Transition from asymptomatic to symptomatic systolic chronic heart failure: rationale and design of TransitionCHF.

AIMS: Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device-based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well-defined cohorts for innovative preclinical and clinical trials. METHODS AND RESULTS: TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all-cause mortality, to cardiovascular mortality, to heart failure mortality, to all-cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. CONCLUSIONS: TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure.

An altered plasma lipidome-phenome network characterizes heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial, multisystemic syndrome that involves alterations in lipid metabolism. This study aimed to test whether distinct plasma lipid profiles or lipid entities or both are associated with clinical and functional echocardiographic parameters in HFpEF. METHODS AND RESULTS: We examined the human plasma lipidome in HFpEF patients (n = 18) with left ventricular ejection fraction ≥50% and N-terminal pro-brain natriuretic peptide (NT-proBNP) >125 pg/mL and control subjects (n = 12) using mass spectrometry-based shotgun lipidomics. The cohort included 8 women and 22 men with average age of 67.8 ± 8.6 SD. The control and disease groups were not significantly different with respect to age, body mass index, systolic and diastolic blood pressure, and waist-to-hip ratio. The disease group experienced more fatigue (P < 0.001), had more often coronary artery disease (P = 0.04), and received more medications (beta-blockers, P < 0.001). The disease group had significantly different levels of HFpEF-relevant parameters, including NT-proBNP (P < 0.001), left ventricular mass index (P = 0.005), left atrial volume index (P = 0.001), and left ventricular filling index (P < 0.001), and lower left ventricular end-diastolic diameter (P = 0.014), with no difference in left ventricular ejection fraction. Significant differences in lipid profiles between HFpEF patients and controls could not be detected, including no significant differences in abundance of circulating lipids binned by carbon chain length or by double bonds, nor at the level of individual lipid species. However, there was a striking correlation between selected lipids with smoking status that was independent of disease status, as well as between specific lipids and hyperlipidaemia [with corresponding significance of either false discovery rate (FDR) <0.1 or FDR < 0.01]. In an exploratory network analysis of correlations, we observed significantly stronger correlations within the HFpEF group between individual lipids from the cholesterol ester and phosphatidylcholine (PC) classes and clinical/echocardiographic parameters such as left atrial volume index, left ventricular end-diastolic diameters, and heart rate (FDR < 0.1). In contrast, the control group showed significantly stronger negative correlations (FDR < 0.1) between individual species from the PC and sphingomyelin classes and left ventricular mass index or systolic blood pressure. CONCLUSIONS: We did not find significant direct associations between plasma lipidomic parameters and HFpEF and therefore could not conclude that any specific lipids are biomarkers of HFpEF. The validation in larger cohort is needed to confidently conclude the absence of first-order associations.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Non-eligibility for pivotal HFpEF/HFmrEF outcome trials and mortality in a contemporary heart failure cohort.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m2, COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need.

Effect of bariatric surgery on cardio-psycho-metabolic outcomes in severe obesity: A randomized controlled trial.

OBJECTIVE: Randomized evidence comparing the cardiovascular effects of surgical and conservative weight management is lacking. PATIENTS & METHODS: In this single-center, open-label randomized trial, obese patients with indication for Roux-en-Y gastric bypass (RYGB) and able to perform treadmill cardiopulmonary exercise testing (CPET) were included. After a 6-12 month run-in phase of multimodal anti-obesity treatment, patients were randomized to RYGB or psychotherapy-enhanced lifestyle intervention (PELI) and co-primary endpoints were assessed 12 months later. Thereafter, PELI patients could opt for surgery and patients were reassessed 24 months after randomization. Co-primary endpoints were mean change (95 % confidence intervals) in peak VO2 (ml/min/kg body weight) in CPET and the physical functioning scale (PFS) of the Short Form health survey (SF-36). RESULTS: Of 93 patients entering the study, 60 were randomized. Among these (median age 38 years; 88 % women; mean BMI 48·2 kg/m2), 46 (RYGB: 22 and PELI: 24) were evaluated after 12 months. Total weight loss was 34·3 % after RYGB vs. 1·2 % with PELI, while peak VO2 increased by +4·3 ml/min/kg (2·7, 5·9) vs +1·1 ml/min/kg (-0·2, 2·3); p < 0·0001. Respective improvement in PFS score was +40 (30, 49) vs +10 (1, 15); p < 0·0001. 6-minute walking distance also favored the RYGB group: +44 m (17, 72) vs +6 m (-14, 26); p < 0·0001. Left ventricular mass decreased after RYGB, but not with PELI: -32 g (-46, -17) vs 0 g (-13,13); p < 0·0001. In the non-randomized follow-up, 34 patients were assessed. Favorable changes were sustained in the RYGB group and were repeated in the 15 evaluated patients that opted for surgery after PELI. CONCLUSIONS: Among adults with severe obesity, RYGB in comparison to PELI resulted in improved cardiopulmonary capacity and quality of life. The observed effect sizes suggest that these changes are clinically relevant.

