Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.

The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.

Ticagrelor or prasugrel vs. clopidogrel in patients with atrial fibrillation undergoing percutaneous coronary intervention for myocardial infarction.

Aims: The efficacy and safety of ticagrelor or prasugrel vs. clopidogrel in patients with atrial fibrillation (AF) on oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI) have not been established. Methods and results: This was a nationwide cohort study of patients on OAC for AF who underwent PCI for MI from 2011 through 2019 and were prescribed a P2Y12 inhibitor at discharge. The primary efficacy outcome was major adverse cardiovascular events (MACE), defined as a composite of death from any cause, stroke, recurrent MI, or repeat revascularization. The primary safety outcome was cerebral, gastrointestinal, or urogenital bleeding requiring hospitalization. Absolute and relative risks for outcomes at 1 year were calculated through multivariable logistic regression with average treatment effect modelling. Outcomes were standardized for the individual components of the CHA2DS2-VASc and HAS-BLED scores as well as type of OAC, aspirin, and proton pump inhibitor use. We included 2259 patients of whom 1918 (84.9%) were prescribed clopidogrel and 341 (15.1%) ticagrelor or prasugrel. The standardized risk of MACE was significantly lower in the ticagrelor or prasugrel group compared with the clopidogrel group (standardized absolute risk, 16.3% vs. 19.4%; relative risk, 0.84, 95% confidence interval, 0.70-0.98; P = 0.02), while the risk of bleeding did not differ (standardized absolute risk, 5.5% vs. 5.1%; relative risk, 1.07, 95% confidence interval, 0.73-1.41; P = 0.69). Conclusion: In patients with AF on OAC who underwent PCI for MI, treatment with ticagrelor or prasugrel vs. clopidogrel was associated with reduced ischaemic risk, without a concomitantly increased bleeding risk.

Metabolic Profiling Identifies 1-MetHis and 3-IPA as Potential Diagnostic Biomarkers for Patients With Acute and Chronic Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Metabolomics has become a valuable tool for identifying potential new biomarkers and metabolic profiles. It has the potential to improve the diagnosis and prognosis of different phenotypes of heart failure. To generate a distinctive metabolic profile, we assessed and compared the metabolic phenotypes of patients with acute decompensated heart failure (ADHF), patients with chronic heart failure (CHF), and healthy controls. METHODS: Plasma metabolites were analyzed by liquid-chromatography mass spectrometry/mass spectrometry and the MxP Quant 500 kit in 15 patients with ADHF, 50 patients with CHF (25 with dilated cardiomyopathy, 25 with ischemic cardiomyopathy), and 13 controls. RESULTS: Of all metabolites identified to be significantly altered, 3-indolepropionic acid and 1-methyl histidine showed the highest concentration differences in ADHF and CHF compared with control. Area under the curve-receiver operating characteristic analysis showed an area under the curve ≥0.8 for 3-indolepropionic acid and 1-methyl histidine, displaying good discrimination capabilities between control and patient cohorts. Additionally, symmetrical dimethylarginine (mean, 1.97±0.61 [SD]; P=0.01) was identified as a suitable biomarker candidate for ADHF and kynurenine (mean, 1.69±0.39 [SD]; P=0.009) for CHF when compared with control, both demonstrating an area under the curve ≥0.85. CONCLUSIONS: Our study provides novel insights into the metabolic differences between ADHF and CHF and healthy controls. We here identify new metabolites for potential diagnostic and prognostic purposes.

Magnetic resonance imaging of organ iron before and after correction of iron deficiency in patients with heart failure.

