Male Heart Failure Patients Research Articles

Effect of sex on sodium-glucose co-transporter-2 antagonists and glucagon-like peptide-1 agonists in heart failure.

Recent evidence suggests that medications not primarily targeting the cardiovascular (CV) system may have cardioprotective effects in patients with heart failure (HF), in particular the anti-diabetic therapies sodium-glucose co-transporter-2 (SGLT-2) antagonists and glucagon-like peptide-1 (GLP-1) agonists. We conducted a systematic review to assess the pooled evidence for the use of SGLT-2 antagonists and GLP-1 agonists in patients with HF and the effect of biological sex on the results. MEDLINE, Embase, Cochrane Library and clinical trial databases were searched until February 2023. Randomized controlled trials (RCTs) published in English that included adult participants with HF who were randomized to an SGLT-2 antagonist or GLP-1 agonist with a primary or secondary outcome of HF hospitalization (HFH) or CV death were eligible for inclusion. Data pooling was undertaken using a random effects model and odds ratios (ORs) to determine the association between drug and outcome. Sub-group analyses to investigate sex differences were conducted. Six RCTs were included (24781 patients). Four studies investigated SGLT-2 antagonists, and two studies examined GLP-1 agonists. SGLT-2 antagonists improved HFH {OR [95% confidence interval (CI)]: 0.69 [0.63, 0.77], P<0.001} and CV death [0.87 (0.78, 0.97), P=0.01] independent of diabetes status, with excellent homogeneity across all four studies. No beneficial effects were found for GLP-1 agonists. The effects of SGLT-2 antagonists on HFH and CV death were similar in men and women [OR (95% CI): HFH, 0.70 (0.64, 0.76), P<0.001 and 0.58 (0.46, 0.74), P<0.001, respectively; CV death, 0.86 (0.78, 0.95), P=0.003 and 0.84 (0.73, 0.96), P=0.01, respectively], and the neutral effect of GLP-1 agonists on HFH and CV death was similar in men and women (all P>0.05). SGLT-2 antagonists but not GLP-1 agonists beneficially affect HFH and CV death in patients with HF with or without diabetes. We show for the first time that GLP-1 agonists have a neutral effect on HFH and CV death in both male and female HF patients and a reduction in HFH and CV death in male and female HF patients taking SGLT-2 antagonists.

The relationship between a series of inflammatory markers on the risk of heart failure in different gender groups: Analysis from NHANES 2015-2018.

A better understanding of the level-grade inflammation for the development and worsening of heart failure (HF) in different gender groups is an unmet need. We performed an updated analysis on the impact of a series of systemic inflammation markers on HF. This compensatory cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (NHANES) 2015-2018. HF was based on the self-reported questions. Univariate and multivariate logistic regression were used to investigate the association between systemic immune-inflammation index (SII), high sensitivity C-reactive protein (hs-CRP), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and HF. For patients of different genders, P for trend was used to analyze potential linear trend relationships and the restricted cubic splines (RCS) were used to describe non-linear relationships. The additive interaction was evaluated by the relative excess risk due to interaction (RERI), attributable proportion (AP), and the synergy index (SI). The multiplicative interaction was evaluated by odds ratio (OR) and 95% confidence interval (CI) of product-term. A total of 5,830 participants from the NHANES database were divided into two groups: the HF group (n = 210) and the non-HF group (n = 5620). After gender stratification, hs-CRP (OR: 1.01, 95% CI: 1.00-1.03), SII (OR: 1.00, 95% CI: 1.00-1.01), NLR (OR: 1.22, 95% CI: 1.11-1.35) and LMR (OR: 0.79, 95% CI: 0.65-0.93) were independent meaningful factors for HF in males, there was no non-linear relationship between the three factors (SII, NLR, hs-CRP, all P for non-linear > 0.05) and the prevalence of HF, but we detected a non-linear relationship between LMR and the prevalence of HF in males (P for non-linear < 0.05). An additive interaction of hs-CRP and NLR on the risk of HF in males (RERI (OR): 0.67, 95% CI: 0.12-1.34; AP (OR): 0.14, 95% CI: 0.02-0.24; SI (OR): 1.22, 95% CI: 1.03-1.44). In summary, hs-CRP, NLR, and LMR are superior meaningful markers for HF in males. SII may be a meaningful systemic inflammation warning marker for HF, which needs to be discriminated against with caution. Only detected a non-linear relationship between LMR and the prevalence of HF in males. NLR and hs-CRP may have an additive interaction in the prevalence of male HF patients. The outcome compensated for previous studies that still needed more studies for validation.