Improvement of exercise and functional capacity and quality of life in patients with heart failure by iron therapy.

Heart failure (HF) is one of the most common causes of death in industrialized countries and increases steadily with age. Patients with HF present many comorbidities that affect their clinical management, quality of life, and prognosis. Iron deficiency is a relevant comorbidity of all patients with heart failure. It remains the most prevalent nutritional deficiency worldwide, affecting an estimated 2 billion people and has a negative prognostic impact on hospitalization and mortality rate. To date, none of the previous studies, have provided evidence of reduced mortality or decrease in hospitalization with intravenous iron supplementation. This review describes the prevalence, clinical implications, and current trials on the treatment of iron deficiency in heart failure and discusses the Improvement of exercise and functional capacity and quality of life in patients with heart failure by iron therapy. Despite compelling evidence of the significant prevalence of ID in HF patients and current guidelines, ID is often not properly managed in clinical practice. Therefore, ID should be given greater consideration in HF health care practice to improve patient quality of life and outcome.

Clinical and Prognostic Relevance of Cardiac Wasting in Patients With Advanced Cancer.

BACKGROUND: Body wasting in patients with cancer can affect the heart. OBJECTIVES: The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. METHODS: This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction <40%) of similar age and sex distribution. RESULTS: Cancer patients presented with lower left ventricular (LV) mass than healthy control subjects or heart failure patients (assessed by transthoracic echocardiography: 177 ± 47 g vs 203 ± 64 g vs 300 ± 71 g, respectively; P < 0.001). LV mass was lowest in cancer patients with cachexia (153 ± 42 g; P < 0.001). Importantly, the presence of low LV mass was independent of previous cardiotoxic anticancer therapy. In 90 cancer patients with a second echocardiogram after 122 ± 71 days, LV mass had declined by 9.3% ± 1.4% (P < 0.001). In cancer patients with cardiac wasting during follow-up, stroke volume decreased (P < 0.001) and resting heart rate increased over time (P = 0.001). During follow-up of on average 16 months, 149 patients died (1-year all-cause mortality 43%; 95% CI: 37%-49%). LV mass and LV mass adjusted for height squared were independent prognostic markers (both P < 0.05). Adjustment of LV mass for body surface area masked the observed survival impact. LV mass below the prognostically relevant cutpoints in cancer was associated with reduced overall functional status and lower physical performance. CONCLUSIONS: Low LV mass is associated with poor functional status and increased all-cause mortality in cancer. These findings provide clinical evidence of cardiac wasting-associated cardiomyopathy in cancer.

Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages.

BACKGROUND: The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A-D. METHODS AND RESULTS: 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( - ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8-2.6] for CKD + , 1.7 [1.4-2.0] for anaemia, and 3.6 [2.9-4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). CONCLUSIONS: Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF.

Spironolactone effect on cardiac structure and function of patients with heart failure and preserved ejection fraction: a pooled analysis of three randomized trials.