AIMS: Intravenous iron therapy (IVIT) is known to improve functional status in chronic heart failure (CHF) patients. The exact mechanism is not completely understood. We correlated magnetic resonance imaging (MRI) patterns of T2* iron signal in various organs to systemic iron and exercise capacity (EC) in CHF before and after IVIT. METHODS AND RESULTS: We prospectively analysed 24 patients with systolic CHF for T2* MRI pattern of the left ventricle (LV), small and large intestines, spleen, liver, skeletal muscle, and brain for iron. In 12 patients with iron deficiency (ID), we restored iron deficit by IVIT using ferric carboxymaltose. The effects after 3 months were analysed by spiroergometry and MRI. Patients with vs. without ID showed lower blood ferritin, haemoglobin (76 ± 63 vs. 196 ± 82 µg/L and 12.3 ± 1.1 vs. 14.2 ± 1.1 g/dL, all P < 0.002), and in trend a lower transferrin saturation (TSAT) (19.1 [13.1; 28.2] vs. 25.1 [21.3; 29.1] %, P = 0.05). Spleen and liver iron was lower as expressed by higher T2* value (71.8 [66.4; 93.1] vs. 36.9 [32.9; 51.7] ms, P < 0.002 and 33.5 ± 5.9 vs. 28.8 ± 3.9 ms, and P < 0.03). There was a strong trend for a lower cardiac septal iron content in ID (40.6 [33.0; 57.3] vs. 33.7 [31.3; 40.2] ms, P = 0.07). After IVIT, ferritin, TSAT, and haemoglobin increased (54 [30; 104] vs. 235 [185; 339] µg/L, 19.1 [13.1; 28.2] vs. 25.0 [21.0; 33.7] %, 12.3 ± 1.1 vs. 13.3 ± 1.3 g/L, all P < 0.04). Peak VO2 improved (18.2 ± 4.2 vs. 20.9 ± 3.8 mL/min/kg-1 , P = 0.05). Higher peak VO2 at anaerobic threshold was associated with higher blood ferritin, reflecting higher metabolic exercise capacity after therapy (r = 0.9, P = 0.0009). Increase in EC was associated with haemoglobin increase (r = 0.7, P = 0.034). LV iron increased by 25.4% (48.5 [36.2; 64.8] vs. 36.2 [32.9; 41.9] ms, P < 0.04). Spleen and liver iron increased by 46.4 and 18.2%, respectively (71.8 [66.4; 93.1] vs. 38.5 [22.4; 76.9] ms, P < 0.04 and 33.5 ± 5.9 vs. 27.4 ± 8.6 ms, P < 0.007). Iron in skeletal muscle, brain, intestine, and bone marrow remained unchanged (29.6 [28.6; 31.2] vs. 30.4 [29.7; 30.7] ms, P = 0.7, 81.0 ± 6.3 vs. 82.9 ± 9.9 ms, P = 0.6, 34.3 ± 21.4 vs. 25.3 ± 14.1 ms, P = 0.2, 9.4 [7.5; 21.8] vs. 10.3 [6.7; 15.7] ms, P = 0.5 and 9.8 ± 1.5 vs. 13.7 ± 8.9 ms, P = 0.1). CONCLUSIONS: CHF patients with ID showed lower spleen, liver, and in trend lower cardiac septal iron. After IVIT, iron signal of the left ventricle as well as spleen and liver increased. Improvement in EC was associated with increase in haemoglobin after IVIT. In ID, liver, spleen, and brain but not heart iron were associated with markers of systemic ID.

Clonal haematopoiesis of indeterminate potential-related mutations and outcome in dilated and ischaemic cardiomyopathy.

AIMS: Clonal haematopoiesis of indeterminate potential (CHIP)-associated mutation is a risk factor for the development of ischaemic cardiomyopathy (ICM), but its association with non-ischaemic dilated cardiomyopathy (DCM) remains unclear. We aimed to determine the prevalence of CHIP in patients with DCM and define its risk for disease progression. METHODS AND RESULTS: Next-generation sequencing targeting 54 common CHIP-associated genes was performed in 48 ICM and 52 DCM patients. The patients were monitored for a median of 3.1 years, and a COX proportional hazards model was used to examine the association between CHIP and adverse clinical outcome with regard to all-cause death or all-cause hospitalization. Overall, the prevalence of CHIP mutations was 19% and 13% in DCM and ICM, respectively. Seventeen per cent of ICM patients over 75 years were CHIP carriers. In DCM cohort, mutation event had already been observed in the patients who were under the age of 45 (13%). Among 54 genes analysed, DNMT3A had the highest mutation frequency, followed by TET2 and CUX1. Kaplan-Meier curve over a median of 3.1 year tracking period showed a trend towards poor clinical outcome in the DCM patients who carried DNMT3A or TET2 mutation; however, such association was not statistically significant. CONCLUSIONS: The prevalence of CHIP is detected at a young age in DCM, and accumulation of mutational frequency in DCM patients is independent of age. However, a larger patient cohort is required to validate the association between CHIP and clinical progression in the DCM patients.

