incidences of cardiovascular hospitalizations (P = 0.011). Subjects with higher scores also had lower 6-min walk distance both at baseline and during follow-up. CONCLUSIONS: The HFA-PEFF score provides a reliable instrument to stratify suspected HFpEF patients by their risk for mortality, symptom burden, and functional status in cohort at risk with a follow-up period of 10 years. As high HFA-PEFF scores are associated with worse outcome, the HFA-PEFF algorithm describes a defining approach towards HFpEF.

Pharmacological treatment options for heart failure with reduced ejection fraction: A 2022 update.

INTRODUCTION: Despite considerable advances in the treatment of heart failure with reduced ejection fraction (HFrEF) over the last 60 years, mortality and morbidity remains high. Fortunately, in the last years, further developments expanded the toolbox for HF treatment. AREAS COVERED: The authors provide an overview of recent developments in HF treatment and bring the recommendations in the HF guidelines of the European Society of Cardiology into perspective. EXPERT OPINION: Nowadays, basic pharmacological treatment of patients with HFrEF consists of a combination of angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and the SGLT2 inhibitors dapagliflozin or empagliflozin. Treatment initiation of all four drug classes should be fast and simultaneous. In some cases, the ARNI sacubitril/valsartan may be initiated even in ACE inhibitor-naïve patients. Further HF treatment has to be individualized. Another important point is that both SGLT2 inhibitors and vericiguat can be used in patients with severely reduced kidney function. Finally, an important piece in the HF management puzzle is the treatment of its comorbidities. For instance, patients hospitalized for acute HF decompensation should be systematically screened for iron deficiency, since HF patients with proven iron deficiency benefit from intravenous ferric carboxymaltose.

NT-proBNP as a marker for atrial fibrillation and heart failure in four observational outpatient trials.

AIMS: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors. METHODS AND RESULTS: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408). CONCLUSIONS: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited.

[The importance of health-related quality of life at baseline in predicting event-free survival in patients with a cardiovascular risk profile]. / Die Bedeutung gesundheitsbezogener Lebensqualität für die Vorhersage des ereignisfreien Überlebens bei Patienten mit kardiovaskulärem Risikoprofil.

The importance of health-related quality of life at baseline in predicting event-free survival in patients with a cardiovascular risk profile Background: Manifest heart failure impairs all dimensions of health-related quality of life (HRQOL). However, the role of HRQOL in patients with risk factors for the development of heart failure with preserved ejection fraction (HFpEF) is only poorly understood. Objective: In this post-hoc analysis of the DIAST-CHF observational study, we tested the hypothesis whether a lower HRQOL at baseline is prognostically associated with an increase in cardiovascular events during follow-up in elderly patients with a cardiovascular risk profile. Methods: The DIAST-CHF observational study enrolled 1.937 patients aged 50 to 85 years with at least one risk factor for the development of HFpEF. HRQOL was assessed using the German version of the Short-Form-36 (SF-36) Health Survey. Results: Patients with comorbid chronic diseases, including manifest heart failure, coronary artery disease, atrial fibrillation, diabetes mellitus and depression, rated their health status (Self-rated health, SRH) significantly worse than those without comorbidities. Older age, higher body-mass index and elevated serum amino-terminal pro-brain natriuretic peptide (NTproBNP) concentration as well as lower left ventricular ejection fraction (LVEF) and impaired 6-minute walk test showed significant relationships to SRH. Kaplan-Meier analyses and Cox regression models using quartiles of either SF-36 subscales "Physical Component Summary" (PCS) or SRH groups demonstrated significant differences in event-free survival (all-cause death or cardiovascular hospitalization), whereas no difference in event-free survival was observed among the quartiles of the SF-36 subscale "Mental Component Summary" (MCS). Conclusion: In patients with risk factors for the development of HFpEF, HRQOL questionnaires are suitable instruments for risk stratification if they capture physical impairments, rather than psychological limitations of quality of life.

Influence of baseline parameters on one-year physical, mental, and health-related quality of life in patients with heart failure and preserved ejection fraction.