AIMS: Spironolactone is currently used in a large proportion of patients with heart failure and preserved ejection fraction (HFpEF), yet its effect on cardiac structure and function in a large population has not been well established. The aim of this study was to evaluate the impact of spironolactone on key echocardiographic parameters in HFpEF. METHODS AND RESULTS: An individual-patient-data meta-analysis of three randomized trials (HOMAGE, Aldo-DHF, and TOPCAT) was performed comparing spironolactone (9-12 month exposure) to placebo (or control) for the changes in left atrial volume index (LAVi), left ventricular mass index (LVMi), interventricular septum (IVS) thickness, E/e' ratio, and left ventricular ejection fraction (LVEF) among patients with stage B (HOMAGE) or C (Aldo-DHF and TOPCAT) HFpEF. Analysis of covariance was used to test the effect of spironolactone on echocardiographic changes. A total of 984 patients were included in this analysis: 452 (45.9%) from HOMAGE, 398 (40.4%) from Aldo-DHF, and 134 (13.6%) from TOPCAT. The pooled-cohort patient's median age was 71 (66-77) years and 39% were women. Median LAVi was 29 (24-35) ml/m2 , LVMi 100 (84-118) g/m2 , IVS thickness 12 (10-13) mm, E/e' ratio 11 (9-13), and LVEF 64 (59-69)%. Spironolactone reduced LAVi by -1.1 (-2.0 to -0.1) ml/m2 (p = 0.03); LVMi by -3.6 (-6.4 to -0.8) g/m2 (p = 0.01); IVS thickness by -0.2 (-0.3 to -0.1) mm (p = 0.01); E/e' ratio by -1.3 (-2.4 to -0.2) (p = 0.02); and increased LVEF by 1.7 (0.8-2.6)% (p < 0.01). No treatment-by-study heterogeneity was found except for E/e' ratio with a larger effect in Aldo-DHF and TOPCAT (interaction p < 0.01). CONCLUSIONS: Spironolactone improved cardiac structure and function of patients with HFpEF.

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.

Dyskalemia in people at increased risk for heart failure: findings from the heart 'OMics' in AGEing (HOMAGE) trial.

AIMS: In people at risk of heart failure (HF) enrolled in the Heart 'OMics' in AGEing (HOMAGE) trial, spironolactone reduced circulating markers of collagen synthesis, natriuretic peptides, and blood pressure and improved cardiac structure and function. In the present report, we explored factors associated with dyskalaemia. METHODS AND RESULTS: The HOMAGE trial was an open-label study comparing spironolactone (up to 50 mg/day) versus standard care in people at risk for HF. After randomization, serum potassium was assessed at 1 and 9 months and was defined as low when ≤3.5 mmol/L (hypokalaemia) and high when ≥5.5 mmol/L (hyperkalaemia). Multivariable logistic regression models were constructed to identify clinical predictors of dyskalaemia. A total of 513 participants (median age 74 years, 75% men, median estimated glomerular filtration rate 71 mL/min/1.73 m2 ) had serum potassium available and were included in this analysis. At randomization, 88 had potassium < 4.0 mmol/L, 367 had potassium 4.0-5.0 mmol/L, and 58 had potassium > 5.0 mmol/L. During follow-up, on at least one occasion, a serum potassium < 3.5 mmol/L was observed in 6 (1.2%) and <4.0 mmol/L in 46 (9%) participants, while a potassium > 5.0 mmol/L was observed in 38 (8%) and >5.5 mmol/L in 5 (1.0%) participants. The median (percentile25-75 ) increase in serum potassium with spironolactone during the study was 0.23 (0.16; 0.29) mmol/L. Because of the low incidence of dyskalaemia, for regression analysis, hypokalaemia and hyperkalaemia thresholds were set at <4.0 and >5.0 mmol/L, respectively. The occurrence of a serum potassium > 5.0 mmol/L during follow-up was positively associated with the presence of diabetes mellitus {odds ratio [OR]: 1.21 [95% confidence interval (CI) 2.14; 3.79]} and randomization to spironolactone (OR: 2.83 [95% CI 1.49; 5.37]). Conversely, the occurrence of a potassium concentration < 4.0 mmol/L was positively associated with the use of thiazides (OR: 2.39 [95% CI 1.32; 4.34]), blood urea concentration (OR: 2.15 [95% CI 1.34; 3.39] per 10 mg/dL), and history of hypertension (OR: 2.32 [95% CI 1.02; 5.29]) and negatively associated with randomization to spironolactone (OR: 0.30 [95% CI 0.18; 0.52]). CONCLUSIONS: In people at risk for developing HF and with relatively normal renal function, spironolactone reduced the risk of hypokalaemia and, at the doses used, was not associated with the occurrence of clinically meaningful hyperkalaemia.