Application of recommended therapies among patients with heart failure during the Syrian conflict: reality and barriers.

AIMS: Lower socio-economic status may delay and even prevent the application of guideline-directed heart failure (HF) therapy for most patients. This study aims to evaluate the feasibility and possible difficulties facing the application of this treatment during the current Syrian conflict. METHODS AND RESULTS: A questionnaire on HF management and feasibility of recommended HF therapy was addressed to physicians practising cardiology in Syria. The questionnaire consisted of 30 questions and focused on the quality of HF management and awareness of recommended drug and device therapy for HF among physicians practising cardiology in Syria. A total of 228 physicians participated in the survey. Awareness of recommended medical and device therapy of HF was very high among participants (98% and 95%, respectively). The majority of participants (>75%) believe that more than half of HF patients do not receive optimal medical HF therapy. Ninety per cent of participants believe that <10% of patients with an appropriate indication for device therapy receive it. More than 75% of participants believe that the cost of medications, alone or in combination with other medical causes, represents the major problem facing the application of optimal HF medical therapy. More than 95% of participants reported that cost alone, or in combination with unavailability, is the primary reason why patients with appropriate indications are not offered device therapy. CONCLUSIONS: Despite the high level of awareness of recommended HF therapies among Syrian cardiologists, the majority of HF patients are still undertreated. Financial difficulties and lack of resources are the main causes of this problem.

Metabolomic Profiling in Patients with Heart Failure and Exercise Intolerance: Kynurenine as a Potential Biomarker.

Aims: Metabolic and structural perturbations in skeletal muscle have been found in patients with heart failure (HF) both with preserved (HFpEF) and reduced (HFrEF) ejection fraction in association with reduced muscle endurance (RME). We aimed in the current study to create phenotypes for patients with RME and HFpEF compared to RME HFrEF according to their metabolomic profiles and to test the potential of Kynurenine (Kyn) as a marker for RME. Methods: Altogether, 18 HFrEF, 17 HFpEF, and 20 healthy controls (HC) were prospectively included in the current study. The following tests were performed on all participants: isokinetic muscle function tests, echocardiography, spiroergometry, and varied blood tests. Liquid chromatography tandem mass spectrometry was used to quantify metabolites in serum. Results: Except for aromatic and branched amino acids (AA), patients with HF showed reduced AAs compared to HC. Further perturbations were elevated concentrations of Kyn and acylcarnitines (ACs) in HFpEF and HFrEF patients (p < 0.05). While patients with HFpEF and RME presented with reduced concentrations of ACs (long- and medium-chains), those with HFrEF and RME had distorted AAs metabolism (p < 0.05). With an area under the curve (AUC) of 0.83, Kyn shows potential as a marker in HF and RME (specificity 70%, sensitivity 83%). In a multiple regression model consisting of short-chain-ACs, spermine, ornithine, glutamate, and Kyn, the latest was an independent predictor for RME (95% CI: −13.01, −3.30, B: −8.2 per 1 µM increase, p = 0.001). Conclusions: RME in patients with HFpEF vs. HFrEF proved to have different metabolomic profiles suggesting varied pathophysiology. Kyn might be a promising biomarker for patients with HF and RME.

A Novel Echocardiographic-Based Classification for the Prediction of Peri-Device Leakage following Left Atrial Appendage Occluder Implantation.

