Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects. Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF. Design, Setting, and Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded. Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise). Main Outcomes and Measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months. Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%). Conclusions and Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.

Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction.

OBJECTIVE: Elevated levels of arginine derivatives in the NO pathway, such as asymmetric dimethylarginine (ADMA), are related to disease severity and reduced exercise capacity in heart failure (HF). We investigated the influence of exercise intervention on these parameters and on L-arginine (L-Arg) and L-homoarginine (L-hArg) in HF with preserved ejection fraction (HFpEF) patients. MATERIAL AND METHODS: Sixty-two patients (65 ± 6 years) were included in this analysis and randomized to supervised endurance/resistance training (ET) or to usual care (UC). EDTA-plasma was analysed for NO metabolites. RESULTS: There were baseline associations for adjusted values of maximum workload with ADMA (r= -0.322, p = 0.028) and L-Arg/ADMA ratio (r = 0.331, p = 0.015), and for the 6-min walk test (6MWT) with ADMA (r= -0.314, p = 0.024) and L-Arg/ADMA ratio (r = 0.346, p = 0.015). No significant differences between UC and ET changes of NO parameters were observed at 3-month follow-up. Higher L-hArg levels were associated with a greater improvement in peak oxygen uptake (peak [Formula: see text]O2) at follow-up: 3.4 ± 2.8 vs. 1.1 ± 2.9 mL/min/kg (p = 0.005). CONCLUSIONS: Exercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak [Formula: see text]O2.

Associations of methylarginines and homoarginine with diastolic dysfunction and cardiovascular risk factors in patients with preserved left ventricular ejection fraction.

BACKGROUND: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction. METHODS AND RESULTS: We investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro-B-type natriuretic peptide and midregional pro-adrenomedullin (P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction (P < .05 for all). CONCLUSIONS: Higher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.

Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial.

IMPORTANCE: Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression. OBJECTIVE: To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction. DESIGN AND SETTING: The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction. INTERVENTION: Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up. MAIN OUTCOME MEASURES: The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months. RESULTS: Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations. CONCLUSIONS AND RELEVANCE: In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

De Novo Lipogenesis-Related Monounsaturated Fatty Acids in the Blood Are Associated with Cardiovascular Risk Factors in HFpEF Patients.

De novo lipogenesis (DNL)-related monounsaturated fatty acids (MUFAs) in the blood are associated with incident heart failure (HF). This observation's biological plausibility may be due to the potential of these MUFAs to induce proinflammatory pathways, endoplasmic reticulum stress, and insulin resistance, which are pathophysiologically relevant in HF. The associations of circulating MUFAs with cardiometabolic phenotypes in patients with heart failure with a preserved ejection fraction (HFpEF) are unknown. In this secondary analysis of the Aldosterone in Diastolic Heart Failure trial, circulating MUFAs were analysed in 404 patients using the HS-Omega-3-Index® methodology. Patients were 67 ± 8 years old, 53% female, NYHA II/III (87/13%). The ejection fraction was ≥50%, E/e' 7.1 ± 1.5, and the median NT-proBNP 158 ng/L (IQR 82-298). Associations of MUFAs with metabolic, functional, and echocardiographic patient characteristics at baseline/12 months follow-up (12 mFU) were analysed using Spearman's correlation coefficients and linear regression analyses, using sex/age as covariates. Circulating levels of C16:1n7 and C18:1n9 were positively associated with BMI/truncal adiposity and associated traits (dysglycemia, atherogenic dyslipidemia, and biomarkers suggestive of non-alcoholic-fatty liver disease). They were furthermore inversely associated with functional capacity at baseline/12 mFU. In contrast, higher levels of C20:1n9 and C24:1n9 were associated with lower cardiometabolic risk and higher exercise capacity at baseline/12 mFU. In patients with HFpEF, circulating levels of individual MUFAs were differentially associated with cardiovascular risk factors. Our findings speak against categorizing FA based on physicochemical properties. Circulating MUFAs may warrant further investigation as prognostic markers in HFpEF.