AIMS: To identify baseline parameters longitudinally influencing overall health-related quality of life (HRQoL), physical function and mental health 1 year later in patients with chronic heart failure and preserved ejection fraction (HFpEF). METHODS AND RESULTS: We performed post hoc analyses of the randomized aldosterone in diastolic heart failure (Aldo-DHF) trial, including 422 patients with HFpEF and NYHA class II or III. Overall HRQoL, measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), physical functioning and mental health, both measured by the Short Form 36 Health Survey (SF-36), after 12 months were predicted in correlation analyses and multivariate regression analyses with continuous values and worst versus three better HRQoL quartiles as dependent variables. The mean age of the study population was 66.8 ± 7.6 years, 52.4% were female, and 86.0% had NYHA class II. All HRQoL variables at 1 year were predicted by their respective baseline values (all P < 0.001), which were also the best variables to predict lowest versus higher HRQoL quartiles (all P < 0.001). For overall HRQoL, six-minute-walking-distance (P = 0.009), Borg-score (P = 0.001), coronary heart disease (P = 0.036) and SF-36 role-emotional (P = 0.005) independently predicted one-year-outcome, while depression diagnosis (P = 0.044), self-reported health status (P = 0.023) and PHQ depression (P = 0.001) were only significant predictors when excluding MLHFQ total score at baseline. In logistic regression analyses, only SF-36 role-emotional (P = 0.016) independently predicted overall HRQoL group status at follow up. For physical functioning, Borg-score (P ≤ 0.001), 6 min walking distance (P = 0.005), coronary heart disease (P = 0.009), and SF-36 vitality (P = 0.001) were significant independent predictors, also when excluding baseline physical functioning. Low SF-36 vitality (P = 0.021) and presence of coronary heart disease (P = 0.027) independently predicted a patient's membership in the lowest quartile 1 year later. For mental health, SF-36 physical functioning (P = 0.025) and HADS anxiety (P = 0.046) were independent predictors, while self-rated fatigue and poor performance (P = 0.033) and SF-36 vitality (P = 0.008) only served as significant predictors when excluding mental health at baseline. HADS anxiety (P = 0.009) also served as independent predictor of a patient's group status after 1 year. CONCLUSION: Overall HRQoL, physical functioning, and mental health of HFpEF patients 1 year later are mainly influenced by their respective baseline values. Other self-rated baseline parameters also showed independent effects while objective severity measures had limited predictive value.

The diagnostic and prognostic value of galectin-3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST-CHF study.

AIMS: Galectin-3 (Gal-3) predicts long-term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal-3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal-3 and clinical manifestations of HFpEF, the relationship between Gal-3 and all-cause mortality, or the composite of cardiovascular hospitalization and death. METHODS AND RESULTS: The observational Diast-CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal-3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non-cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut-off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal-3, and the diagnostic power to detect HFpEF was superior to N-terminal pro-brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal-3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal-3 predicted incident HFpEF (P < 0.05), adjusted all-cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N-terminal pro-brain natriuretic peptide. CONCLUSIONS: Gal-3 differentiated patients with HFpEF from an overall cohort of well-characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal-3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow-up. In conjunction with clinical parameters, Gal-3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable.

Outcome assessment using estimation of left ventricular filling pressure in asymptomatic patients at risk for heart failure with preserved ejection fraction.

AIMS: High prevalence and lack of pharmacological treatment are making heart failure with preserved ejection fraction (HFpEF) a growing public health problem. No algorithm for the screening of asymptomatic patients with risk for HFpEF exists to date. We assessed whether HFA/ESC 2007 diagnostic criteria for HFpEF are helpful to investigate the cardiovascular outcome in asymptomatic patients. METHODS AND RESULTS: We performed an analysis of the Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that recruited patients with cardiovascular risk factors. All patients underwent a comprehensive diagnostic workup at baseline. Asymptomatic patients with preserved LVEF (>50%) were selected and classified according to HFA/ESC surrogate criteria for left ventricular elevated filling pressure (mean E/e' >15 or E/e' >8 and presence of either NT-proBNP > 220 ng/l, BNP > 200 ng/l or atrial fibrillation) into elevated filling pressure (FPe) or controls. Cardiovascular hospitalizations and all-cause death were assessed for both groups over a 10-year-follow-up.851 asymptomatic patients (age 65.5 ± 7.6 years, 44% female) were included in the analysis. FPe-patients were significantly older (p < 0.001), more often female (p = 0.003) and more often had a history of coronary artery disease, atrial fibrillation and renal dysfunction (p < 0.001, respectively) compared to controls. Incidence of death was significantly higher in the FPe group after a 10-year follow-up (p < 0.001), whereas cardiovascular hospitalization did not differ between groups. CONCLUSION: Asymptomatic patients that fulfill HFA/ESC diagnostic criteria for HFpEF are at higher risk of symptomatic HFpEF and have a worse 10-year-outcome than those who do not fulfill criteria.

Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction.

AIMS: Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. METHODS AND RESULTS: We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e' medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. CONCLUSIONS: Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities.

Amount or intensity? Potential targets of exercise interventions in patients with heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) remains a common condition with no pharmacological treatment. Physical activity (PA) improves symptoms and quality of life (QoL), but no clear recommendations exist on PA in HFpEF patients. We investigated the association of PA (amount/intensity) on clinical phenotype in HFpEF. METHODS AND RESULTS: The Aldosterone in Diastolic Heart Failure trial investigated spironolactone vs. placebo in stable HFpEF patients. At baseline, all patients underwent detailed phenotypization including echocardiography, cardiopulmonary exercise testing, 6 minute walking test (6MWT), and QoL assessment (36-item Short-Form questionnaire). PA was assessed by a self-report questionnaire, classified in metabolic equivalents of task (MET) and analysed with regard to exercise capacity, diastolic function, and QoL. Four hundred twenty-two patients (52% women, age 67 ± 8 years, New York Heart Association II and III) were classified by weekly MET hours into a low (<70), middle (70-140), or high (>140) level of PA. Total PA correlated positively with 6MWT distance (r = 0.17; P = 0.002) and physical function of QoL (r = 0.10; P = 0.05), but not with peak oxygen uptake (peakVO2 ). In contrast, both 6MWT distance and peakVO2 were significantly higher in patients who performed high-intensity PA for >8 h/week (P < 0.001, P = 0.02, respectively). Time of high-intensity PA was related to higher 6MWT distance (r = 0.21, P < 0.001), peakVO2 , and better physical function of QoL (both r = 0.13, P = 0.01), whereas low-intensity PA did not show significant associations. Interestingly, PA was not related to any measure of diastolic function. CONCLUSIONS: A higher amount of PA is related to higher submaximal exercise capacity and physical function of QoL. Regarding maximal exercise capacity, only high-intensity PA showed significant association in HFpEF patients.

Exercise training in Diastolic Heart Failure (Ex-DHF): rationale and design of a multicentre, prospective, randomized, controlled, parallel group trial.

Heart failure with preserved ejection fraction (HFpEF) is a common disease with high incidence and increasing prevalence. Patients suffer from functional limitation, poor health-related quality of life, and reduced prognosis. A pilot study in a smaller group of HFpEF patients showed that structured, supervised exercise training (ET) improves maximal exercise capacity, diastolic function, and physical quality of life. However, the long-term effects of ET on patient-related outcomes remain unclear in HFpEF. The primary objective of the Exercise training in Diastolic Heart Failure (Ex-DHF) trial is to investigate whether a 12 month supervised ET can improve a clinically meaningful composite outcome score in HFpEF patients. Components of the outcome score are all-cause mortality, hospitalizations, NYHA functional class, global self-rated health, maximal exercise capacity, and diastolic function. After undergoing baseline assessments to determine whether ET can be performed safely, 320 patients at 11 trial sites with stable HFpEF are randomized 1:1 to supervised ET in addition to usual care or to usual care alone. Patients randomized to ET perform supervised endurance/resistance ET (3 times/week at a certified training centre) for 12 months. At baseline and during follow-up, anthropometry, echocardiography, cardiopulmonary exercise testing, and health-related quality of life evaluation are performed. Blood samples are collected to examine various biomarkers. Overall physical activity, training sessions, and adherence are monitored and documented throughout the study using patient diaries, heart rate monitors, and accelerometers. The Ex-DHF trial is the first multicentre trial to assess the long-term effects of a supervised ET programme on different outcome measures in patients with HFpEF.

Arterial stiffness and elevated left ventricular filling pressure in patients at risk for the development or a previous diagnosis of HF-A subgroup analysis from the DIAST-CHF study.