(1) Background: The assessment of residual peri-device leakages (PDL) after left atrial appendage occlusion (LAAO) remains crucial for post-procedural management. Our study aimed to verify a novel echocardiographic classification for the prediction of PDL. (2) Methods: Echocardiographic data of 72 patients who underwent percutaneous LAAO were evaluated. All echo images were analyzed by two independent investigators using standard analysis software (Image-Arena IA-4.6.4.44 by TomTec®, Munich, Germany). A total number of 127 studies was evaluated. Forty-four patients had baseline studies, at 45 days and at 6 months post-implantation. We propose a morphological classification of LAA devices based on the amount of echodensity inside the devices into three types: type A showing complete homogenous thrombosis, type B incompletely thrombosed device with inhomogeneous echo-free space <50% of device, and type C with partially thrombosed device in which the echo free space was >50% of device in various planes, which we called the "ice-cream cone" sign. Each type was matched to the degree of PDL and clinical outcome parameters. (3) Results: Patients with type C had the highest percentage of PDL at 45 days follow-up (type A: 24%, type B: 31%, type C 100% PDL, p < 0.001) and at 6 months follow-up (type A: 7%, type B: 33%, type C 100% PDL, p < 0.001). Notably, device size in patients with PDL was larger than that in patients without PDL at 6 months follow-up (25.6 ± 3.5 mm vs. 28.7 ± 3.4 mm, p = 0.004). Device size in patients with type C appearance was the largest of the three types (type A: 25.9 ± 3.6 mm, type B: 25.8 ± 3.4 mm, type C 29.8 ± 3.0 mm, type A vs. C; p = 0.019; type B vs. C, p = 0.007). (4) Conclusions: In conclusion, PDL are common post-LAAO, and their frequency is underestimated and under-recognized. PDL are much more common in patients with larger LAA ostial sizes and likely lower longitudinal compression. Type C appearance of the LAAO devices ("ice-cream cone sign") has a high positive predictive value for PDL. Further studies are needed for better delineation of the clinical importance of this proposed classification.

Relation of left atrial function with exercise capacity and muscle endurance in patients with heart failure.

AIMS: Both left atrial strain (LAS) and skeletal muscle endurance demonstrate a linear relationship to peak VO2 . Less is known about the relationship between central (cardiac) and peripheral (muscle endurance) limitations of exercise capacity in patients with heart failure (HF). We investigated this relationship using novel cardiac markers such as LAS and left atrial emptying fraction (LAEF). METHODS AND RESULTS: We analysed echocardiographic measurements, cardiopulmonary exercise testing (CPET), and isokinetic muscle function in 55 subjects with HF and controls [17 heart failure with preserved ejection fraction (HFpEF), 18 heart failure with reduced ejection fraction (HFrEF), and 20 healthy controls]. Patients with reduced LAEF showed reduced peak VO2 : 14.3 ± 3.5 vs. 18.5 ± 3.5 mL/min/kg, P = 0.003, and reduced muscle endurance (RME): 64.3 ± 23.9 vs. 88.5 ± 32.3 Nm/kg, P = 0.028. Patients with reduced LAS showed similar results. Neither left ventricular global longitudinal strain (LVGLS) nor left atrial volume index (LAVI) was associated with RME. The area under the curve of LAS and LAEF in patients with HF in association with RME were (0.76 vs. 0.80) with 95% confidence interval (CI) (0.59-0.96, P = 0.012 vs. 0.63-0.98, P = 0.006, respectively). In a multiple linear regression, LAEF and working load measured during CPET (watt) were independent factors for RME after adjusting for age, LVGLS, and 6 min walk test (6MWT) [LAEF (B: 0.09, 95% CI: 1.01; 1.18, P = 0.024), working load (B: 0.05, 95% CI: 1.01; 1.08, P = 0.006)]. Peak torque of the left leg was associated with E/LAS (E: early diastolic) in patients with HFpEF (r = -0.6, P = 0.020). Endurance of the left leg was associated with LAEF (r = 0.79, P = 0.001) in patients with HFrEF. CONCLUSIONS: LAS/LAEF are potential cardiac markers in demonstrating the link between cardiac and peripheral limitations of exercise capacity. Thus, integrating LAS/LAEF in the evaluation of exercise intolerance in patients with HF could be useful.

Analysis of Metabolic Markers in Patients with Chronic Heart Failure before and after LVAD Implantation.