Navigating Heart Failure: Unveiling Sex Disparities in Guideline-Directed Medical Therapy Combinations

Major heart failure (HF) trials remain insufficient in terms of assessing the differences in clinical characteristics, biomarkers, treatment efficacy, and safety because of the under-representation of women. The study aimed to present sex-related disparities in HF management, including differences in demographics, co-morbidities, cardiac biomarkers, prescribed medications, and treatment outcomes. The study utilized anonymized data from the Turkish Ministry of Health's National Electronic Database between January 1, 2016, and December 31, 2022. The cohort analysis included 2,501,231 adult patients with HF. Specific therapeutic combinations were analyzed using a Cox regression model to obtain relative risk reduction for all-cause death. The primary end point was all-cause mortality. In the cohort, 48.7% (n = 1,218,911) were male, whereas 51.3% (n = 1,282,320) were female. Female patients exhibited a higher median age (71 vs 68 years) and manifested higher prevalence of diabetes mellitus, anemia, atrial fibrillation, anxiety, and ischemic stroke. Male patients demonstrated higher rates of previous myocardial infarction, dyslipidemia, chronic obstructive pulmonary disease, and chronic kidney disease. Higher concentrations of natriuretic peptides were observed in female patients. Renin-angiotensin aldosterone inhibitor, β blockers, mineralocorticoid receptor antagonists, sodium/glucose cotransporter 2 inhibitor (SGLT2i), and ivabradine were more commonly prescribed in male patients, whereas loop diuretics, digoxin, and ferric carboxymaltose were more frequent in female patients. Male patients had higher rates of cardiac resynchronization therapy and implantable cardioverter defibrillator implantation rates. All-cause mortality and hospitalization rates were higher in male patients. Compared with monotherapy, all combinations, including SGLT2i, showed a beneficial effect on all-cause mortality in both female and male patients with HF. In hospitalized patients with HF, the addition of digoxin to renin-angiotensin aldosterone inhibitor, mineralocorticoid receptor antagonists, and β blockers was superior to monotherapy regarding all-cause mortality in female patients with HF compared with male patients with HF. In conclusion, this study highlights that sex-specific responses to HF medication combinations compared with monotherapy and differences in co-morbidities underscore the importance of tailored management strategies. Digoxin showed a contrasting effect on all-cause mortality between both sexes after hospitalization, whereas SGLT2i exhibited a consistent beneficial effect in both sexes when added to all combinations.

Sex-Related Disparities in Prescription Patterns of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Type 2 Diabetes and Heart Failure.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). In consideration of emerging evidence that there are clinically relevant sex-related differences in the course of T2DM and subsequent cardiovascular outcomes, it is unknown if SGLT2i therapy is sex-independently utilized in daily clinical practice. Methods: Patients with T2DM and HF admitted to a tertiary academic center between January 2014 and April 2020 were identified through a search of electronic health records. Data on antidiabetic therapy were acquired at discharge and were screened for SGLT2i prescription. Results: Overall, 812 patients (median age 70 years, 29.7% female) were included in the present analysis. Only 17.3% of the study population received an SGLT2i. In comparison between sexes, females show lower rates of SGLT2i prescription (11.2% vs. 19.8%, p = 0.003), despite comparable patient characteristics. Furthermore, male HF patients showed a significantly higher probability of SGLT2i prescription with an adjusted odds ratio of 2.59 (95% confidence interval 1.29-5.19; p = 0.008). Females who did not receive an SGLT2i showed higher rates of chronic kidney disease (25.2% vs. 7.4%, p = 0.039) and greater levels of N-terminal pro b-type natriuretic peptide (NT-proBNP; 2092 vs. 825 pg/mL, p = 0.011) as compared to female SGLT2i recipients, which did not explain the observed sex-related disparities. Conclusion: SGLT2i are potentially underutilized in female patients with HF and T2DM, despite an overall increasing prescription trend during the observation period. Reasons for withholding therapy could not be objectified. The present data indicate a major need to increase awareness of guideline-directed therapy, especially in female HF patients.

Communication disconnect concerning erectile dysfunction in male heart failure patients: cardiologists and GPs need to talk about sex