Trans-fatty acid blood levels of industrial but not natural origin are associated with cardiovascular risk factors in patients with HFpEF: a secondary analysis of the Aldo-DHF trial.

BACKGROUND: Industrially processed trans-fatty acids (IP-TFA) have been linked to altered lipoprotein metabolism, inflammation and increased NT-proBNP. In patients with heart failure with preserved ejection fraction (HFpEF), associations of TFA blood levels with patient characteristics are unknown. METHODS: This is a secondary analysis of the Aldo-DHF-RCT. From 422 patients, individual blood TFA were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were: 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e' 7.1 ± 1.5; NT-proBNP 158 ng/L (IQR 82-298). A principal component analysis was conducted but not used for further analysis as cumulative variance for the first two PCs was low. Spearman's correlation coefficients as well as linear regression analyses, using sex and age as covariates, were used to describe associations of whole blood TFA with metabolic phenotype, functional capacity, echocardiographic markers for LVDF and neurohumoral activation at baseline and after 12 months. RESULTS: Blood levels of the naturally occurring TFA C16:1n-7t were inversely associated with dyslipidemia, body mass index/truncal adiposity, surrogate markers for non-alcoholic fatty liver disease and inflammation at baseline/12 months. Conversely, IP-TFA C18:1n9t, C18:2n6tt and C18:2n6tc were positively associated with dyslipidemia and isomer C18:2n6ct with dysglycemia. C18:2n6tt and C18:2n6ct were inversely associated with submaximal aerobic capacity at baseline/12 months. No significant association was found between TFA and cardiac function. CONCLUSIONS: In HFpEF patients, higher blood levels of IP-TFA, but not naturally occurring TFA, were associated with dyslipidemia, dysglycemia and lower functional capacity. Blood TFAs, in particular C16:1n-7t, warrant further investigation as prognostic markers in HFpEF. Higher blood levels of industrially processed TFA, but not of the naturally occurring TFA C16:1n-7t, are associated with a higher risk cardiometabolic phenotype and prognostic of lower aerobic capacity in patients with HFpEF.

Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise training improves peak oxygen uptake (V.O2peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined. OBJECTIVES: The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF. METHODS: This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values. RESULTS: At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training. CONCLUSIONS: In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V.O2peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947).

Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients: the Aldo-DHF randomized controlled trial.

OBJECTIVES: To evaluate associations of omega-3 fatty acid (O3-FA) blood levels with cardiometabolic risk markers, functional capacity and cardiac function/morphology in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: O3-FA have been linked to reduced risk for HF and associated phenotypic traits in experimental/clinical studies. METHODS: This is a cross-sectional analysis of data from the Aldo-DHF-RCT. From 422 patients, the omega-3-index (O3I = EPA + DHA) was analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were; 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e' 7.1 ± 1.5; median NT-proBNP 158 ng/L (IQR 82-298). Pearson's correlation coefficient and multiple linear regression analyses, using sex and age as covariates, were used to describe associations of the O3I with metabolic phenotype, functional capacity, echocardiographic markers for LVDF, and neurohumoral activation at baseline/12 months. RESULTS: The O3I was below (< 8%), within (8-11%), and higher (> 11%) than the target range in 374 (93%), 29 (7%), and 1 (0.2%) patients, respectively. Mean O3I was 5.7 ± 1.7%. The O3I was inversely associated with HbA1c (r = - 0.139, p = 0.006), triglycerides-to-HDL-C ratio (r = - 0.12, p = 0.017), triglycerides (r = - 0.117, p = 0.02), non-HDL-C (r = - 0.101, p = 0.044), body-mass-index (r = - 0.149, p = 0.003), waist circumference (r = - 0.121, p = 0.015), waist-to-height ratio (r = - 0.141, p = 0.005), and positively associated with submaximal aerobic capacity (r = 0.113, p = 0.023) and LVEF (r = 0.211, p < 0.001) at baseline. Higher O3I at baseline was predictive of submaximal aerobic capacity (ß = 15.614, p < 0,001), maximal aerobic capacity (ß = 0.399, p = 0.005) and LVEF (ß = 0.698, p = 0.007) at 12 months. CONCLUSIONS: Higher O3I was associated with a more favorable cardiometabolic risk profile and predictive of higher submaximal/maximal aerobic capacity and lower BMI/truncal adiposity in HFpEF patients. Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients. Higher O3I was associated with a more favorable cardiometabolic risk profile and aerobic capacity (left) but did not correlate with echocardiographic markers for left ventricular diastolic function or neurohumoral activation (right). An O3I-driven intervention trial might be warranted to answer the question whether O3-FA in therapeutic doses (with the target O3I 8-11%) impact on echocardiographic markers for left ventricular diastolic function and neurohumoral activation in patients with HFpEF. This figure contains modified images from Servier Medical Art ( https://smart.servier.com ) licensed by a Creative Commons Attribution 3.0 Unported License.

