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.

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.

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.

Effects of long-term endurance and resistance training on diastolic function, exercise capacity, and quality of life in asymptomatic diastolic dysfunction vs. heart failure with preserved ejection fraction.

BACKGROUND: The long-term effects of exercise training (ET) in diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF) are unknown. The present study compared the long-term effects of ET on exercise capacity, diastolic function, and quality of life (QoL) in patients with DD vs. HFpEF. METHODS: A total of n = 43 patients with asymptomatic DD (n = 19) or HFpEF [DD and New York Heart Association (NYHA) ≥II, n = 24] and left ventricular ejection fraction ≥50% performed a combined endurance/resistance training over 6 months (2-3/week) on top of usual care. Cardiopulmonary exercise testing, echocardiography, and QoL were obtained at baseline and follow-up. RESULTS: Patients were 62 ± 8 years old (37% female). In the HFpEF group, 67% of patients were in NYHA class II (33% in NYHA III). Exercise capacity (peak oxygen consumption, peak VO2 ) differed at baseline (DD 29.2 ± 8.7 mL/min/kg vs. HFpEF 17.8 ± 4.6 mL/min/kg; P = 0.004). After 6 months, peak VO2 increased significantly (P < 0.044) to 19.7 ± 5.8 mL/min/kg in the HFpEF group and also in the DD group (to 32.8 ± 8.5 mL/min/kg; P < 0.002) with no overall difference between the groups (P = 0.217). E/e' ratio (left ventricular filling index) decreased from 12.2 ± 3.5 to 10.1 ± 3.0 (P < 0.002) in patients with HFpEF and also in patients with DD (10.7 ± 3.1 vs. 9.5 ± 2.3; P = 0.03; difference between groups P = 0.210). In contrast, left atrial volume index decreased in the HFpEF group (P < 0.001) but remained stable within the DD group (difference between groups P = 0.015). After 6 months, physical QoL (Minnesota living with heart failure Questionnaire, 36-item short form health survey), general health perception, and 9-item patient health questionnaire score only improved in HFpEF (P < 0.05). In contrast, vitality improved in both groups (difference between groups P = 0.708). CONCLUSION: A structured 6 months ET programme effectively improves exercise capacity and diastolic function in patients with DD and overt HFpEF. Therefore, controlled lifestyle modification with physical activity is effective both in DD and HFpEF.

Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study.

OBJECTIVES: We sought to determine whether structured exercise training (ET) improves maximal exercise capacity, left ventricular diastolic function, and quality of life (QoL) in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Nearly one-half of patients with heart failure experience HFpEF, but effective therapeutic strategies are sparse. METHODS: A total of 64 patients (age 65 ± 7 years, 56% female) with HFpEF were prospectively randomized (2:1) to supervised endurance/resistance training in addition to usual care (ET, n = 44) or to usual care alone (UC) (n = 20). The primary endpoint was the change in peak Vo(2) after 3 months. Secondary endpoints included effects on cardiac structure, diastolic function, and QoL. RESULTS: Peak Vo(2) increased (16.1 ± 4.9 ml/min/kg to 18.7 ± 5.4 ml/min/kg; p < 0.001) with ET and remained unchanged (16.7 ± 4.7 ml/min/kg to 16.0 ± 6.0 ml/min/kg; p = NS) with UC. The mean benefit of ET was 3.3 ml/min/kg (95% confidence interval [CI]: 1.8 to 4.8, p < 0.001). E/e' (mean difference of changes: -3.2, 95% CI: -4.3 to -2.1, p < 0.001) and left atrial volume index (milliliters per square meter) decreased with ET and remained unchanged with UC (-4.0, 95% CI: -5.9 to -2.2, p < 0.001). The physical functioning score (36-Item Short-Form Health Survey) improved with ET and remained unchanged with UC (15, 95% CI: 7 to 24, p < 0.001). The ET-induced decrease of E/e' was associated with 38% gain in peak Vo(2) and 50% of the improvement in physical functioning score. CONCLUSIONS: Exercise training improves exercise capacity and physical dimensions of QoL in HFpEF. This benefit is associated with atrial reverse remodeling and improved left ventricular diastolic function. (Exercise Training in Diastolic Heart Failure-Pilot Study: A Prospective, Randomised, Controlled Study to Determine the Effects of Physical Training on Exercise Capacity and Quality of Life [Ex-DHF-P]; ISRCTN42524037).