Abstract Background Heart failure (HF) and erectile dysfunction (ED) share risk and pathogenetic factors manifesting in a higher prevalence of ED in male HF patients. Despite being a recognized comorbidity, scientific research in this field is limited. Purpose This research aims to better understand the patient journey from a patients' as well as health care professionals' (HCP) perspective in terms of communication, education and ED treatment as recognized concomitant disease in HF patients. Methods Data was collected using two independent online surveys between Nov 21 and Jan 22 from diagnosed male HF patients (N=927) and HCPs including general practitioners (GP), cardiologists and internists (N=78) on quality of life (QoL) with focus on sexual life. As part of the patient survey, male HF patients with ED (N=176) were asked to provide further information about their experiences and ED-related communication with HCPs. Results Male HF patients reported their sexual life as being important (56%*) and their sexual health impacting QoL, with 43% of all men asked (N=927) being unsatisfied with their sexual life. Focusing on HF patients with ED (N=176), half was not aware of the link between HF and ED. Only 33% of male HF patients stated that they were informed about a potential link by their HCP, equally distributed to GPs, cardiologists and urologists. HCPs in turn reported that only 20% of their patients proactively consult them, but the majority of male HF patients with ED (69%) stated that they feel left alone and wish for more personal exchange regarding the topic of ED with a doctor (74%). HCPs reported awareness of strong ED burden in 70% of their male HF patients. In contrast to the patients' perspective, 56% of HCPs report that they do address the topic of ED to their HF patients. Top ranked reason for not addressing the topic of ED from HCP side were the assumption and/or knowledge that patients feel uncomfortable talking about ED. Interestingly, only 7% of male HF patients with ED indeed indicated feeling uncomfortable. Despite their pronounced sexual dissatisfaction only 40% of male HF patients with ED indicated that they talk to a doctor about ED treatment options. In consequence, only 22% of them take prescription drugs. More frequently, HCPs reported that about one third of their patients are non-compliant with HF medication due to ED highlighting the high importance of sexual health for patients' QoL. Conclusions We identified a communication disconnect between HCPs and HF patients regarding ED. As patients' QoL is strongly affected by sexual health, they wish for more personal exchange and information. There is a strong need to proactively address the topic of ED by cardiologists and GPs as the first point of contact for HF patients. New ideas for tools generating a better understanding and more confident conversations about HF and ED are warranted. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

Living with heart failure: quality of life, particularly sexual life, is impaired by emotional burden as reported by patients

Abstract Background Symptoms of heart failure (HF) include shortness of breath and limited exercise capacity as a result of fluid retention and circulatory disorders. Life expectancy of HF patients has improved, mainly driven by current treatment modalities. The burden of HF in terms of quality of life (QoL) and emotional well-being is frequently neglected and is less well described than typical HF symptoms. Purpose The aim of this study is to better understand the impact of HF on patients' QoL and emotional well-being from the patients' perspective. Methods Data on disease perception and physical as well as emotional burden was collected using an online survey from Nov to Dec 21 from patients with HF diagnosis (Nfemale=830; Nmale=927). Results Overall, the majority of HF patients considered being capable of fulfilling everyday routines as highly important. In detail, 87% of HF patients rated taking care of themselves, 82% running the household independently, 83% mobility outside the house and 74% social life with highest importance*. Impairments in the same QoL determining aspects from above showed a bimodal distribution of HF patients meaning that they were either highly affected or not affected at all. Male and female HF patients rated QoL aspects in terms of importance and impairment equally, except sexual life importance and sexual impairments, which were ranked higher by men (56% vs. 42%*, 39% vs. 32%§, respectively). Being asked about their biggest concern regarding HF via an open-ended question, death was the most commonly reported term. However, 20% indicated social and emotional worries as their first concern. Indeed, HF patients were frequently emotionally affected and almost every second HF patient stated considerable restrictions of their daily obligations and every third of their social life due to emotional problems. Patient-reported emotions were being worried (53%#), listless/without energy (47%#), fatigue (45%#) and/or afraid (42%#). Interestingly, the fraction of HF patients being unsatisfied with their sexual life was larger when patients indicated feeling emotionally affected (worried, listless, fatigue, afraid). On the other hand, HF patients indicating no negative emotions were more satisfied with their sexual life highlighting the importance of sexual health contributing to QoL. Conclusion(s) The emotional burden experienced by HF patients is as high as their physical impairments culminating in considerable restrictions of their daily routines due to emotional problems. Additionally, emotional well-being is strongly linked with sexual satisfaction. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. §On a scale from 1 = “not affected” to 10 = “no activity possible” rated ≥7. #On a scale of 1 = “never” to 10 = “very often” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

Induction of Day-Time Periodic Breathing is Associated With Augmented Reflex Response From Peripheral Chemoreceptors in Male Patients With Systolic Heart Failure.