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 .

Left atrial strain predicts exercise capacity in heart failure independently of left ventricular ejection fraction.

AIMS: We hypothesized that left atrial (LA) remodelling and function are associated with poor exercise capacity as prognostic marker in chronic heart failure (CHF) across a broad range of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: One hundred seventy-one patients with CHF were analysed [age 65 ± 11 years, 136 males (80%); 86 heart failure with reduced ejection fraction (HFrEF), 27 heart failure with mid-range ejection fraction (HFmrEF), 58 heart failure with preserved ejection fraction (HFpEF)]. All patients underwent echocardiography and maximal cardiopulmonary exercise testing and were classified according to a prognostic cut-off of peak VO2 (pVO2 ; 14 mL/kg/min). Seventy-seven (45%) patients reached pVO2  < 14 and 94 (55%) pVO2  ≥ 14 mL/kg/min. Between the two groups, there was a considerable difference in both left atrial volume (LAVi, 53 ± 24 vs. 44 ± 18 mL/m2 , P = 0.005) and function (LA reservoir strain 12 ± 5 vs. 20 ± 10%, P < 0.0001). Receiver-operating characteristic curves identified LA reservoir strain (area under the curve: 0.73 [0.65-0.80], P < 0.0001) as strong predictor for impaired pVO2 among all echocardiographic variables; LA reservoir strain < 23% had 37% specificity but a very high sensitivity (96%) in identifying a severely reduced pVO2 . In logistic regression analysis, LA reservoir strain < 23% was associated with a highly increased risk of pVO2  < 14 mL/kg/min (odds ratio 16.0 [4.7-54.6]; P < 0.0001). The multivariate analysis showed that a reduced LA reservoir strain was associated with pVO2  < 14 mL/kg/min after adjustment for age, body mass index (BMI), and clinical variables, that is, New York Heart Association class, atrial fibrillation, haemoglobin, and creatinine (b 0.22 [95% confidence interval, CI, 0.12-0.31]; P < 0.0001), and after adjustment for echocardiographic variables, that is, LVEF or left ventricular global longitudinal strain (LVGLS) and tricuspid annular plane systolic excursion (TAPSE) (b 0.16 [95% CI 0.08-0.24]; P < 0.0001). Patients with HFrEF, HFmrEF, and HFpEF were separately analysed. Among LA reservoir strain, LAVi, LVEF, LVGLS, and TAPSE, LA reservoir strain was the only one significantly associated with pVO2 in all subgroups (after adjustment for sex and BMI, P = 0.003, 0.04, and 0.01, respectively). CONCLUSIONS: In patients with CHF, an impaired LA reservoir function is independently associated with a severely reduced pVO2 . LA dysfunction represents a marker of poor prognosis across LVEF borders in the CHF population.

Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction.

AIMS: Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes. METHODS AND RESULTS: From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (P < 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m2 , n = 464] as compared to lean HFpEF (BMI <30 kg/m2 , n = 535) and obese no-HF patients (BMI ≥30 kg/m2 , n = 387) (P < 0.001 for both); these findings were verified in the Aldo-DHF validation cohort (P < 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates. CONCLUSION: Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.

Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure.

AIMS: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure. METHODS: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR. RESULTS: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson's r, range 0.80-0.88, depending on equation used), precision (r2 , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P < 0.05) but weak (Pearson's r, range 0.35-0.39). Observed decreases of eGFR by more than 15% had a low sensitivity (range 38%-46%, depending on equation used) in detecting true worsening mGFR, defined by a >15% decrease in mGFR. CONCLUSIONS: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure.

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.

Left atrial function and maximal exercise capacity in heart failure with preserved and mid-range ejection fraction.