Saturated Fatty Acid Blood Levels and Cardiometabolic Phenotype in Patients with HFpEF: A Secondary Analysis of the Aldo-DHF Trial.

BACKGROUND: Circulating long-chain (LCSFAs) and very long-chain saturated fatty acids (VLSFAs) have been differentially linked to risk of incident heart failure (HF). In patients with heart failure with preserved ejection fraction (HFpEF), associations of blood SFA levels with patient characteristics are unknown. METHODS: From the Aldo-DHF-RCT, whole blood SFAs were analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were 67 ± 8 years, 53% female, NYHA II/III (87%/13%), ejection fraction ≥50%, E/e' 7.1 ± 1.5; and median NT-proBNP 158 ng/L (IQR 82-298). Spearman´s correlation coefficients and linear regression analyses, using sex and age as covariates, were used to describe associations of blood SFAs with metabolic phenotype, functional capacity, cardiac function, and neurohumoral activation at baseline and after 12-month follow-up (12 mFU). RESULTS: In line with prior data supporting a potential role of de novo lipogenesis-related LCSFAs in the development of HF, we showed that baseline blood levels of C14:0 and C16:0 were associated with cardiovascular risk factors and/or lower exercise capacity in patients with HFpEF at baseline/12 mFU. Contrarily, the three major circulating VLSFAs, lignoceric acid (C24:0), behenic acid (C22:0), and arachidic acid (C20:0), as well as the LCSFA C18:0, were broadly associated with a lower risk phenotype, particularly a lower risk lipid profile. No associations were found between cardiac function and blood SFAs. CONCLUSIONS: Blood SFAs were differentially linked to biomarkers and anthropometric markers indicative of a higher-/lower-risk cardiometabolic phenotype in HFpEF patients. Blood SFA warrant further investigation as prognostic markers in HFpEF. One Sentence Summary: In patients with HFpEF, individual circulating blood SFAs were differentially associated with cardiometabolic phenotype and aerobic capacity.

Cardiovascular risk factors, exercise capacity and health literacy in patients with chronic ischaemic heart disease and type 2 diabetes mellitus in Germany: Baseline characteristics of the Lifestyle Intervention in Chronic Ischaemic Heart Disease and Type 2 Diabetes study.

BACKGROUND: Lifestyle interventions are a cornerstone in the treatment of chronic ischaemic heart disease (CIHD) and type 2 diabetes mellitus (T2DM). This study aimed at identifying differences in clinical characteristics between categories of the common lifestyle intervention targets BMI, exercise capacity (peak V̇O2) and health literacy (HL). METHODS: Cross-sectional baseline characteristics of patients enrolled in the LeIKD trial (Clinicaltrials.gov NCT03835923) are presented in total, grouped by BMI, %-predicted peak V̇O2 and HL (HLS-EU-Q16), and compared to other clinical trials with similar populations. RESULTS: Among 499 patients (68.3±7.7 years; 16.2% female; HbA1c, 6.9±0.9%), baseline characteristics were similar to other trials and revealed insufficient treatment of several risk factors (LDL-C 92±34 mg/dl; BMI, 30.1±4.8 kg/m2; 69.6% with peak V̇O2<90% predicted). Patients with lower peak V̇O2 showed significantly higher (p < 0.05) CIHD and T2DM disease severity (HbA1c, CIHD symptoms, coronary artery bypass graft). Obese patients had a significantly higher prevalence of hypertension and higher triglyceride levels, whereas in patients with low HL both quality of life components (physical, mental) were significantly reduced. CONCLUSIONS: In patients with CIHD and T2DM, peak V̇O2, BMI and HL are important indicators of disease severity, risk factor burden and quality of life, which reinforces the relevance of lifestyle interventions.