Spontaneous day-time periodic breathing (sPB) constitutes a common phenomenon in systolic heart failure (HF). However, it is unclear whether PB during wakefulness could be easily induced and what are the physiological and clinical correlates of patients with HF in whom PB induction is possible. Fifty male HF patients (age 60.8 ± 9.8 years, left ventricle ejection fraction 28.0 ± 7.4%) were prospectively screened and 46 enrolled. After exclusion of patients with sPB the remaining underwent trial of PB induction using mild hypoxia (stepwise addition of nitrogen gas to breathing mixture) which resulted in identification of inducible (iPB) in 51%. All patients underwent assessment of hypoxic ventilatory response (HVR) using transient hypoxia and of hypercapnic ventilatory response (HCVR) employing Read’s rebreathing method. The induction trial did not result in any adverse events and minimal SpO2 during nitrogen administration was ∼85%. The iPB group (vs. non-inducible PB group, nPB) was characterized by greater HVR (0.90 ± 0.47 vs. 0.50 ± 0.26 L/min/%; p <0.05) but comparable HCVR (0.88 ± 0.54 vs. 0.67 ± 0.68 L/min/mmHg; p = NS) and by worse clinical and neurohormonal profile. Mean SpO2 which induced first cycle of PB was 88.9 ± 3.7%, while in sPB mean SpO2 preceding first spontaneous cycle of PB was 96.0 ± 2.5%. There was a reverse relationship between HVR and the relative variation of SpO2 during induced PB (r = −0.49, p = 0.04). In summary, PB induction is feasible and safe in HF population using simple and standardized protocol employing incremental, mild hypoxia. Pathophysiology of iPB differs from sPB, as it relies mostly on overactive peripheral chemoreceptors. At the same time enhanced HVR might play a protective role against profound hypoxia during iPB.

41 Circulating levels and prognostic cut-offs of sST2, high-sensitivity troponin T, and NT-proBNP in women vs. men with chronic heart failure

Abstract Aims Limited evidence exists on sex-related differences in clinical value of biomarkers in chronic heart failure (HF). We aimed to define plasma levels, determinants, and optimal prognostic cut-offs of soluble suppression of tumourigenesis-2 (sST2), high-sensitivity troponin T (hs-TnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in female and male chronic HF patients. Methods and results Individual data of patients from the BIOS (Biomarkers In Heart Failure Outpatient Study) Consortium with sST2, hs-TnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1-year cardiovascular death and HF hospitalization. The secondary endpoints were 5-year cardiovascular and all-cause death. The cohort included 4540 patients (age: 67 ± 12 years, LVEF 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/ml, P &amp;lt; 0.001) and hs-TnT level (15 vs. 20 ng/l, P &amp;lt; 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/l, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/ml) and hs-TnT (22 vs. 25 ng/l), while NT-proBNP cut-off was higher in women (2339 ng/l vs. 2145 ng/l). The use of sex-specific cut-offs improved risk prediction compared to the use of previously standardized prognostic cut-offs (Figure). Conclusions In patients with chronic HF, levels of sST2 and hs-TnT, but not of NT-proBNP are lower in women. Lower sST2 and hs-TnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Development and validation of a liquid chromatography method using UV/fluorescence detection for the quantitative determination of metabolites of the kynurenine pathway in human urine: Application to patients with heart failure

Recent evidence indicates the relevant role of the tryptophan (TRP) metabolites in the pathophysiology of cardiovascular diseases via inflammatory and oxidative stress mechanisms. Therefore, quantification of TRP and its metabolites in biological samples can be a powerful tool to elucidate the disease mechanisms. The aim of this work was to develop and validate a liquid chromatography with ultraviolet (UV) and fluorescence detection (FD) (LCUV/FD) method for the quantification of TRP and its metabolites (L-kynurenine (KYN) and kynurenic acid (KA)) in urine samples from heart failure (HF) patients. Biochemical parameters and inflammatory markers were quantified, and data correlated with urinary concentrations of TRP and its metabolites. Optimized chromatographic conditions were achieved using a Luna® 3 μm PFP(2) analytical column, a mobile phase of 20 mM of ammonium formate in ultra-pure water (with 0.01 % of formic acid), acetonitrile and ethanol (95/2/3, v/v/v), a flow rate of 0.7 mL/min and a column oven temperature set at 25 °C. The method was validated according to the European Medicines Agency (EMA) guidelines and showed to be linear (r2 >0.99), accurate (82–116%) and precise (%RSD below 15 %). The limits of quantification varied between 50 and 125 ng/mL. The method was applied to the quantification of TRP, KYN and KA in healthy volunteers and male HF patients. The results obtained through this pilot study (small group of patients) showed a relationship between biochemical parameters, inflammatory markers and changes in the concentration of TRP, KYN and KA. The KYN/TRP and KA/KYN ratios were calculated. Results support the hypothesis that KYN/TRP ratio is related with enzymatic activity and that KA/KYN ratio can be a good neuroprotection indicator. The potential of the LCUV/FD method for the monitoring of the selected compounds in cardiac patients was also demonstrated.

Sex Differences in the Association between Atrial Fibrillation and 90-Day Adverse Outcomes among Older Adults with Heart Failure: A Retrospective Cohort Study.

Sex differences in the prognostic impact of coexisting atrial fibrillation (AF) in older patients with heart failure (HF) have not been well-studied. This study, therefore, compared sex differences in the association between AF and its 90-day adverse outcomes (hospital readmissions and emergency room (ER) visits) among older adults with HF. