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Background: Cardiac amyloidosis (CA) often mimics heart failure with preserved ejection fraction (HFpEF). Due to very different treatment strategies, an exact diagnosis and differentiation between pure HFpEF and CA-related heart failure (HF) is important. In the present study, we assessed the recently published H2FPEF score in patients with pure HFpEF, transthyretin (ATTR), as well as light chain (AL) amyloidosis-related HFpEF and tested whether it differentiates between these entities., Methods: The H2FPEF scores consists of easy-to-assess clinical (Body Mass Index, number of hypertensive drugs, presence of atrial fibrillation, age) and echocardiographic (systolic pulmonary arterial pressure, E/E´) parameters. It can be computed in a categorical way resulting in scores between 0 and 9 points (0-1: HFpEF rule out, 2-5: further testing required, 6-9: HFpEF rule in), or in a continual way providing an exact percentage of a patient's HFpEF probability. Continuous and categorical variables were compared using the Kruskal-Wallis, Mann-Whitney-U, and χ 2 -tests. Diagnostic accuracy was computed from 2x2 tables. Survival analysis was performed with Kaplan-Meier curves. A P value of <0.05 was set as the level of significance., Results: A total of 100 patients with pure HFpEF, 53 patients with ATTR, and 34 patients with AL CA were included in the present study. Median age (HFpEF: 71.5 years; ATTR CA: 77.0 years; AL CA: 60.0 years; P<0.001), gender distribution (HFpEF [female]: 73.0%, ATTR (female): 18.9%, AL [female]: 38.2%; P<0.001), and N-terminal prohormone of brain natriuretic peptide (HFpEF: 1045pg/mL; ATTR CA: 1927pg/mL; AL CA: 4308pg/mL; P<0.001) differed significantly between study cohorts. Median H2FPEF scores were highest among HFpEF (categorical: 5.0 points; continual: 95.1%), followed by ATTR (categorical: 4.0 points; continual: 89.0%), and AL CA (categorical: 3.0 points; continual: 31.2%). Respective P values were <0.001. Low H2FPEF scores (0-1 points) were found among patients in the AL CA cohort (29.4%), but not among HFpEF or ATTR CA patients (P<0.001). The majority of patients, irrespective of disease entity were in the intermediate score range (2-5 points, HFpEF: 80.0% ATTR CA: 94.3%, AL CA: 67.9%; P=0.006). High scores (6-9 points) were most often found among HFpEF patients (20.0%), followed by ATTR CA (5.7%) and AL CA (2.9%), (P=0.007)., Conclusions: The H2FPEF score should be used with caution, as there is a significant overlap between HFpEF and CA-related HF.

Aims: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF., Methods and Results: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred., Conclusion: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period., Competing Interests: Conflict of interest: E.G. received grants/contracts from Bayer, MSD, United Therapeutics and OMT; consulting fees from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics; payments/honoraria from Bayer, Janssen and MSD; support for attending meetings and/or travel from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics. E.G. participated on data monitoring/advisory boards for Janssen, United Therapeutics, and Acceleron. I.P. has received honoraria for lectures from Orion, AOP Orphan and Amomed. D.B. received financial support for the present manuscript in form of an unrestricted research grant by Bayer (all payments were made to the Medical University of Vienna); research grants by Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi (all payments were made to the Medical University of Vienna); and payments/honoraria from Bayer AG, Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi, Astra Zeneca, Boehringer Ingelheim, Zoll, Janssen, AOP Orphan, and MSD. All other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Precise risk stratification remains challenging. The one-minute sit-to-stand-test (1-min STST), a quick, objective test of functional capacity may be helpful for stratification of clinical profile in HFpEF patients., Objective: The aim of this initial investigation was to prospectively examine whether the 1-min STST can be used for the evaluation of exercise capacity in HFpEF patients and whether it is in line with echocardiographic as well as quality of life (QoL) findings., Methods: 39 HFpEF patients were prospectively studied. Functional performance was examined with the 1-min STST and QoL with the CAMPHOR questionnaire. Clinical parameters including echocardiographic measurements [estimated pulmonary artery systolic pressure (ePASP), tricuspid regurgitation velocity (TRV)] were obtained. Patients were divided into two groups based on their number of 1-min STST repetitions (Group I: ≤50% of predicted 1-min STST repetitions using the norm-reference values developed by Strassmann et al. for healthy people, N=24; Group II: >50% of predicted 1-min STST repetitions, N=15)., Results: Patients in group I with limited 1-min STST performance showed worse echocardiographic