Peak O2 -pulse predicts exercise training-induced changes in peak V̇O2 in heart failure with preserved ejection fraction.

AIMS: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2 ) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter-individual responses vary significantly. Because it is unlikely that ET-induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2 -pulse (V̇O2  × HR-1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2 , is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. METHODS AND RESULTS: This was a secondary analysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2 , peak O2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2 -pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2 -pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2 -pulse was associated with a decreased mean change in peak V̇O2 of -1.45% (95% CI, -2.30 to -0.60, P = 0.001) compared with a mean change of -0.08% (95% CI, -1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). CONCLUSIONS: In patients with HFpEF, the easily measurable peak O2 -pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2 -pulse, patients with high O2 -pulse may need to use additional therapies to significantly increase peak V̇O2 .

Impaired physical quality of life in patients with diastolic dysfunction associates more strongly with neurohumoral activation than with echocardiographic parameters: quality of life in diastolic dysfunction.

BACKGROUND: Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure. METHODS: In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. RESULTS: Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association. CONCLUSIONS: Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.

Lifestyle Intervention in Chronic Ischaemic Heart Disease and Type 2 Diabetes (the LeIKD study): study protocol of a prospective, multicentre, randomised, controlled trial.

INTRODUCTION: Guidelines recommend lifestyle intervention in chronic ischaemic heart disease (CIHD) and type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials is scarce in patients with combined entities. METHODS AND ANALYSIS: The Lifestyle Intervention in Chronic Ischaemic Heart Disease and Type 2 Diabetes (LeIKD) trial is a prospective, multicentre study that will randomise (1:1) patients with CIHD (ICD-10: I20-I25) and T2DM (ICD-10: E11) from one health insurance company into a lifestyle intervention (LS) or usual care (UC). Active LS consists of an individual combined exercise programme of strength and endurance training and nutritional counselling with regular feedback for 6 months. Intervention is supported by telemedicine. Follow-up without individualised feedback will continue for 6 months. The study aims to investigate whether an individualised telemedical supported LS intervention is superior to UC in improving cardiovascular risk factors, physical activity, quality of life, health literacy, major cardiovascular events and health economics in patients with both CIHD and T2DM. Primary endpoint is the change in HbA1c from baseline to 6 months. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the Technical University of Munich (registration number: 144/18-S) and at each study site. The study will be conducted according to the World Medical Association Declaration of Helsinki, and results will be published in articles and reports. It is funded by the Federal Joint Committee (www.innovationsfonds.g-ba.de), reference number 01NVF17015, which has no impact on data collection, analysis or interpretation. Dissemination is independent of the funding source. TRIAL REGISTRATION NUMBER: Clinical trials.gov identifier: NCT03835923. German registry for clinical studies (DRKS): DRKS00015140.

The Effect of Exercise Intensity and Volume on Metabolic Phenotype in Patients with Metabolic Syndrome: A Randomized Controlled Trial.

