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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., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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 m 2 ) 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 (percentile 25-75 ) 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., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Although the number of patients suffering from heart failure with preserved ejection fraction (HFpEF) increases, the routine diagnosis remains a challenge. In the absence of a pathognomonic sign for HFpEF or specific treatment strategies, a prognosis-based characterization of suspected patients remains promising for both the risk stratification of the patients and a disease definition. The Heart Failure Association (HFA) of the European Society of Cardiology has introduced an algorithm with different levels of likelihood regarding the diagnosis of HFpEF, the HFA-PEFF score. We aimed to evaluate the predictive value of this algorithm in a large cohort regarding mortality, symptom burden, and the functional status., Methods and Results: DIAST-CHF is a multicentre, population-based, prospective, observational study in subjects with at least one risk factor for HFpEF between the age of 50 and 85. We calculated the HFA-PEFF score (n = 1668) and analysed the risk groups for overall mortality, cardiovascular hospitalization, and submaximal functional capacity (6-min walk distance) at baseline and after a follow-up period of 10 years. Patients with high HFA-PEFF score values 5&6 showed a higher mortality than those with an intermediate score (score values 2-4) and low score values (high 21.3% vs. intermediate 10.1% vs. low 4.3%, P < 0.001). Also, the burden of MACE (death, cardiovascular hospitalization, new myocardial infarction, first diagnosis of HF) was increased in the high score values group (high 40.7% vs. intermediate 25.9% vs. low 13.9%, P < 0.001). Similarly, patients with higher scores had higher cumulative incidences of cardiovascular hospitalizations (P = 0.011). Subjects with higher scores also had lower 6-min walk distance both at baseline and during follow-up., Conclusions: The HFA-PEFF score provides a reliable instrument to stratify suspected HFpEF patients by their risk for mortality, symptom burden, and functional status in cohort at risk with a follow-up period of 10 years. As high HFA-PEFF scores are associated with worse outcome, the HFA-PEFF algorithm describes a defining approach towards HFpEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure with preserved ejection fraction (HFpEF) is one of the most rapidly growing cardiovascular health burden worldwide, but there is still a lack of understanding about the HFpEF pathophysiology. The nitric oxide (NO) signalling pathway has been identified as a potential key element. The aim of our study was to investigate markers of NO metabolism [l-arginine (l-Arg), homoarginine (hArg), and asymmetric and symmetric dimethylarginine (ADMA and SDMA)], additional biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), endothelin-1 (ET-1), mid-regional pro-adrenomedullin (MR-proADM), copeptin, and high-sensitivity C-reactive protein (hsCRP)], and the endothelial function in an integrated approach focusing on associations with clinical characteristics in patients with HFpEF., Methods and Results: Seventy-three patients, prospectively enrolled in the 'German HFpEF Registry', were analysed. Inclusion criteria were left ventricular ejection fraction (LVEF) ≥ 50%; New York Heart Association functional class ≥ II; elevated levels of NT-proBNP > 125 pg/mL; and at least one additional criterion for structural heart disease or diastolic dysfunction. All patients underwent transthoracic echocardiography, cardiopulmonary exercise testing, and pulse amplitude tonometry (EndoPAT™). Patients were categorized in two groups based on their retrospectively calculated HFA-PEFF score. Serum concentrations of l-Arg, hArg, ADMA, SDMA, NT-proBNP, ET-1, MR-proADM, copeptin, and hsCRP were determined. Patients had a median age of 74 years, 47% were female, and median LVEF was 57%. Fifty-two patients (71%) had an HFA-PEFF score ≥ 5 (definitive HFpEF), and 21 patients (29%) a score of 3 to 4 (risk for HFpEF). Overall biomarker concentrations were 126 ± 32 μmol/L for l-Arg, 1.67 ± 0.55 μmol/L for hArg, 0.74 (0.60;0.85) μmol/L for SDMA, and 0.61 ± 0.10 μmol/L for ADMA. The median reactive hyperaemia index (RHI) was 1.55 (1.38;1.87). SDMA correlated with NT-proBNP (r = 0.291; P = 0.013), ET-1 (r = 0.233; P = 0.047), and copeptin (r = 0.381; P = 0.001). ADMA correlated with ET-1 (r = 0.250; P = 0.033) and hsCRP (r = 0.303; P = 0.009). SDMA was associated with the left atrial volume index (β = 0.332; P = 0.004), also after adjustment for age, sex, and comorbidities. Biomarkers were non-associated with the RHI. A principal component analysis revealed two contrary clusters of biomarkers., Conclusions: Our findings suggest an impaired NO metabolism as one possible key pathogenic determinant in at least a subgroup of patients with HFpEF. We argue for further evaluation of NO-based therapies. Upcoming studies should clarify whether subgroups of HFpEF patients can take more benefit from therapies that are targeting NO metabolism and pathway., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Treatment response to vericiguat, based on baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1-Q3] vs. the upper quartile [Q4]., Methods and Results: VICTORIA participants with available baseline NT-proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1-Q3 (NT-proBNP: Q1, ≤1556 pg/mL; Q2, >1556-2816 pg/mL; and Q3, >2816-5314 pg/mL), patients in Q4 (NT-proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P < 0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1-Q3, patients in Q4 had higher mean Meta-Analysis Global Group in Chronic Heart Failure risk score (27.3 ± 6.6 vs. 23.5 ± 6.4; P < 0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5 ± 25.5 vs. 65.0 ± 26.8 mL/min/1.73 m 2 ; P < 0.0001) and haemoglobin (12.8 ± 2.0 vs. 13.6 ± 1.9 g/dL; P < 0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P = 0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P < 0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1-Q3 and Q4, respectively (P < 0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient-years for vericiguat and placebo in Q1-Q3 [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69-0.88, P < 0.001] and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99-1.34, P = 0.070). Serious adverse events were more frequent in NT-proBNP Q4 (total population) compared with Q1-Q3 (38.3 vs. 32.3%; P = 0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1-Q3 (5.8 vs. 2.4%; P < 0.0001)., Conclusions: Plasma NT-proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT-proBNP values are probably too far advanced, suffering more co-morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O 2 ) 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 V̇O 2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O 2 -pulse (V̇O 2  × HR -1 , reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O 2 , is inversely associated with the change in peak V̇O 2 (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 V̇O 2 (%) was analysed as a function of baseline peak V̇O 2 and its determinants (absolute peak V̇O 2 , peak O 2 -pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O 2 through changes in peak O 2 -pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O 2 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 