Left ventricular filling pressure (LVFP) is a marker for diastolic dysfunction and heart failure (HF) with preserved ejection fraction (pEF). The interaction between arterial stiffness (AS) and elevated LVFP has not been sufficiently investigated. In 257 patients with preserved left ventricular ejection fraction (mean age: 66 years, 53% female, mean left ventricular ejection fraction: 61%) and at least one cardiovascular risk factor (eg, hypertension and diabetes) for the development of HF or a previous diagnosis of HF, LVFP was estimated in accordance with the recommendations of the American Society of Echocardiography (elevated when E/e' ≥ 13, left atrial volume index ≥ 34 mL/m2). LVFP was correlated with radial pulse wave analysis (augmentation index normalized by 75 b/min [AIx@75]) and carotid-femoral pulse wave velocity (cfPWV). Thirty-eight percent of patients demonstrated an elevated LVFP. These patients were significantly older (68.3 ± 7.4 vs. 63.5 ± 7.6 years, P < .001), demonstrated a higher body mass index (29.8 ± 4.6 vs. 28.0 ± 5.0; P < .01), presented more often with hypertension (89.7% vs. 73.1%, P < .01), hypercholesterolemia (32.0% vs. 21.3%, P < .05), dyspnea on exertion (28.4% vs. 16.6%, P < .05), and peripheral edema (25.3% vs. 10.2%, P < .01). cfPWV and AIx@75 and were significantly elevated in patients with elevated LVFP (12.2 ± 2.7 m/s vs. 10.5 ± 2.6 m/s, P < .001, an 29.2 ± 6.7% vs. 27.4 ± 6.7%, P < .05 respectively). cfPWV and AIx@75 were correlated with echocardiographic parameters, that is, posterior wall thickness (r = 0.292, P < .001; r = 0.167, P < .01), left ventricular mass index (r = 0.255, P < .001; r = -0.192, P < .01), e' (r = -0.508, P < .001; r = -0.159, P < .05), and E/e' (r = 0.380, P < .001; r = 0.200, P < .01). cfPWV correlated with left atrial volume index (r = 0.189, P < .05) and increasing E/A ratio (r = -0.334, P < .001). Multivariate linear regression analysis demonstrated age and PWV as most important and independent predictors of LVFP elevation in the cohort. Increased AS measured by cfPWV was associated with an elevated LVFP in patients with preserved systolic function. Whether targeting AS as a major component of diastolic dysfunction and HF with preserved ejection fraction needs to be further investigated.

Ghrelin and hormonal markers under exercise training in patients with heart failure with preserved ejection fraction: results from the Ex-DHF pilot study.

BACKGROUND: Over 50% of patients with symptomatic heart failure (HF) experience HF with preserved ejection fraction (HFpEF). Exercise training (ET) is effective in improving cardiorespiratory fitness and dimensions of quality of life in patients with HFpEF. A systemic pro-inflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations has been proposed in HFpEF. ET modifies myocardial structure and has been related to inflammatory state. We investigated Ghrelin, related adipokines, markers of inflammation, and neuro-hormonal activation in patients undergoing a structured ET vs. usual care are with HFpEF. METHODS AND RESULTS: Ex-DHF-P was a prospective, controlled, randomized multi-centre trial on structured and supervised ET in patients with HFpEF. We performed a post hoc analysis in 62 patients from Ex-DHF-P. Ghrelin, adiponectin, leptin, IL-1ß, IL-6, IL-10, tumour necrosis factor-alpha, MR-proANP, MR-proADM, CT-proET1, and CT-proAVP were assessed to seize the impact of ET on these markers in patients with HFpEF. Thirty-six (58%) patients were female, mean age was 64 years, and median ghrelin was 928 pg/mL (interquartile range 755-1156). When stratified for high versus low ghrelin, groups significantly differed at baseline in presence obesity, waist circumference, and adiponectin levels (P < 0.05, respectively). Overall, ghrelin levels rose significantly to 1013 pg/mL (interquartile range 813-1182) (P < 0.001). Analysis of covariance modelling for change in ghrelin identified ET (P = 0.013) and higher baseline adiponectin levels (P = 0.035) as influencing factors. CONCLUSIONS: Exercise training tended to increase ghrelin levels in Ex-DHF-P. This increase was especially pronounced in patients with higher baseline adiponectin levels. Future trials are needed to investigate the effect of ET on endogenous ghrelin levels in regard to interactions with cardiac structure and clinically meaningful surrogate parameters.

Elevated Plasma C-Terminal Endothelin-1 Precursor Fragment Concentrations Are Associated with Less Anxiety in Patients with Cardiovascular Risk Factors. Results from the Observational DIAST-CHF Study.