Background: Moderate intensity continuous training (MICT) ameliorates dysmetabolism in patients with metabolic syndrome (MetS). The impact of low- (1HIIT) versus high-volume high-intensity interval training (4HIIT) versus MICT on central adiposity, insulin resistance, and atherogenic dyslipidemia in patients with MetS has not yet been reported. Methods: Twenty-nine patients with MetS according to International Diabetes Federation criteria (nine females, age 61 ± 5 years, body mass index 31.1 ± 3.7 kg/m2, waist circumference (WC) ♀ 102.2 ± 10.6 cm, ♂ 108.5 ± 8.6 cm) were randomized (1:1:1) to 16 weeks of (1) MICT (5 × 30 min/week, 35%-50% heart rate reserve (HRR), (2) 1HIIT (3 × 17 min/week incl. 4 min @80%-90% HRR), and (3) 4HIIT (3 × 38 min/week incl. 4 × 4 min @80%-90% HRR). Peak oxygen uptake (V̇O2peak), WC and anthropometric/metabolic indices indicative of MetS, fasting glucose/insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), dyslipidemia, and respiratory exchange ratio (RER) at warm-up were quantified at baseline and study completion. Analysis of variance and paired t tests were used for statistical analysis. Analyses were performed after checking for parametric distribution. Results: There were no significant differences between groups in waist-to-height ratio (♀: Δ -0.10 ± -0.05, ♂: Δ -0.08 ± -0.06, P = 0.916), WC (♀: Δ -1.4 ± -0.1 cm, ♂: Δ 0.1 ± 0.9 cm, P = 0.590), fasting glucose (Δ -1.18 ± 16.7 µU/mL, P = 0.773), fasting insulin (Δ 0.76 ± 13.4 µU/mL, P = 0.509), HOMA-IR (Δ 0.55 ± 4.1, P = 0.158), atherogenic dyslipidemia [triglycerides (TAG) Δ -10.1 ± 46.9 mg/dL, P = 0.468, high-density lipoprotein cholesterol (HDL-C) Δ 1.5 ± 5.4, P = 0.665, TAG/HDL-C -0.19 ± 1.3, P = 0.502], V̇O2peak (P = 0.999), or RER (P = 0.842). In the entire group, waist-to-height-ratio and V̇O2peak significantly improved by a clinically meaningful amount (Δ 2.7 ± 0.9 mL/min/kg; P < 0.001) and RER at warm-up significantly decreased (Δ -0.03 ± 0.06, P = 0.039). Conclusion: In patients with MetS, there was no significant difference between HIIT, irrespective of volume, to MICT for improving exercise capacity or metabolic health.

Iron Deficiency Impacts Diastolic Function, Aerobic Exercise Capacity, and Patient Phenotyping in Heart Failure With Preserved Ejection Fraction: A Subanalysis of the OptimEx-Clin Study.

AIMS: Iron deficiency (ID) is linked to reduced aerobic exercise capacity and poor prognosis in patients with heart failure (HF) with reduced ejection fraction (HFrEF); however, data for HF with preserved ejection fraction (HFpEF) is scarce. We assessed the relationship between iron status and diastolic dysfunction as well as aerobic exercise capacity in HFpEF, and the contribution of iron status to patient phenotyping. METHODS AND RESULTS: Among 180 patients with HFpEF (66% women; median age, 71 years) recruited for the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx-Clin) trial, baseline iron status, including iron, ferritin, and transferrin saturation, was analyzed (n = 169) in addition to exercise capacity (peak oxygen uptake [peak V̇O2]) and diastolic function (E/e'). ID was present in 60% of patients and was more common in women. In multivariable linear regression models, we found that diastolic function and peak V̇O2 were independently related to iron parameters; however, these relationships were present only in patients with HFpEF and ID [E/e' and iron: ß-0.19 (95% confidence interval -0.32, -0.07), p = 0.003; E/e' and transferrin saturation: ß-0.16 (-0.28, -0.04), p = 0.011; peak V̇O2 and iron: ß 3.76 (1.08, 6.44), p = 0.007; peak V̇O2 and transferrin saturation: ß 3.58 (0.99, 6.16), p = 0.007]. Applying machine learning, patients were classified into three phenogroups. One phenogroup was predominantly characterized by the female sex and few HFpEF risk factors but a high prevalence of ID (86%, p < 0.001 vs. other phenogroups). When excluding ID from the phenotyping analysis, results were negatively influenced. CONCLUSION: Iron parameters are independently associated with impaired diastolic function and low aerobic capacity in patients with HFpEF and ID. Patient phenotyping in HFpEF is influenced by including ID. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02078947.