O 2 -pulse explained approximately 72% of the difference in changes in peak V̇O 2 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 O 2 -pulse on change in peak V̇O 2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O 2 -pulse was associated with a decreased mean change in peak V̇O 2 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 V̇O 2 (P > 0.05). Change in V̇O 2 at VT1 was not associated with any of the investigated factors (P > 0.05)., Conclusions: In patients with HFpEF, the easily measurable peak O 2 -pulse seems to be a good indicator of the potential for improving peak V̇O 2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O 2 -pulse, patients with high O 2 -pulse may need to use additional therapies to significantly increase peak V̇O 2 ., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In heart failure with preserved ejection fraction (HFpEF), the reduction of nitric oxide (NO)-bioavailability and consequently endothelial dysfunction leads to LV stiffness and diastolic dysfunction of the heart. Besides shear stress, high-density lipoprotein (HDL) stimulates endothelial cells to increased production of NO via phosphorylation of endothelial nitric oxide synthase (eNOS). For patients with heart failure with reduced ejection fraction, earlier studies demonstrated a positive impact of exercise training (ET) on HDL-mediated eNOS activation. The study aims to investigate the influence of ET on HDL-mediated phosphorylation of eNOS in HFpEF patients., Methods and Results: The present study is a substudy of the OptimEx-Clin trial. The patients were randomized to three groups: (i) HIIT (high-intensity interval training; (ii) MCT (moderate-intensity continuous training); and (iii) CG (control group). Supervised training at study centres was offered for the first 3 months. From months 4-12, training sessions were continued at home with the same exercise protocol as performed during the in-hospital phase. Blood was collected at baseline, after 3, and 12 months, and HDL was isolated by ultracentrifugation. Human aortic endothelial cells were incubated with isolated HDL, and HDL-induced eNOS phosphorylation at Ser 1177 and Thr 495 was assessed. Subsequently, the antioxidative function of HDL was evaluated by measuring the activity of HDL-associated paraoxonase-1 (Pon1) and the concentration of thiobarbituric acid-reactive substances (TBARS). After 3 months of supervised ET, HIIT resulted in increased HDL-mediated eNOS-Ser 1177 phosphorylation. This effect diminished after 12 months of ET. No effect of HIIT was observed on HDL-mediated eNOS-Thr 495 phosphorylation. MCT had no effect on HDL-mediated eNOS phosphorylation at Ser 1177 and Thr 495 . HIIT also increased Pon1 activity after 12 months of ET and reduced the concentration of TBARS in the serum after 3 and 12 months of ET. A negative correlation was observed between TBARS concentration and HDL-associated Pon1 activity in the HIIT group (r = -0.61, P < 0.05), and a trend was evident for the correlation between the change in HDL-mediated eNOS-Ser 1177 phosphorylation and the change in peak V̇O 2 after 3 months in the HIIT group (r = 0.635, P = 0.07)., Conclusions: The present study documented that HIIT but not MCT exerts beneficial effects on HDL-mediated eNOS phosphorylation and HDL-associated Pon1 activity in HFpEF patients. These beneficial effects of HIIT were reduced as soon as the patients switched to home-based ET., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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 VO 2 (pVO 2 ; 14 mL/kg/min). Seventy-seven (45%) patients reached pVO 2  < 14 and 94 (55%) pVO 2  ≥ 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/m 2 , 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 pVO 2 among all echocardiographic variables; LA reservoir strain < 23% had 37% specificity but a very high sensitivity (96%) in identifying a severely reduced pVO 2 . In logistic regression analysis, LA reservoir strain < 23% was associated with a highly increased risk of pVO 2  < 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 pVO 2  < 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 pVO 2 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 pVO 2 . LA dysfunction represents a marker of poor prognosis across LVEF borders in the CHF population., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Although the prevalence of coronary artery disease (CAD) is high among patients with atrial fibrillation (AF), studies on stress perfusion cardiac magnetic resonance (CMR) imaging frequently exclude patients with AF, and its prognostic and diagnostic value in high-risk patients with suspected or known CAD remains unclear., Methods and Results: In this longitudinal cohort study, we included 164 consecutive patients with AF during vasodilator perfusion CMR. Diagnostic value was evaluated regarding invasive coronary angiography in a subset of patients. We targeted a follow-up of >5 years and used CMR results as stratification, and the primary outcome was major adverse cardiac events [MACE, cardiovascular (CV) death and myocardial infarction (MI)]. Secondary outcomes included late coronary revascularization or stroke and the components of the primary outcome. Of the whole cohort (73.8% male, mean age 72.2 years ± 7.8 SD), 99.4% were successfully scanned (163/164 patients). Median CHA2DS2-VASc score was 4 [interquartile range (IQR) 3-5], and median 10-year risk for CV events based on SMART risk score was high (24%, IQR 16-32%). Thirty-two patients (19.6%) presented with ischaemia and 52 patients (31.9%) with late gadolinium enhancement (LGE). A combination of LGE and inducible ischaemia was present in 20 patients (12.3%). Diagnostic accuracy was 86.2% [confidence interval (CI) 68.3-96.1%]. The median follow-up was 6.6 years (IQR 3.6-7.8). Ischaemia in vasodilator perfusion CMR was significantly associated with the occurrence of MACE [P < 0.01; hazard ratio (HR) 2.65, CI 1.39-5.08], as well as LGE (P = 0.03; 1.74, CI 1.07-3.64) and the combination of both (P < 0.01; HR 2.67, CI 1.59-5.62). After adjustment by age, left ventricular ejection fraction, and the presence of diabetes, ischaemia in vasodilator perfusion CMR remained significantly associated with the occurrence of MACE (2.10, CI 1.08-4.10; P = 0.03). In secondary endpoint analysis, there was a significant association of ischaemia in CMR with CV death (P < 0.05; HR 1.93, CI 0.95-3.9) and MI (P < 0.01; HR 13, CI 1.35-125.4), while no significant association was found regarding the occurrence of revascularization (P = 0.45; HR 1.43, CI 0.57-3.58) or stroke (P = 0.99; HR 0.99, CI 0.21-2.59)., Conclusions: Vasodilator stress perfusion CMR demonstrated an excellent diagnostic and significant prognostic value at long-term follow-up in high-risk patients with persistent AF and suspected or known CAD., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors., Methods and Results: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408)., Conclusions: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF., Methods and Results: Heart failure with preserved ejection fraction-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca 2+ ) transients were assessed. ZSF-1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e' ratio), and preserved LV ejection fraction. ZSF-1 obese animals developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF-1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca 2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca 2+ release with increased stimulation frequency was lost in ZSF-1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF-1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF-1 