AIMS: Exercise intolerance is the leading manifestation of heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF), and left atrial (LA) function might contribute to modulating left ventricular filling and pulmonary venous pressures. We aim to assess the association between LA function and maximal exercise capacity in patients with HFpEF or HFmrEF. METHODS AND RESULTS: Sixty-five patients, prospectively enrolled in the German HFpEF Registry, were analysed. Inclusion criteria were New York Heart Association functional class ≥ II, left ventricular ejection fraction > 40%, structural heart disease or diastolic dysfunction, and elevated levels of N terminal pro brain natriuretic peptide (NT-proBNP). LA function was evaluated through speckle-tracking echocardiography by central reading in the Charité Academic Echocardiography core lab. All patients underwent maximal cardiopulmonary exercise test and were classified according to a peak VO2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO2  < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO2  ≥ 14 mL/kg/min (mean value 19.4 ± 3.9). There was no significant difference in left ventricular ejection fraction (60 ± 9 vs. 59 ± 8%), left ventricular mass (109 ± 23 vs. 112 ± 32 g/m2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m2 ), or E/e´ (13.1 ± 4.7 vs. 13.0 ± 6.0) between these groups. In contrast, all LA strain measures were impaired in patients with lower peak VO2 (reservoir strain 14 ± 5 vs. 21 ± 9%, P = 0.002; conduit strain 9 ± 2 vs. 13 ± 4%, P = 0.001; contractile strain 7 ± 4 vs. 11 ± 6%, P = 0.02; reported lower limits of normality for LA reservoir, conduit and contractile strains: 26.1%, 12.0%, and 7.7%). In linear regression analysis, lower values of LA reservoir strain were associated with impaired peak VO2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [ß 0.29, 95% confidence interval (CI) 0.02-0.30, P = 0.02], with an odds ratio 1.22 (95% CI 1.05-1.42, P = 0.01) for peak VO2  < 14 mL/kg/min for LA reservoir strain decrease after adjustment for these five covariates. Adding left ventricular ejection fraction, it did not influence the results. On the other hand, the addition of LA strain to the adjustment parameters alone described above provided a significant increase of the predictive value for lower peak VO2 values (R2 0.50 vs. 0.45, P = 0.02). With receiver operating characteristic curve analysis, we identified LA reservoir strain < 22% to have 93% sensitivity and 49% specificity in predicting peak VO2  < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO2  < 14 mL/kg/min in logistic regression analysis after comprehensive adjustment for age, sex, body mass index, heart rhythm, and log-NTproBNP [odds ratio 95% CI 10.4 (1.4-74), P = 0.02]. CONCLUSIONS: In this HFpEF and HFmrEF cohort, a reduction in LA reservoir strain was a sensible marker of decreased peak exercise capacity. Therefore, LA reservoir strain might be of clinical value in predicting exercise capacity in patients with HFpEF or HFmrEF.

Suppression of Tumourigenicity 2 in Heart Failure With Preserved Ejection Fraction.

Heart failure (HF), with steadily increasing incidence rates and mortality in an ageing population, represents a major challenge. Evidence suggests that more than half of all patients with a diagnosis of HF suffer from HF with preserved ejection fraction (HFpEF). Emerging novel biomarkers to improve and potentially guide the treatment of HFpEF are the subject of discussion. One of these biomarkers is suppression of tumourigenicity 2 (ST2), a member of the interleukin (IL)-1 receptor family, binding to IL-33. Its two main isoforms - soluble ST2 (sST2) and transmembrane ST2 (ST2L) - show opposite effects in cardiovascular diseases. While the ST2L/IL-33 interaction is considered as being cardioprotective, sST2 antagonises this beneficial effect by competing for binding to IL-33. Recent studies show that elevated levels of sST2 are associated with increased mortality in HF with reduced ejection fraction. Nevertheless, the significance of sST2 in HFpEF remains uncertain. This article aims to give an overview of the current evidence on sST2 in HFpEF with an emphasis on prognostic value, clinical association and interaction with HF treatment. The authors conclude that sST2 is a promising biomarker in HFpEF. However, further research is needed to fully understand underlying mechanisms and ultimately assess its full value.

Motivational interviewing can support physical activity in elderly patients with diastolic heart failure: results from a pilot study.

AIMS: Patients suffering from heart failure with preserved ejection fraction (HFpEF) report similar symptoms and reduction in quality of life to those with reduced ejection fraction but remain largely untreated. We conducted a preliminary evaluation of the acceptance, feasibility, and efficacy of a motivational interviewing (MI) intervention to support elderly patients suffering from HFpEF in maintaining or starting physical activity. METHODS AND RESULTS: At the conclusion of the exercise training in diastolic heart failure parent trial that examined the effects of supervised exercise, patients with HFpEF were offered participation in a two-group pilot study. Based on their preference, consenting patients were assigned to either a 6 month MI intervention group (n = 19) or their physicians' usual care (n = 20). To support participants in increasing and/or maintaining their physical activity, counsellors delivered a mean of 6.5 MI sessions (face to face and via telephone) and also provided a physical activity diary as self-management tool. At baseline and 6 months, we assessed participants' physical activity motivation (Sportbezogene Selbstkonkordanz Scale) and their physical improvements with the 6 min walk test and a cardiopulmonary exercise test. Of the entire sample (N = 39), 46% were female, their mean age was 73, 90% were in New York Heart Association Class II, and the mean ejection fraction was 61.4%. The majority of MI participants rated the intervention as acceptable, 90% perceived MI as helpful in setting specific exercise goals and overcoming barriers concerning physical activity, and 58% considered the physical activity diary as very helpful. Three-quarters of MI participants (79%) reported an increase in their physical activity compared with the previous year. Intervention participants showed a greater increase in median peak VO2 from baseline to 6 months (baseline: 18.4 mL/kg/min; 6 months: 20.4 mL/kg/min) compared with the control group (baseline: 20.0 mL/kg/min; 6 months: 19.2 mL/kg/min; P = 0.015). There was no significant change in motivation on the Sportbezogene Selbstkonkordanz Scale for either group (MI: 1.7 vs. 3, P = 0.55; control: 4.7 vs. 4, P = 0.26) nor did patients show any significant improvements in the 6 min walk test (MI: 549 vs. 540 m, P = 0.80; control: 572 vs. 580 m, P = 0.37). Counsellors rated the implementation of the MI intervention as feasible. CONCLUSIONS: The results from this pilot study suggest that our MI intervention was well accepted by participants and deemed feasible. It also appears to be an effective treatment to increase and maintain physical activity and exercise capacity in patients suffering from HFpEF. Our findings need to be confirmed in a randomized clinical trial with larger and unselected patient cohorts.

Diastolic stress test echocardiography in patients with suspected heart failure with preserved ejection fraction: a pilot study.

AIMS: The purpose of this pilot study was to assess the potential usefulness of diastolic stress test (DST) echocardiography in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Patients with suspected HFpEF (left ventricular ejection fraction ≥ 50%, exertional dyspnoea, septal E/e' at rest 9-14, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at rest < 220 pg/mL; n = 13) and a control group constituted from asymptomatic patients with arterial hypertension (n = 19) and healthy subjects (n = 18) were included. All patients were analysed by two-dimensional and Doppler echocardiography at rest and during exercise (DST) and underwent cardiopulmonary exercise testing and NT-proBNP analysis during exercise. HFpEF during exercise was defined as exertional dyspnoea and peak VO2  ≤ 20.0 mL/min/kg. In patients with suspected HFpEF at rest, 84.6% of these patients developed HFpEF during exercise, whereas in the group of asymptomatic patients with hypertension and healthy subjects, the rate of developed HFpEF during exercise was 0%. Regarding the diagnostic performance of DST to detect HFpEF during exercise, an E/e' ratio >15 during exercise was the most accurate parameter to detect HFpEF (accuracy 86%), albeit a low sensitivity (45.5%). Nonetheless, combining E/e' with tricuspid regurgitation (TR) velocity > 2.8 m/s during exercise provided a significant increase in the sensitivity to detect patients with HFpEF during exercise (sensitivity 72.7%, specificity 79.5%, and accuracy 78%). Consistent with these findings, an increase of E/e' was significantly linked to worse peak VO2 , and the combination of an increase of both E/e' and TR velocity was associated with elevated NT-proBNP values during exercise. CONCLUSIONS: The findings of this pilot study suggest that DST using E/e' ratio and TR velocity could be of potential usefulness to diagnose HFpEF during exercise in patients with suspected HFpEF at rest.