BACKGROUND: The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety. METHODS: Plasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: Among the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(ß) = 0.247, 95%-confidence interval [95%-CI] = 0.067-0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(ß) = 0.114, 95%-CI = 0.023-0.566, p = 0.008). CONCLUSIONS: Our data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

[GDF-15, MRproADM, CTproET1, and CTproAVP in patients with asymptomatic diastolic dysfunction]. / GDF-15, MRproADM, CTproET1 und CTproAVP bei Patienten mit asymptomatischer diastolischer Dysfunktion.

BACKGROUND: The role of biomarkers in asymptomatic diastolic dysfunction (DD) has not been investigated so far. The aim of the study was to evaluate the clinical associations and the diagnostic property of different biomarkers in patients with asymptomatic DD. METHODS: Within a population based observational study, healthy participants (50-85 years) with an LVEF ≥ 50 % and no cardiovascular risk factor were prospectively identified. Patients were classified as having either DD (grade ≥ 1, n = 103) or no DD (CON: n = 85). All patients underwent physical examination including medical history, six-minute-walk-testing, QoL (SF-36), comprehensive echocardiography and blood sampling to measure routine values and specified biomarkers (NTproBNP, MRproANP, GDF-15, MRproADM, CTproET1, CTproAVP). RESULTS: In the DD-group plasma concentration of GDF-15 (p = 0,002), MRproADM (p < 0,001), and CTproAVP (p = 0,003) were significantly higher than in the CON-group. In contrast, NTproBNP (p = 0,390), MRproANP (p = 287), and CTproET1 (p = 0,393) did not differ. GDF-15, MRproADM and CTproAVP were significantly associated with the presence of DD. However, the significance of the seen associations was lost after multiple adjustments. NTproBNP, MRproANP, and MRproADM were significantly related to E / e' as a continuous measure of diastolic function. The significance of the seen associations was lost after multiple adjustments. In ROC analyses, none of the investigated biomarkers was able to relevantly improve the diagnosis of DD. CONCLUSION: In patients with asymptomatic DD plasma concentrations of GDF-15, MRproADM and CT-proAVP were significantly higher when compared with controls. In contrast, NTproBNP, MRproANP and CTproET1 did not differ. After adjustment for age, sex, BMI and renal function, no significant association between DD or E / e' and different biomarkers could be observed. Furthermore, none of the investigated biomarkers was able to substantially improve the diagnosis of DD.

Higher plasma levels of MR-pro-atrial natriuretic peptide are linked to less anxiety: results from the observational DIAST-CHF study.

AIMS: Growing evidence suggests that natriuretic peptides play a role in the neurobiology of anxiety. In the present study, we investigated whether in patients with cardiovascular risk factors higher plasma levels of natriuretic peptides are linked to reduced anxiety. METHODS: A total of 1,360 patients from the observational DIAST-CHF study (mean age 65.9 ± 8.2 years, 48.7 % males, mean left ventricular ejection fraction 60.0 ± 8.2 %) with risk factors for diastolic heart failure were included. Study participants underwent physical examination, echocardiography, and assessment of anxiety using the Hospital Anxiety and Depression Scale (HADS). In addition, plasma concentrations of natriuretic peptides were measured. RESULTS: Among the total study population, there were n = 117 patients (8.6 %) with HADS anxiety scores above the cut-off (≥11) suggestive of clinically relevant anxiety. In bivariate analyses, we found a significant inverse association between elevated HADS anxiety and log-transformed mid-regional pro-atrial natriuretic peptide (MR-proANP) (p < 0.001) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) (p = 0.008). Logistic regression models adjusted for sex, age, body mass index, and Framingham score confirmed that plasma MR-proANP (exp(ß) = 0.35, 95 % confidence interval [95 % CI] 0.14-0.92, p = 0.032) concentrations were significantly and inversely associated with clinically relevant anxiety, while NT-proBNP (exp(ß) = 0.67, 95 % CI 0.41-1.07, p = 0.094) failed to reach the significance level in independently predicting anxiety. CONCLUSIONS: In our study population of outpatients with cardiovascular risk factors, plasma concentrations of MR-proANP were negatively and independently related to clinically relevant anxiety. Further investigations are required to search for possible anxiolytic effects of this circulating natriuretic peptide in medical outpatients with cardiovascular risk factors for diastolic dysfunction.

Determinants of submaximal exercise capacity in patients at risk for heart failure with preserved ejection fraction-results from the DIAST-CHF study.