obese rats., Conclusions: Right ventricular dysfunction in obese ZSF-1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca 2+ amplitudes, loss of frequency-dependent augmentation of Ca 2+ release, and increased myofilament Ca 2+ sensitivity., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Skeletal muscle (SM) alterations contribute to exercise intolerance in heart failure patients with preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction (LVEF). Protein degradation via the ubiquitin-proteasome-system (UPS), nuclear apoptosis, and reduced mitochondrial energy supply is associated with SM weakness in HFrEF. These mechanisms are incompletely studied in HFpEF, and a direct comparison between these groups is missing., Methods and Results: Patients with HFpEF (LVEF ≥ 50%, septal E/e' > 15 or >8 and NT-proBNP > 220 pg/mL, n = 20), HFrEF (LVEF ≤ 35%, n = 20) and sedentary control subjects (Con, n = 12) were studied. Inflammatory markers were measured in serum, and markers of the UPS, nuclear apoptosis, and energy metabolism were determined in percutaneous SM biopsies. Both HFpEF and HFrEF showed increased proteolysis (MuRF-1 protein expression, ubiquitination, and proteasome activity) with proteasome activity significantly related to interleukin-6. Proteolysis was more pronounced in patients with lower exercise capacity as indicated by peak oxygen uptake in per cent predicted below the median. Markers of apoptosis did not differ between groups. Mitochondrial energy supply was reduced in HFpEF and HFrEF (complex-I activity: -31% and -53%; malate dehydrogenase activity: -20% and -29%; both P < 0.05 vs. Con). In contrast, short-term energy supply via creatine kinase was increased in HFpEF but decreased in HFrEF (47% and -45%; P < 0.05 vs. Con)., Conclusions: Similarly to HFrEF, skeletal muscle in HFpEF is characterized by increased proteolysis linked to systemic inflammation and reduced exercise capacity. Energy metabolism is disturbed in both groups; however, its regulation seems to be severity-dependent., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Wearable cardioverter defibrillator (WCD, LifeVest, and Zoll) therapy has become a useful tool to bridge a temporarily increased risk for sudden cardiac death. However, despite extensive use, there is a lack of evidence whether patients with myocarditis and impaired LVEF may benefit from treatment with a WCD., Methods and Results: We conducted a single-centre retrospective observational study analysing patients with a WCD prescribed between September 2015 and April 2020 at our institution. In total, 135 patients were provided with a WCD, amongst these 76 patients (mean age 48.9 ± 13.7 years; 84.2% male) for clinically suspected myocarditis. Based on the results of the endomyocardial biopsy and, where available cardiac magnetic resonance imaging, 39 patients (51.3%) were diagnosed with myocarditis and impaired LVEF and 37 patients (48.7%) with dilated cardiomyopathy (DCM) without evidence of cardiac inflammation. The main immunohistopathological myocarditis subtype was lymphocytic myocarditis in 36 (92.3%) patients, and four patients (10.3%) of this group had an acute myocarditis. Three patients had cardiac sarcoidosis (7.7%). Ventricular tachycardia occurred in seven myocarditis (in total 41 VTs; 85.4% non-sustained) and one DCM patients (in total one non-sustained ventricular tachycardia). Calculated necessary WCD wearing time until ventricular tachycardia occurrence is 86.41 days in myocarditis compared with 6.46 years in DCM patients., Conclusions: Our data suggest that myocarditis patients may benefit from WCD therapy. However, as our study is not powered for outcome, further randomized studies powered for the outcome morbidity and mortality are necessary., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Galectin-3 (Gal-3) predicts long-term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal-3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal-3 and clinical manifestations of HFpEF, the relationship between Gal-3 and all-cause mortality, or the composite of cardiovascular hospitalization and death., Methods and Results: The observational Diast-CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal-3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non-cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut-off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal-3, and the diagnostic power to detect HFpEF was superior to N-terminal pro-brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal-3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal-3 predicted incident HFpEF (P < 0.05), adjusted all-cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N-terminal pro-brain natriuretic peptide., Conclusions: Gal-3 differentiated patients with HFpEF from an overall cohort of well-characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal-3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow-up. In conjunction with clinical parameters, Gal-3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Although heart failure (HF) is a leading cause for hospitalization and mortality, normalized and comparable non-invasive assessment of haemodynamics and myocardial action remains limited. Moreover, myocardial deformation has not been compared between the guideline-defined HF entities. The distribution of affected and impaired segments within the contracting left ventricular (LV) myocardium have also not been compared. Therefore, we assessed myocardial function impairment by strain in patients with HF and control subjects by magnetic resonance imaging after clinically phenotyping these patients., Methods and Results: This prospective study conducted at two centres in Germany between 2017 and 2018 enrolled stable outpatient subjects with HF [n = 56, including HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF)] and a control cohort (n = 12). Parameters assessed included measures for external myocardial function, for example, cardiac index and myocardial deformation measurements by cardiovascular magnetic resonance imaging, left ventricular global longitudinal strain (GLS), the global circumferential strain (GCS) and the regional distribution of segment deformation within the LV myocardium, as well as basic phenotypical characteristics. Comparison of the cardiac indices at rest showed no differences neither between the HF groups nor between the control group and HF patients (one-way ANOVA P = 0.70). The analysis of the strain data revealed differences between all groups in both LV GLS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -20.48 ± 1.62 vs. -19.27 ± 1.25. HFpEF vs. HFmrEF: -19.27 ± 1.25 vs. -15.72 ± 2.76. HFmrEF vs. HFrEF: -15.72 ± 2.76 vs. -11.51 ± 3.97.) and LV GCS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -19.74 ± 2.18 vs. -17.47 ± 2.10. HFpEF vs. HFmrEF: -17.47 ± 2.10 vs. -12.78 ± 3.47. HFrEF: -11.41 ± 3.27). Comparing the segment deformation distribution patterns highlighted the discriminating effect between the groups was much more prominent between the groups (one-way ANOVA P < 0.01) when compared by a score combining regional effects and a global view on the LV. Further analyses of the patterns among the segments affected showed that while the LVEF is preserved in HFpEF, the segments impaired in their contractility are located in the ventricular septum. The worse the LVEF is, the more segments are affected, but the septum remains an outstanding location with the most severe contractility impairment throughout the HF entities., Conclusions: While cardiac index