Chronic heart failure (HF) is a clinical syndrome characterized by functional impairments of the myocardium. Metabolic and clinical changes develop with disease progression. In an advanced state, left ventricular assist devices (LVADs) are implanted for mechanical unloading. Our study aimed to assess the effects of LVAD implantation on the metabolic phenotypes and their potential to reverse the latter in patients with advanced HF. Plasma metabolites were analyzed by LC-MS/MS in 20 patients with ischemic cardiomyopathy (ICM), 20 patients with dilative cardiomyopathy (DCM), and 20 healthy controls. Samples were collected in HF patients before, 30 days after, and >100 days after LVAD implantation. Out of 188 measured metabolites, 63 were altered in HF. Only three metabolites returned to pre-LVAD concentrations 100 days after LVAD implantation. Pre-LVAD differences between DCM and ICM were mainly observed for amino acids and biogenic amines. This study shows a reversal of metabolite abnormalities in HF as a result of LVAD implantation. The etiology of the underlying disease plays an essential role in defining which specific metabolic parameter is altered in HF and reversed by LVAD implantation. Our findings provide a detailed insight into the disease pattern of ICM and DCM and the potential for reversibility of metabolic abnormalities in HF.

Psychosocial factors, mental health, and coordination capacity in patients with heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction.

AIMS: Patients with heart failure (HF) suffer from reduced quality-of-life (QoL). We aimed to compare QoL, depression, and anxiety scores among outpatients with preserved (HFpEF) and reduced (HFrEF) ejection fraction and non-HF controls and its relationship to coordination capacity. METHODS AND RESULTS: Fifty-five participants were recruited prospectively at the University Hospital Jena, Germany (17 HFpEF, 18 HFrEF, and 20 non-HF controls). All participants underwent echocardiography, cardiopulmonary exercise testing (CPET), 10 m walking test (10-MWT), isokinetic muscle function and coordination tests, and QoL assessments using the short form of health survey (SF-36), and hospital anxiety and depression scale (HADS). Furthermore, inflammatory biomarkers such as growth differentiation factor-15 (GDF-15) were assessed. Patients with HFpEF showed compared with HFrEF and non-HF controls reduced QoL [mental component score (MCS): 43.6 ± 7.1 vs. 50.2 ± 10.0 vs. 50.5 ± 5.0, P = 0.03), vitality (VT): 47.5 ± 8.4 vs. 53.6 ± 8.6 vs. 57.1 ± 5.2, P = 0.004), and elevated anxiety (6.5 ± 3.2 vs. 3.3 ± 2.8 vs. 3.8 ± 2. 8, P = 0.02) and depression scores (6.5 [3.5-10.0] vs. 3.0 [1.0-6.5] vs. 2.0 [0.75-3.0], P = 0.01)]. After adjusting to multiple comparisons, anxiety remained higher in HFpEF patients compared with HFrEF (ppost-hoc  = 0.009). HFpEF and HFrEF patients showed reduced coordination capacity compared with non-HF controls (P < 0.05). In a logistic regression, the presence of depression score ≥8 remained an independent factor for predicting reduced coordination capacity after adjusting for peak VO2 , GDF-15, 10-MWT, physical component score (PCS), and peak torque of the leg [odds ratio (OR): 0.1, 95% confidence interval (CI): 0.004-0.626, P = 0.02]. CONCLUSION: Outpatients with HFpEF had worse QoL and higher anxiety and depression scores compared with HFrEF and non-HF controls. Depression is associated with reduced QoL and is an independent predictor for reduced coordination capacity.

Extra-cardiac targets in the management of cardiometabolic disease: Device-based therapies.

Heart failure (HF) does not occur in a vacuum and is commonly defined and exacerbated by its co-morbid conditions. Neurohormonal imbalance and systemic inflammation are some of the key pathomechanisms of HF but also commonly encountered co-morbidities such as arterial hypertension, diabetes mellitus, cachexia, obesity and sleep-disordered breathing. A cornerstone of HF management is neurohormonal blockade, which in HF with reduced ejection fraction has been tied to a reduction in morbidity and mortality. Pharmacological treatment effective in patients with HF with reduced ejection fraction did not show substantial effects in HF with preserved ejection fraction. Here, we review novel device-based therapies using neuromodulation of extra-cardiac targets to treat cardiometabolic disease.

The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy.

Oversupply of fatty acids (FAs) to cardiomyocytes (CMs) is associated with increased ceramide content and elevated the risk of lipotoxic cardiomyopathy. Here we investigate the role of ceramide accumulation on mitochondrial function and mitophagy in cardiac lipotoxicity using CMs derived from human induced pluripotent stem cell (hiPSC). Mature CMs derived from hiPSC exposed to the diabetic-like environment or transfected with plasmids overexpressing serine-palmitoyltransferase long chain base subunit 1 (SPTLC1), a subunit of the serine-palmitoyltransferase (SPT) complex, resulted in increased intracellular ceramide levels. Accumulation of ceramides impaired insulin-dependent phosphorylation of Akt through activating protein phosphatase 2A (PP2A) and disturbed gene and protein levels of key metabolic enzymes including GLUT4, AMPK, PGC-1α, PPARα, CD36, PDK4, and PPARγ compared to controls. Analysis of CMs oxidative metabolism using a Seahorse analyzer showed a significant reduction in ATP synthesis-related O2 consumption, mitochondrial ß-oxidation and respiratory capacity, indicating an impaired mitochondrial function under diabetic-like conditions or SPTLC1-overexpression. Further, ceramide accumulation increased mitochondrial fission regulators such as dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF) as well as auto/mitophagic proteins LC3B and PINK-1 compared to control. Incubation of CMs with the specific SPT inhibitor (myriocin) showed a significant increase in mitochondrial fusion regulators the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) as well as p-Akt, PGC-1 α, GLUT-4, and ATP production. In addition, a significant decrease in auto/mitophagy and apoptosis was found in CMs treated with myriocin. Our results suggest that ceramide accumulation has important implications in driving insulin resistance, oxidative stress, increased auto/mitophagy, and mitochondrial dysfunction in the setting of lipotoxic cardiomyopathy. Therefore, modulation of the de novo ceramide synthesis pathway may serve as a novel therapeutic target to treat metabolic cardiomyopathy.

Association of liver fibrosis risk scores with clinical outcomes in patients with heart failure with preserved ejection fraction: findings from TOPCAT.

AIMS: Non-alcoholic fatty liver disease leads to progressive liver fibrosis and appears to be a frequent co-morbid disease in heart failure with preserved ejection fraction (HFpEF). It is well known that liver fibrosis severity predicts future liver-related morbidity and mortality, but its impact on outcomes in patients with HFpEF remains unknown. This analysis aimed to describe the prevalence of liver fibrosis, as assessed using surrogate biomarkers, in patients with HFpEF and the association of such biomarkers in predicting clinical outcomes in these patients. METHODS AND RESULTS: Patients with HFpEF from TOPCAT Americas were included in the analysis. The non-alcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 (FIB-4) scores were calculated using a combination of clinical characteristics and laboratory parameters. Risk of advanced fibrosis was classified as low, intermediate, and high. For the 1423 with sufficient data, we used Cox regression analysis to test the association between the risk of fibrosis severity and the combined primary endpoint of all cardiovascular death, aborted cardiac arrest, and hospitalization for heart failure. Advanced fibrosis, as determined by high fibrosis scores, was present in 37.57% by the NFS and 8.02% by the FIB-4. Higher risk of advanced hepatic fibrosis was associated with older age. In unadjusted models, the risk of advanced fibrosis was associated with the primary cardiovascular outcome [NFS high vs. low, hazard ratio (HR) 1.709 (95% confidence interval, CI 1.238-2.358, P = 0.0011) and FIB-4 high vs. low, HR 1.561 (95% CI 1.139-2.140, P = 0.0056)]. After multivariable adjustment, this association was diminished [NFS high vs. low, HR 1.349 (95% CI 0.938-1.939, P = 0.1064) and FIB-4 high vs. low, HR 1.415 (95% CI 0.995-2.010, P = 0.0531)]. CONCLUSIONS: Our study suggests that advanced liver fibrosis, as estimated by fibrosis risk scores, may not be uncommon in patients with HFpEF, and there appears to be a limited independent association between liver fibrosis risk scores and clinical outcomes related to heart failure events.

Metabolomic profiling of patients with high gradient aortic stenosis undergoing transcatheter aortic valve replacement.