parameters [higher ePASP (p=0.038), higher TRV (p=0.018) and more reduced tricuspid annular plane systolic excursion (TAPSE) (p=0.001)], worse six-minute walk test (6MWT) (p<0.001) and worse QoL (p<0.001) compared to patients in group II., Conclusion: Our study shows potential usefulness of the 1-min STST as an evaluative tool for exercise capacity in HFpEF patients, because patients with worse 1-min STST performance have worse clinical parameters and QoL., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET)., Methods: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO 2 at follow-up was defined as ∆peak VO 2 ≥1.0 mL/(kg·min), stable peak VO 2 was defined as 0≤∆peak VO 2 <1.0 mL/(kg·min), and decline in peak VO 2 was defined by ∆peak VO 2 <0 mL/(kg·min)., Results: Baseline peak VO 2 >14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization ( P =0.002, P =0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance ( P =0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO 2 ( P <0.0001), an improvement of peak VO 2 ( P <0.0001), and better physical performance at follow-up ( P <0.0001). Patients with stable or improved peak VO 2 had less advanced heart disease at baseline ( P =0.046)., Conclusions: Our findings demonstrate that baseline peak VO 2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls ( p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity ( p = 0.031) and correlated with neutrophil mNEP ( p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both ( p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Background: Heart failure with preserved ejection fraction (HFpEF) is among the most common forms of heart failure (HF). We aimed to investigate the prognostic significance of serum potassium levels and its interaction with type-2 diabetes mellitus in patients with HFpEF., Methods: Consecutive HFpEF patients were prospectively included in a registry study. The primary endpoint was a composite of cardiac death or HF hospitalization., Results: 363 HFpEF patients were enrolled (median age: 73.0 years; females: 70.3%). Median serum potassium (K+) was 4.3 mmol/L. A total of 128 (35.3%) patients had type-2 diabetes mellitus, of whom 92 were treated with oral anti-diabetic drugs and 35 with insulin. The study population was divided into two groups, according to their serum potassium levels. Significant differences between the groups were detected with regards to combined endpoint [n = 27 (61.4%) versus n = 87 (27.3%); p < 0.0001]. Lower serum potassium levels were significantly associated with adverse outcome in the Cox proportional hazard analysis [hazard ratio (HR): 1.83; 95% confidence interval (CI) 1.14-2.94; p = 0.0118]. Further independent predictors of adverse outcome were a history of HF hospitalizations (HR: 2.77; 95% CI 1.82-4.21; p < 0.0001), higher NT-pro BNP (HR: 1.93; 95% CI 1.82-4.21; p = 0.0084) as well as type-2 diabetes mellitus (HR: 1.57; 95% CI 1.05-2.34; p = 0.0027). Patients with diabetes and K+ ≤ 3.71 mmol/L faced the worst outcome as compared to the remainder of the group (p = 0.0001)., Conclusion: In HFpEF patients, the combination of diabetes and low serum potassium levels are associated with an adverse outcome., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Cardiac amyloidosis (CA) leads to signs and symptoms of heart failure (HF). The mechanisms of biventricular dysfunction and their impact on outcome in subtypes of CA are poorly understood. Our aim was to compare right ventricular (RV) and left ventricular (LV) parameters in patients with light chain (AL) and wild-type transthyretin amyloidosis (ATTRw) and evaluate their ability to predict cardiac outcome., Methods and Results: We included patients with CA into a prospective registry. Baseline assessment included biventricular 2D speckle tracking imaging parameters. Patients were followed-up in regular intervals. The composite endpoint was defined as cardiovascular death, heart transplantation or ventricular assist device implantation, and HF hospitalization. We included 122 patients with CA. Sixty-two of these patients (50.8%) were diagnosed with ATTRw and 60 (49.2%) with AL. In ATTRw, parameters of RV size and function correlated well with symptom severity and only morphological and functional parameters of the RV predicted outcome. RV free wall strain was the only independent predictor of outcome with a hazard ratio (HR) of 1.185 [95% confidence interval (CI) 1.047-1.342, P = 0.007]. In AL on the other hand, RV function correlated well with symptoms but was not associated with outcome. In contrast, global longitudinal strain of the LV (LV-GLS) was predictive for outcome. After adjusting in a multivariable model, LV-GLS remained predictive with a HR of 1.180 (95% CI 1.032-1.348, P = 0.015)., Conclusion: Our data suggest that mechanisms underlying HF differ between ATTRw and AL. This may have substantial implications in particular in light of emerging therapies for both subtypes of CA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)