at rest did not differ significantly between controls and stable HF patients suffering from HFrEF, HFmrEF, or HFpEF, the groups did differ significantly in LV GLS and LV GCS values. Regional strain analysis revealed that the LV septum is the location affected most, with reduced values already visible in HFpEF and further reductions in HFmrEF and HFrEF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with reduced exercise capacity elicited by skeletal muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF is available. Identification of the ideal animal model mimicking the human condition is a critical step in developing and testing treatment strategies. Several HFpEF animals have been described, but the most suitable in terms of comparability with SM alterations in HFpEF patients is unclear. The aim of the present study was to investigate molecular changes in SM of three different animal models and to compare them with alterations of muscle biopsies obtained from human HFpEF patients., Methods and Results: Skeletal muscle tissue was obtained from HFpEF and control patients and from three different animal models including the respective controls-ZSF1 rat, Dahl salt-sensitive rat, and transverse aortic constriction surgery/deoxycorticosterone mouse. The development of HFpEF was verified by echocardiography. Protein expression and enzyme activity of selected markers were assessed in SM tissue homogenates. Protein expression between SM tissue obtained from HFpEF patients and the ZSF1 rats revealed similarities for protein markers involved in muscle atrophy (MuRF1 expression, protein ubiquitinylation, and LC3) and mitochondrial metabolism (succinate dehydrogenase and malate dehydrogenase activity, porin expression). The other two animal models exhibited far less similarities to the human samples., Conclusions: None of the three tested animal models mimics the condition in HFpEF patients completely, but among the animal models tested, the ZSF1 rat (ZSF1-lean vs. ZSF1-obese) shows the highest overlap to the human condition. Therefore, when studying therapeutic interventions to treat HFpEF and especially alterations in the SM, we suggest that the ZSF1 rat is a suitable model., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Atrial contractile dysfunction contributes to worse prognosis in hypertensive heart disease (HHD), but the role of cardiomyocyte dysfunction in atrial remodelling in HHD is not well understood. We investigated and compared cellular mechanisms of left (LA) and right atrial (RA) contractile dysfunction in pigs with HHD., Methods and Results: In vivo electrophysiological and magnetic resonance imaging studies were performed in control and pigs treated with 11-deoxycorticosterone acetate (DOCA)/high-salt/glucose diet (12 weeks) to induce HHD. HHD leads to significant atrial remodelling and loss of contractile function in LA and a similar trend in RA (magnetic resonance imaging). Atrial remodelling was associated with a higher inducibility of atrial fibrillation but unrelated to changes in atrial refractory period or fibrosis (histology). Reduced atrial function in DOCA pigs was related to reduced contraction amplitude of isolated LA (already at baseline) and RA myocytes (at higher frequencies) due to reduced intracellular Ca release (Fura 2-AM, field stimulation). However, Ca regulation differed in LA and RA cardiomyocytes: LA cardiomyocytes showed reduced sarcoplasmic reticulum (SR) [Ca], whereas in RA, SR [Ca] was unchanged and SR Ca 2+ -ATPase activity was increased. Sodium-calcium exchanger (NCX) activity was not significantly altered. We used ORM-10103 (3 μM), a specific NCX inhibitor to improve Ca availability in LA and RA cardiomyocytes from DOCA pigs. Partial inhibition of NCX increased Ca 2+ transient amplitude and SR Ca in LA, but not RA cells., Conclusions: In this large animal model of HHD, atrial remodelling in sinus rhythm in vivo was related to differential LA and RA cardiomyocyte dysfunction and Ca signalling. Selective acute inhibition of NCX improved Ca release in diseased LA cardiomyocytes, suggesting a potential therapeutic approach to improve atrial inotropy in HHD., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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 VO 2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO 2  < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO 2  ≥ 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/m 2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m 2 ), 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 VO 2 (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 VO 2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [β 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 VO 2  < 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 VO 2 values (R 2 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 VO 2  < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO 2  < 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., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The diagnostic and treatment of patients with heart failure with preserved ejection fraction (HFpEF) are both hampered by an incomplete understanding of the pathophysiology of the disease. Novel imaging tools to adequately identify these patients from individuals with a normal cardiac function and respectively patients with HF with reduced EF are warranted. Computing multilayer myocardial strain with feature tracking is a fast and accurate method to assess cardiac deformation. Our purpose was to assess the HFpEF diagnostic ability of multilayer strain parameters and compare their sensitivity and specificity with other established parameters., Methods and Results: We included 20 patients with a diagnosis of HFpEF and, respectively, 20 matched controls. We assessed using feature-tracking cardiac magnetic resonance longitudinal and circumferential myocardial strain at three distinct layers of the myocardium: subendocardial (Endo-), mid-myocardial (Myo-), and subepicardial (Epi-). Comparatively, we additionally assessed various others clinical, imaging, and biochemical parameters with a putative role in HFpEF diagnostic: left ventricular end-diastolic volume (LVEDV), left ventricular mass (LVM), interventricular septum (IVS) wall thickness and free wall thickness, left atrial volume and strain, septal and lateral mitral annular early diastolic velocity (e`), E/e´ ratio, and plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Global longitudinal strain (GLS) is significantly impaired at Endo (-20.8 ± 4.0 vs. -23.2 ± 3.4, P = 0.046), Myo- (-18.0 ± 3.0 vs. -21.0 ± 2.5, P = 0.002), and Epi- (-12.2 ± 2.0 vs. -16.2 ± 2.5, P < 0.001) levels. Compared with any other imaging parameter, an Epi-GLS lower than 13% shows the highest ability to detect patients with HFpEF [area under the curve (AUC) = 0.90 (0.81-1), P < 0.001] and in tandem with NT-proBNP can diagnose with maximal sensibility (93%) and specificity (100%), patients with HFpEF from normal, composed variable [AUC = 0.98 (0.95-1), P < 0.001]. In a logistic regression model, a composite predictive variable taking into account both GLS Epi and NT-proBNP values in each individual subject reached a sensitivity of 89% and a specificity of 100% with an AUC of 0.98 (0.95-1), P < 0.001, to detect HFpEF., Conclusions: Epi-GLS is a promising new imaging parameter to be considered in the clinical assessment of HFpEF patients. Given its excellent specificity, in tandem with a highly sensitive parameter such as NT-proBNP, Epi-GLS holds the potential to greatly improve the current diagnostic algorithms., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: The Cardiac Lipid Panel (CLP) is a newly discovered panel of metabolite-based biomarkers that has shown to improve the diagnostic value of N terminal pro B type natriuretic peptide (NT-proBNP). However, little is known about its usefulness in predicting outcomes. In this study, we developed a risk score for 4-year cardiovascular death in elderly chronic heart failure (CHF) patients using the CLP., Methods and Results: From the Cardiac Insufficiency Bisoprolol Study in Elderly trial, we included 280 patients with CHF aged >65 years. A targeted metabolomic analysis of the CLP biomarkers was performed on baseline serum samples. Cox regression was used to determine the association of the biomarkers with the outcome after accounting for established risk factors. A risk score ranging from 0 to 4 was calculated by counting the number of biomarkers above the cut-offs, using Youden index. During the mean (standard deviation) follow-up period of 50 (8) months, 35 (18%) subjects met the primary endpoint of cardiovascular death. The area under the receiver operating curve for the model based on clinical variables was 0.84, the second model with NT-proBNP was 0.86, and the final model with the CLP was 0.90. The categorical net reclassification index was 0.25 using three risk categories: 0-60% (low), 60-85% (intermediate), and >85% (high). The continuous net reclassification index was 0.772, and the integrated discrimination index was 0.104., Conclusions: In patients with CHF, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term cardiovascular death more precisely. This novel approach holds promise to improve clinical risk assessment in CHF patients., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The purpose of this retrospective analysis was to examine the association of left atrial (LA) strain (i.e. LA reservoir function) with left ventricular diastolic dysfunction (DD) in patients with heart failure with reduced and preserved left ventricular ejection fraction (LVEF)., Methods and Results: We analysed the baseline echocardiographic recordings of 300 patients in sinus rhythm from the SOCRATES-PRESERVED and SOCRATES-REDUCED studies. LA volume index was normal in 89 (29.7%), of whom 60.6% had an abnormal LA reservoir strain (i.e. ≤23%). In addition, the extent of LA strain impairment was significantly associated with the severity of DD according to the 2016 American Society of Echocardiography recommendations (DD grade I: LA strain 22.2 ± 6.6, rate of abnormal LA strain 62.9%; DD grade II: LA strain 16.6 ± 7.4, rate of abnormal LA strain 88.6%; DD grade III: LA strain 11.1 ± 5.4%, rate of abnormal LA strain 95.7%; all P < 0.01). In line with these findings, LA strain had a good diagnostic performance to determine severe DD [area under the curve 0.83 (95% CI 0.77-0.88), cut-off 14.1%, sensitivity 80%, specificity 77.8%], which was significantly better than for LA volume index, LA total emptying fraction, and the mitral E/e' ratio., Conclusions: The findings of this analysis suggest that LA strain could be a useful parameter in the evaluation of DD in patients with heart failure and sinus rhythm, irrespective of LVEF., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Whereas syncopal episodes are a frequent complication of cardiovascular disorders, including heart failure (HF), little is known whether syncopes impact the prognosis of patients with HF. We aimed to assess the impact of a history of syncope (HoS) on overall and hospitalization-free survival of these patients., Methods and Results: We pooled the data of prospective, nationwide, multicentre studies conducted within the framework of the German Competence Network for Heart Failure including 11 335 subjects. Excluding studies with follow-up periods <10 years, we assessed 5318 subjects. We excluded a study focusing on cardiac changes in patients with an HIV infection because of possible confounding factors and 849 patients due to either missing key parameters or missing follow-up data, resulting in 3594 eligible subjects, including 2130 patients with HF [1564 patients with heart failure with reduced ejection fraction (HFrEF), 314 patients with heart failure with mid-range ejection fraction, and 252 patients with heart failure with preserved ejection fraction (HFpEF)] and 1464 subjects without HF considered as controls. HoS was more frequent in the overall cohort of patients with HF compared with controls (P < 0.001)-mainly driven by the HFpEF subgroup (HFpEF vs. controls: 25.0% vs. 12.8%, P < 0.001). Of all the subjects, 14.6% reported a HoS. Patients with HFrEF in our pooled cohort showed more often syncopes than subjects without HF (15.0% vs. 12.8%, P = 0.082). Subjects with HoS showed worse overall survival [42.4% vs. 37.9%, hazard ratio (HR) = 1.21, 99% confidence interval (0.99, 1.46), P = 0.04] and less days alive out of hospital [HR = 1.39, 99% confidence interval (1.18, 1.64), P < 0.001] compared with all subjects without HoS. Patients with HFrEF with HoS died earlier [30.3% vs. 41.6%, HR = 1.40, 99% confidence interval (1.12, 1.74), P < 0.001] and lived fewer days out of hospital than those without HoS. We could not find these changes in mortality and hospital-free survival in the heart failure with mid-range ejection fraction and HFpEF cohorts. HoS represented a clinically high-risk profile within the HFrEF group-combining different risk factors. Further analyses showed that among patients with HFrEF with HoS, known cardiovascular risk factors (e.g. age, male sex, diabetes mellitus, and anaemia) were more prevalent. These constellations of the risk factors explained the effect of HoS in a multivariable Cox regression models., Conclusions: In a large cohort of patients with HF, HoS was found to be a clinically and easily accessible predictor of both overall and hospitalization-free survival in patients with HFrEF and should thus routinely be assessed., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Cardiac resynchronization therapy (CRT) improves functional status, induces reverse left ventricular remodelling, and reduces hospitalization and mortality in patients with symptomatic heart failure, left ventricular systolic dysfunction, and QRS prolongation. However, the impact of iron deficiency on CRT response remains largely unclear. The purpose of the study was to assess the effect of functional and absolute iron deficiency on reverse cardiac remodelling, clinical response, and outcome after CRT implantation., Methods and Results: The relation of iron deficiency and cardiac resynchronization therapy response (RIDE-CRT) study is a prospective observational study. We enrolled 77 consecutive CRT recipients (mean age 71.3 ± 10.2 years) with short-term follow-up of 3.3 ± 1.9 months and long-term follow-up of 13.0 ± 3.2 months. Primary endpoints were reverse cardiac remodelling on echocardiography and clinical CRT response, assessed by change in New York Heart Association classification. Echocardiographic CRT response was defined as relative improvement of left ventricular ejection fraction ≥ 20% or left ventricular global longitudinal strain ≥ 20%. Secondary endpoints were hospitalization for heart failure and all-cause mortality (mean follow-up of 29.0 ± 8.4 months). At multivariate analysis, iron deficiency was identified as independent predictor of echocardiographic (hazard ratio 4.97; 95% confidence interval 1.15-21.51; P = 0.03) and clinical non-response to CRT (hazard ratio 4.79; 95% confidence interval 1.30-17.72, P = 0.02). We found a significant linear-by-linear association between CRT response and type of iron