Cluster Randomized Controlled Trial on the Effects of 12 Months of Combined Exercise Training during Hemodialysis in Patients with Chronic Kidney Disease-Study Protocol of the Dialysis Training Therapy (DiaTT) Trial.

Patients with chronic kidney disease (CKD) on hemodialysis (HD) experience treatment-related immobility and physical deconditioning, which is responsible for an increased risk of frailty and a high burden of multi-morbidity. Exercise has been shown to counteract this vicious cycle; however, its effectiveness has only been investigated in small cohorts. Therefore, the objective of the Dialysis Training Therapy (DiaTT) trial will be to assess the effects of a 12-month intradialytic exercise program on physical functioning, frailty and health economics in a large cohort of HD patients in a real-world setting. DiaTT will be a prospective, cluster-randomized (1:1), controlled, multi-center, interventional clinical trial across 28 dialysis units, aiming at the recruitment of >1100 CKD patients on HD. The intervention group will receive 12 months' intradialytic exercise (combined aerobic and resistance training), whereas the usual care group will not receive intervention. The primary endpoint will be a change on the sit-to-stand test (STS60) result between baseline and 12 months. Secondary endpoints will include physical functioning, frailty, quality of life, 3-point MACE, hospitalizations, survival, quality of HD, health literacy and health care costs. By including almost as many patients as previously investigated in smaller trials, DiaTT will be the largest randomized, controlled trial assessing frailty, quality of life and mortality in the field of nephrology.

miR-181c level predicts response to exercise training in patients with heart failure and preserved ejection fraction: an analysis of the OptimEx-Clin trial.

AIMS: In patients with heart failure with preserved ejection fraction (HFpEF), exercise training improves the quality of life and aerobic capacity (peakV·O2). Up to 55% of HF patients, however, show no increase in peakV·O2 despite adequate training. We hypothesized that circulating microRNAs (miRNAs) can distinguish exercise low responders (LR) from exercise high responders (HR) among HFpEF patients. METHODS AND RESULTS: We selected HFpEF patients from the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx) study which attended ≥70% of training sessions during 3 months (n = 51). Patients were defined as HR with a change in peakV·O2 above median (6.4%), and LR as below median (n = 30 and n = 21, respectively). Clinical, ergospirometric, and echocardiographic characteristics were similar between LR and HR. We performed an miRNA array (n = 377 miRNAs) in 14 age- and sex-matched patients. A total of 10 miRNAs were upregulated in LR, of which 4 correlated with peakV·O2. Validation in the remaining 37 patients indicated that high miR-181c predicted reduced peakV·O2 response (multiple linear regression, ß = -2.60, P = 0.011), and LR status (multiple logistic regression, odds ratio = 0.48, P = 0.010), independent of age, sex, body mass index, and resting heart rate. Furthermore, miR-181c decreased in LR after exercise training (P-group = 0.030, P-time = 0.048, P-interaction = 0.037). An in silico pathway analysis identified several downstream targets involved in exercise adaptation. CONCLUSIONS: Circulating miR-181c is a marker of the response to exercise training in HFpEF patients. High miR-181c levels can aid in identifying LR prior to training, providing the possibility for individualized management.

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.

Exercise training in patients with a left ventricular assist device (Ex-VAD): rationale and design of a multicentre, prospective, assessor-blinded, randomized, controlled trial.

AIMS: Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline-mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long-term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy. METHODS: The primary objective of Ex-VAD is to investigate whether a 12-week supervised ET can improve peak oxygen uptake (peakVO2 ) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow-up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac-specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries. CONCLUSIONS: The Ex-VAD trial will assess the effects of a supervised ET programme on peakVO2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD-supported patients with advanced HF.

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.