OBJECTIVES AND BACKGROUND: The aim of this study was to identify determinants of submaximal exercise capacity as measured by 6 min walking distance in patients at risk for heart failure with preserved ejection fraction (HFpEF). METHODS: A cross-sectional analysis from the prospective cohort programme Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that included a total of 1937 patients (age, 50-85 years) with >1 risk factor (hypertension, atherosclerotic disease, diabetes mellitus, and obstructive sleep apnoea) was carried out. Besides comprehensive clinical phenotyping, standardized 6 min walk test and state-of-the-art echocardiography were performed, and blood samples for biomarker assessment were obtained. Patients with an ejection fraction <50% or without evaluable exercise test were excluded from this analysis. RESULTS: One thousand three hundred eighty-seven patients fulfilled all criteria for this analysis. In the univariate analysis, 6 min walk distance was inversely related to E/e' values (P < 0.001). In the multivariate analysis, 6 min walk distance decreased significantly with age, female sex, increasing body mass index, diabetes, chronic obstructive lung disease, and peripheral artery disease. However, the association of 6 min walk distance with resting parameters of diastolic function was significantly attenuated with multivariate regression. In contrast, mid-regional pro-adrenomedullin, mid-regional pro-atrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide were independently associated with submaximal exercise capacity when added to the base model (all P < 0.001). CONCLUSIONS: Classical risk factors for heart failure and neuroendocrine activation are independently associated with sub-maximal exercise capacity, while diastolic function parameters obtained at rest were not. This observation substantiates the role of co-morbidities as relevant contributors to the clinical picture of HFpEF and the limitation of resting indices of diastolic function for diagnosing HFpEF.

Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial.

AIMS: Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin-3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to assess the association between galectin-3 and clinical outcomes. METHODS AND RESULTS: Aldo-DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II-III, LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2 ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline, and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline galectin-3 was 12.1 ng/mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2 (P = 0.021), 6 min walk distance (P = 0.002), and Short Form 36 (SF-36) physical functioning (P = 0.001), and directly correlated with NYHA class (P = 0.007). Baseline NT-proBNP correlated with E/e' velocity ratio (P ≤ 0.001), left atrial volume index (P < 0.001), and LV mass index (P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with all-cause death or hospitalization independent of treatment arm [hazard ratio (HR) 3.319, 95% confidence interval (CI) 1.214-9.07, P = 0.019] and NT-proBNP (HR 3.127, 95% CI 1.144-8.549, P = 0.026). Spironolactone did not influence galectin-3 levels. CONCLUSION: Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP.

Effects of exercise training on different quality of life dimensions in heart failure with preserved ejection fraction: the Ex-DHF-P trial.

BACKGROUND: Despite suffering from poor prognosis, progressive exercise intolerance, and impaired quality of life (QoL), effective therapeutic strategies in heart failure with preserved ejection fraction (HFpEF) are sparse. Exercise training (ET) improves physical QoL in HFpEF, but the effects on other aspects of QoL are unknown. METHODS: The multicentre, prospective, randomized, controlled Exercise training in Diastolic Heart Failure Pilot study included 64 HFpEF patients (65 ± 7 years, 56% female). They were randomized to supervised endurance/resistance training in addition to usual care (ET, n = 44) or usual care alone (UC, n = 20). At baseline and after 3 months, QoL was assessed (36-item Short-form Health Survey (SF-36), Minnesota Living With Heart Failure Questionnaire (MLWHFQ), and Patient Health Questionnaire (PHQ-9). RESULTS: Exercise improved the following SF-36 dimensions: physical functioning (p < 0.001, p = 0.001 vs. UC), bodily pain (p = 0.046), general health perception (p < 0.001, p = 0.016 vs. UC), general mental health (p = 0.002), vitality (p = 0.003), social functioning (p < 0.001) physical (p < 0.001, p = 0.001 vs. UC), and mental component score (p = 0.030). ET did not improve role limitations due to physical and emotional problems. The MLWHFQ total scale (p < 0.001) and the MLWHFQ physical limitation scale (p < 0.001, p = 0.04 vs. UC) also improved with ET. The MLWHFQ emotional limitation scale did not change with ET. With ET, also the PHQ-9 total score improved significantly (p = 0.004, p = 0.735 vs. UC). CONCLUSIONS: In patients with HFpEF, exercise training improved emotional status, physical and social dimensions of QoL as well as symptoms of depression from pre to post test. Physical dimensions of QoL and general health perception also improved significantly with exercise in comparison to usual care.