deficiency (P = 0.004 for left ventricular ejection fraction improvement, P = 0.02 for left ventricular global longitudinal strain improvement, and P = 0.003 for New York Heart Association response). Iron deficiency was also significantly associated with an increase in all-cause mortality (P = 0.045) but not with heart failure hospitalization., Conclusions: Iron deficiency is a negative predictor of effective CRT therapy as assessed by reverse cardiac remodelling and clinical response. Assessment of iron substitution might be a relevant treatment target to increase CRT response and outcome in chronic heart failure patients., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Although the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin-converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background-medication-based individualized comparators (BMICs) on N-terminal pro-B-type natriuretic peptide (NT-proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial., Methods: PARALLAX is a prospective, randomized, controlled, double-blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II-IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co-morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT-proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden., Conclusions: PARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co-morbidities improves NT-proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Although heart failure (HF) with preserved ejection fraction (HFpEF) is a leading cause for hospitalization, its overall costs remain unclear. Therefore, we assessed the health care-related costs of ambulatory HFpEF patients and the effect of spironolactone., Methods and Results: The aldosterone receptor blockade in diastolic HF trial is a multicentre, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2011 at 10 sites in Germany and Austria that included 422 ambulatory patients [mean age: 67 years (standard deviation: 8); 52% women]. All subjects suffered from chronic New York Heart Association (NYHA) class II or III HF and preserved left ventricular ejection fraction of 50% or greater. They also showed evidence of diastolic dysfunction. 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. We used a single-patient approach to explore the resulting general cost structure and included medication, number of general practitioner and cardiologist visits, and hospitalization in both acute and rehabilitative care facilities. The average annual costs per patient in this cohort came up to €1, 118 (±2,475), and the median costs were €332. We confirmed that the main cost factor was hospitalization and spironolactone did not affect the overall costs. We identified higher HF functional class (NYHA), male patients with low haemoglobin level, with high oxygen uptake (VO 2 max) and coronary artery disease, hyperlipidaemia, and atrial fibrillation as independent predictors for higher costs., Conclusions: In this relatively young, oligosymptomatic, and with regard to the protocol without major comorbidities patient cohort, the overall costs are lower than expected compared with the HFrEF population. Further investigation is needed to investigate the impact of, for example, comorbidities and their effect over a longer period of time. Simultaneously, this analysis suggests that prevention of comorbidities are necessary to reduce costs in the health care system., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: A multitude of cardiac magnetic resonance (CMR) techniques are used for myocardial strain assessment; however, studies comparing them are limited. We sought to compare global longitudinal (GLS), circumferential (GCS), segmental longitudinal (SLS), and segmental circumferential (SCS) strain values, as well as reproducibility between CMR feature tracking (FT), tagging (TAG), and fast-strain-encoded (fast-SENC) CMR techniques., Methods and Results: Eighteen subjects (11 healthy volunteers and seven patients with heart failure) underwent two CMR scans (1.5T, Philips) with identical parameters. Global and segmental strain values were measured using FT (Medis), TAG (Medviso), and fast-SENC (Myocardial Solutions). Friedman's test, linear regression, Pearson's correlation coefficient, and Bland-Altman analyses were used to assess differences and correlation in measured GLS and GCS between the techniques. Two-way mixed intra-class correlation coefficient (ICC), coefficient of variance (COV), and Bland-Altman analysis were used for reproducibility assessment. All techniques correlated closely for GLS (Pearson's r: 0.86-0.92) and GCS (Pearson's r: 0.85-0.94). Intra-observer and inter-observer reproducibility was excellent in all techniques for both GLS (ICC 0.92-0.99, CoV 2.6-10.1%) and GCS (ICC 0.89-0.99, CoV 4.3-10.1%). Inter-study reproducibility was similar for all techniques for GLS (ICC 0.91-0.96, CoV 9.1-10.8%) and GCS (ICC 0.95-0.97, CoV 7.6-10.4%). Combined segmental intra-observer reproducibility was good in all techniques for SLS (ICC 0.914-0.953, CoV 12.35-24.73%) and SCS (ICC 0.885-0.978, CoV 10.76-19.66%). Combined inter-study SLS reproducibility was the worst in FT (ICC 0.329, CoV 42.99%), while fast-SENC performed the best (ICC 0.844, CoV 21.92%). TAG had the best reproducibility for combined inter-study SCS (ICC 0.902, CoV 19.08%), while FT performed the worst (ICC 0.766, CoV 32.35%). Bland-Altman analysis revealed considerable inter-technique biases for GLS (FT vs. fast-SENC 3.71%; FT vs. TAG 8.35%; and TAG vs. fast-SENC 4.54%) and GCS (FT vs. fast-SENC 2.15%; FT vs. TAG 6.92%; and TAG vs. fast-SENC 2.15%). Limits of agreement for GLS ranged from ±3.1 (TAG vs. fast-SENC) to ±4.85 (FT vs. TAG) for GLS and ±2.98 (TAG vs. fast-SENC) to ±5.85 (FT vs. TAG) for GCS., Conclusions: We found significant differences in measured GLS and GCS between FT, TAG, and fast-SENC. Global strain reproducibility was excellent for all techniques. Acquisition-based techniques had better reproducibility than FT for segmental strain., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

This study aims to assess the usefulness of strain-encoded magnetic resonance (SENC) for the quantification of myocardial deformation ('strain') in healthy volunteers and for the diagnostic workup of patients with different cardiovascular pathologies. SENC was initially described in the year 2001. Since then, the SENC sequence has undergone several technical developments, aiming at the detection of strain during single-heartbeat acquisitions (fast-SENC). Experimental and clinical studies that used SENC and fast-SENC or compared SENC with conventional cine or tagged magnetic resonance in phantoms, animals, healthy volunteers, or patients were systematically searched for in PubMed. Using 'strain-encoded magnetic resonance and SENC' as keywords, three phantom and three animal studies were identified, along with 27 further clinical studies, involving 185 healthy subjects and 904 patients. SENC (i) enabled reproducible assessment of myocardial deformation in vitro, in animals and in healthy volunteers, (ii) showed high reproducibility and substantially lower time spent compared with conventional tagging, (iii) exhibited incremental value to standard cine imaging for the detection of inducible ischaemia and for the risk stratification of patients with ischaemic heart disease, and (iv) enabled the diagnostic classification of patients with transplant vasculopathy, cardiomyopathies, pulmonary hypertension, and diabetic heart disease. SENC has the potential to detect a wide range of myocardial diseases early, accurately, and without the need of contrast agent injection, possibly enabling the initiation of specific cardiac therapies during earlier disease stages. Its one-heartbeat acquisition mode during free breathing results in shorter cardiovascular magnetic resonance protocols, making its implementation in the clinical realm promising., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF., Methods and Results: We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e' medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]., Conclusions: Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