AIM: Aim of our study was to evaluate metabolic changes in patients with aortic stenosis (AS) before and after transcatheter aortic valve replacement (TAVR) and to assess whether this procedure reverses metabolomic alterations. METHODS: 188 plasma metabolites of 30 patients with severe high-gradient aortic valve stenosis (pre-TAVR and 6 weeks post-TAVR) as well as 20 healthy controls (HC) were quantified by liquid chromatography tandem mass spectrometry. Significantly altered metabolites were then correlated to an extensive patient database of clinical parameters at the time of measurement. RESULTS: Out of the determined metabolites, 26.6% (n = 50) were significantly altered in patients with AS pre-TAVR compared to HC. In detail, 5/40 acylcarnitines as well as 10/42 amino acids and biogenic amines were mainly increased in AS, whereas 29/90 glycerophospholipids and 6/15 sphingomyelins were mainly reduced. In the post-TAVR group, 10.1% (n = 19) of metabolites showed significant differences when compared to pre-TAVR. Moreover, we found nine metabolites revealing reversible concentration levels. Correlation with clinically important parameters revealed strong correlations between sphingomyelins and cholesterol (r = 0.847), acylcarnitines and brain natriuretic peptide (r = 0.664) and showed correlation of acylcarnitine with an improvement of left ventricular (LV) ejection fraction (r = - 0.513) and phosphatidylcholines with an improvement of LV mass (r = - 0.637). CONCLUSION: Metabolic profiling identified significant and reversible changes in circulating metabolites of patients with AS. The correlation of circulating metabolites with clinical parameters supports the use of these data to identify novel diagnostic as well as prognostic markers for disease screening, pathophysiological studies as well as patient surveillance.

A current and future outlook on upcoming technologies in remote monitoring of patients with heart failure.

Heart failure is a major health and economic challenge in both developing and developed countries. Despite advances in pharmacological and device therapies for patients with a reduced left ventricular ejection fraction (LVEF) and heart failure, their quality of life and exercise capacity are often persistently impaired, morbidity and mortality remain high and the health economic and societal costs are considerable. For patients with heart failure and preserved LVEF, diuretic management has an essential role for controlling congestion and symptoms, even if no intervention has convincingly shown to reduce morbidity or mortality. Remote monitoring might improve care delivery and clinical outcomes for patients regardless of LVEF. A great variety of innovative remote monitoring technologies and algorithms are being introduced, including patient self-managed testing, wearable devices, technologies either integrated into established clinically indicated therapeutic devices, such as pacemakers and defibrillators, or as stand-alone are in development providing the promise of further improvements in service delivery and clinical outcomes. In this article, we will discuss unmet needs in the management of patients with heart failure, how remote monitoring might contribute to future solutions, and provide an overview of current and novel remote monitoring technologies.

Skeletal Muscle Function, Structure, and Metabolism in Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Reduced exercise capacity in patients with heart failure (HF) could be partially explained by skeletal muscle dysfunction. We compared skeletal muscle function, structure, and metabolism among clinically stable outpatients with HF with preserved ejection fraction, HF with reduced ejection fraction, and healthy controls (HC). Furthermore, the molecular, metabolic, and clinical profile of patients with reduced muscle endurance was described. METHODS: Fifty-five participants were recruited prospectively at the University Hospital Jena (17 HF with preserved ejection fraction, 18 HF with reduced ejection fraction, and 20 HC). All participants underwent echocardiography, cardiopulmonary exercise testing, 6-minute walking test, isokinetic muscle function, and skeletal muscle biopsies. Expression levels of fatty acid oxidation, glucose metabolism, atrophy genes, and proteins as well as inflammatory biomarkers were assessed. Mitochondria were evaluated using electron microscopy. RESULTS: Patients with HF with preserved ejection fraction showed compared with HF with reduced ejection fraction and HC reduced muscle strength (eccentric extension: 13.3±5.0 versus 18.0±5.9 versus 17.9±5.1 Nm/kg, P=0.04), elevated levels of MSTN-2 (myostatin-2), FBXO-32 (F-box only protein 32 [Atrogin1]) gene and protein, and smaller mitochondrial size (P<0.05). Mitochondrial function and fatty acid and glucose metabolism were impaired in HF-patients compared with HC (P<0.05). In a multiple regression analysis, GDF-15 (growth and differentiation factor 15), CPT1B (carnitine palmitoyltransferase IB)-protein and oral anticoagulation were independent factors for predicting reduced muscle endurance after adjusting for age (log10 GDF-15 [pg/mL] [B, -54.3 (95% CI, -106 to -2.00), P=0.043], log10 CPT1B per fold increase [B, 49.3 (95% CI, 1.90-96.77), P=0.042]; oral anticoagulation present [B, 44.8 (95% CI, 27.90-61.78), P<0.001]). CONCLUSIONS: Patients with HF with preserved ejection fraction have worse muscle function and predominant muscle atrophy compared with those with HF with reduced ejection fraction and HC. Inflammatory biomarkers, fatty acid oxidation, and oral anticoagulation were independent factors for predicting reduced muscle endurance.

Muscle wasting as an independent predictor of survival in patients with chronic heart failure.

BACKGROUND: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information. METHODS: Two hundred sixty-eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co-morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual-energy X-ray absorptiometry was present in 47 patients (17.5%). RESULTS: During a mean follow-up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N-terminal pro-B-type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01-3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction. CONCLUSIONS: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co-morbidity.

Heart failure and sleep-disordered breathing: susceptibility to reduced muscle strength and preclinical congestion (SICA-HF cohort).

AIMS: Increased sympathetic activation in patients with heart failure (HF) and sleep-disordered breathing (SDB) provokes cardiac decompensation and protein degradation and could lead to muscle wasting and muscle weakness. The aim of this study was to investigate the differences in body composition, muscle function, and the susceptibility of preclinical congestion among patients with HF and SDB compared with those without SDB. METHODS AND RESULTS: We studied 111 outpatients with stable HF who were enrolled into the Studies Investigating Co-morbidities Aggravating Heart Failure. Echocardiography, short physical performance battery (SPPB), cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, bioelectrical impedance analysis (BIA), tests of muscle strength, and polygraphy were performed. SDB was defined as apnoea/hypopnoea index (AHI) >5 per hour of sleep. Central sleep apnoea (CSA) and obstructive sleep apnoea (OSA) were defined as AHI >50% of central or obstructive origin, respectively. A total of 74 patients (66.7%) had any form of SDB [CSA (24 patients, 32.4%), OSA (47 patients, 63.5%)]. Patients with SDB showed increased muscle weakness (chair stand), reduced muscle strength, and lower values of SPPB score (P < 0.05). Patients with SDB did not show overt clinical signs of cardiac decompensation compared with those without SDB (P > 0.05) but had increased amounts of water (total body water, intracellular, and extracellular) measured using BIA (P < 0.05). Increased amounts of total body water were associated with the severity of SDB and inversely with muscle strength and exercise capacity measured by anaerobic threshold (P < 0.05). Altogether, 17 patients had muscle wasting. Of these, 11 (65%) patients had SDB (statistically not significant). CONCLUSIONS: SDB is highly prevalent in patients with HF. Patients with SDB have lower muscle strength and tend to be more susceptible to preclinical congestion.

Longitudinal metabolic profiling of cardiomyocytes derived from human-induced pluripotent stem cells.

Human-induced pluripotent stem cells (h-iPSCs) are a unique in vitro model for cardiovascular research. To realize the potential applications of h-iPSCs-derived cardiomyocytes (CMs) for drug testing or regenerative medicine and disease modeling, characterization of the metabolic features is critical. Here, we show the transcriptional profile during stages of cardiomyogenesis of h-iPSCs-derived CMs. CM differentiation was not only characterized by the expression of mature structural components (MLC2v, MYH7) but also accompanied by a significant increase in mature metabolic gene expression and activity. Our data revealed a distinct substrate switch from glucose to fatty acids utilization for ATP production. Basal respiration and respiratory capacity in 9 days h-iPSCs-derived CMs were glycolysis-dependent with a shift towards a more oxidative metabolic phenotype at 14 and 28 day old CMs. Furthermore, mitochondrial analysis characterized the early and mature forms of mitochondria during cardiomyogenesis. These results suggest that changes in cellular metabolic phenotype are accompanied by increased O2 consumption and ATP synthesis to fulfill the metabolic needs of mature CMs activity. To further determine functionality, the physiological response of h-iPSCs-derived CMs to ß-adrenergic stimulation was tested. These data provide a unique in vitro human heart model for the understanding of CM physiology and metabolic function which may provide useful insight into metabolic diseases as well as novel therapeutic options.