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 VO 2  ≤ 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 VO 2 , 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., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Progressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3-LVH trial will test the hypothesis that the β 3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction., Methods and Results: Beta3-LVH is a randomized, placebo-controlled, double-blind, two-armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co-primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e' ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F-fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed., Conclusions: Beta3-LVH is the first large-scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3-LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Myocarditis is often associated with parvovirus B19 (B19V) persistence, which can induce vascular damage. Based on the antiviral and anti-inflammatory properties of telbivudine, we aimed to evaluate its efficacy to protect B19V-infected endothelial cells in vitro and to treat chronic lymphocytic myocarditis patients with B19V transcriptional activity., Methods and Results: We evaluated the endothelial-protective potential of telbivudine in human microvascular endothelial cells-1, which were infected with B19V. Treatment with 10 ng/mL of telbivudine decreased the B19V-induced endothelial cell apoptosis and endothelial-to-mesenchymal transition. Along with this finding, telbivudine reduced the expression of transforming growth factor-β1 and of tenascin-C. The endothelial-protective properties of telbivudine were also found in tumour necrosis factor-α-stressed human microvascular endothelial cells-1. In addition, oxidative stress in angiotensin II-stressed and transforming growth factor-β1-stressed HL-1 cardiomyocytes and fibroblasts, respectively, was reduced upon telbivudine treatment, illustrating that telbivudine exerts multimodal protective effects. Based on these in vitro findings, four patients severely suffering from an endomyocardial biopsy-proven myocarditis associated with B19V transcriptional activity (VP1/VP2-mRNA positive) were treated with telbivudine (600 mg/dL) for 6 months in a single-patient-use approach. Follow-up biopsies 6 months after treatment showed that VP1/VP2-mRNA levels and CD3 cells decreased in all patients and were associated with an improvement in ejection fraction and New York Heart Association class. These findings were paralleled by a drop in tenascin-C expression as shown via matrix-assisted laser desorption ionization-imaging mass spectrometry., Conclusions: Telbivudine exerts endothelial-protective effects in B19V-infected endothelial cells and improves chronic myocarditis associated with B19V transcriptional activity. These findings will be further evaluated in the clinical exploratory trial: the PreTopic study., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: In heart failure, various biomarkers are established for diagnosis and risk stratification; however, little is known about the relevance of serial measurements during an episode worsening heart failure (WHF). This study sought to investigate the trajectory of natriuretic peptides and multiple novel biomarkers during hospitalization for WHF and to determine the best time point to predict outcome., Methods and Results: MOLITOR (Impact of Therapy Optimisation on the Level of Biomarkers in Patients with Acute and Decompensated Chronic Heart Failure) was an eight-centre prospective study of 164 patients hospitalized with a primary diagnosis of WHF. C-terminal fragment of pre-pro-vasopressin (copeptin), N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and C-terminal pro-endothelin-1 (CT-proET1) were measured on admission, after 24, 48, and 72 h, and every 72 h thereafter, at discharge and follow-up visits. Their performance to predict all-cause mortality and rehospitalization at 90 days was compared. All biomarkers decreased during recompensation (P < 0.05) except MR-proADM. Copeptin at admission was the best predictor of 90 day mortality or rehospitalization (χ 2  = 16.63, C-index = 0.724, P < 0.001), followed by NT-proBNP (χ 2  = 10.53, C-index = 0.646, P = 0.001), MR-proADM (χ 2  = 9.29, C-index = 0.686, P = 0.002), MR-proANP (χ 2  = 8.75, C-index = 0.631, P = 0.003), and CT-proET1 (χ 2  = 6.60, C-index = 0.64, P = 0.010). Re-measurement of copeptin at 72 h and of NT-proBNP at 48 h increased prognostic value (χ 2  = 23.48, C-index = 0.718, P = 0.00001; χ 2  = 14.23, C-index = 0.650, P = 0.00081, respectively)., Conclusions: This largest sample of serial measurements of multiple biomarkers in WHF found copeptin at admission with re-measurement at 72 h to be the best predictor of 90 day mortality and rehospitalization., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

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 (peakVO 2 ). In contrast, both 6MWT distance and peakVO 2 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), peakVO 2 , 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., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Aims: Previous studies demonstrated poor public awareness of heart failure (HF) compared with myocardial infarction and stroke. With respect to several activities to improve HF awareness in recent years, we present data on the development of HF awareness and information sources in Germany over 8 years., Methods and Results: In 2007, 2012, and 2015, respectively, 2531, 359, and 171 respondents answered questions about causes, presentation, prognosis, and treatment of HF from a survey developed by the German Competence Network HF. Relationships between respondents' sociodemographic data and their HF knowledge were explored and changes in knowledge and use of information sources analysed. Sixty-eight per cent of respondents knew HF as 'weakness of the heart'. Seventy-nine per cent knew shortness of breath, 74% reduced exercise tolerance, and 52% knew leg edema as symptoms. Only 40% knew all three symptoms. Although up to 34% of the respondents were directly or indirectly affected by HF, they demonstrated poor knowledge about severity and prognosis. Between 2007 and 2015, overall HF awareness has not changed; awareness about treatment has dropped significantly. Younger respondents used all media, especially internet, for information about health; older respondents preferred printed/verbal media and their physician., Conclusions: We found rather insufficient public knowledge on HF etiology and symptoms but especially about management, severity, and prognosis, which is essential for good self-care and adherence of patients. Heart failure awareness has not improved even though awareness campaigns were held over the years. It seems that especially older patients should be much more approached by their family physicians., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

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-1 ß , 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.

We report the case of a 17-year-old female patient with known hypertrophic cardiomyopathy and a Wolff-Parkinson-White syndrome. She came to our department for further evaluation of a new diagnosed dilated cardiomyopathy characterized by an enlargement of the left ventricle and a fall in ejection fraction. Clinically, she complained about atypical chest pain, arrhythmic episodes with presyncopal events, and dyspnea (NYHA III) during the last 6 months. Non-invasive and invasive examinations including magnetic resonance imaging, electrophysiological examinations, and angiography did not lead to a conclusive diagnosis. Therefore, endomyocardial biopsies (EMBs) were taken to investigate whether a specific myocardial disease caused the impairment of the left ventricular function. EMB analysis resulted in the diagnosis of a virus-negative, active myocarditis. Based on this diagnosis, an immunosuppressive treatment with prednisolone and azathioprine was started, which led to an improvement of cardiac function and symptoms within 3 months after initiating therapy. In conclusion, we show that external stress triggered by myocarditis can induce a reversible transition from a hypertrophic cardiomyopathy to a dilated cardiomyopathy phenotype. This case strongly underlines the need for a thorough and invasive examination of heart failure of unknown causes, including EMB investigations as recommend by the actual ESC position statement.

Aims: This study aimed to evaluate ventricular diastolic properties using three-dimensional echocardiography and tissue Doppler imaging at rest and during exercise in heart failure with preserved ejection fraction (HFpEF) patients with borderline evidence of diastolic dysfunction at rest., Methods and Results: Results obtained from 52 HFpEF patients (left ventricular ejection fraction ≥ 50%) identified on the basis of heart failure symptoms and E / E ' values between 8 and 15 were compared with those obtained in 26 control patients with no evidence of cardiovascular disease. Mitral flow patterns, tissue Doppler imaging, and volume analysis obtained by three-dimensional echocardiography were performed at rest and during bicycle exercise. Diastolic compliance was indexed by the E / E ' ratio and left ventricular end-diastolic volume [( E / E ')/EDV]. There were no significant differences in end-diastolic volume (EDV), stroke volume (SV), or ejection fraction at rest between groups. In 27 of the 52 patients, E / E ' increased during exercise (11.2 ± 3.7 to 16.8 ± 10.5), driven by a failure to augment early diastole ( E '). This correlated with a fall in SV and was associated with an increase in the diastolic index ( E / E ')/EDV as a measure for LV stiffness (0.122 ± 0.038 to 0.217 ± 0.14/mL), indicating that impaired diastolic reserve (designated PEF-I D R) contributed to exercise intolerance. Of the 52 patients, 25 showed no changes in E / E ' during exercise associated with a significant rise in SV and cardiac output, still inappropriate compared with controls. Despite disturbed early diastole ( E '), a blunted increase in estimated systolic LV elastance indicated that impaired systolic reserve and chronotropic incompetence rather than primarily diastolic disturbances contributed to exercise intolerance in this group (designated PEF)., Conclusion: Three-dimensional stress echocardiography may allow non-invasive analysis of changes in cardiac output that can differentiate HFpEF patients with an inappropriate increase or a fall in SV during exercise. Impaired systolic or diastolic reserve can contribute to these haemodynamic abnormalities, which may arise from different underlying pathophysiologic mechanisms.

Objectives and Background: The aim of this study was to identify determinants of submaximal exercise capacity as measured by 6 min walking distance in patients at risk for heart failure with preserved ejection fraction (HFpEF)., Methods: A cross-sectional analysis from the prospective cohort programme Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that included a total of 1937 patients (age, 50-85 years) with >1 risk factor (hypertension, atherosclerotic disease, diabetes mellitus, and obstructive sleep apnoea) was carried out. Besides comprehensive clinical phenotyping, standardized 6 min walk test and state-of-the-art echocardiography were performed, and blood samples for biomarker assessment were obtained. Patients with an ejection fraction <50% or without evaluable exercise test were excluded from this analysis., Results: One thousand three hundred eighty-seven patients fulfilled all criteria for this analysis. In the univariate analysis, 6 min walk distance was inversely related to E/e' values (P < 0.001). In the multivariate analysis, 6 min walk distance decreased significantly with age, female sex, increasing body mass index, diabetes, chronic obstructive lung disease, and peripheral artery disease. However, the association of 6 min walk distance with resting parameters of diastolic function was significantly attenuated with multivariate regression. In contrast, mid-regional pro-adrenomedullin, mid-regional pro-atrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide were independently associated with submaximal exercise capacity when added to the base model (all P < 0.001)., Conclusions: Classical risk factors for heart failure and neuroendocrine activation are independently associated with sub-maximal exercise capacity, while diastolic function parameters obtained at rest were not. This observation substantiates the role of co-morbidities as relevant contributors to the clinical picture of HFpEF and the limitation of resting indices of diastolic function for diagnosing HFpEF., (© 2015 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

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 VO 2 ) 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 VO 2 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., (© 2014 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)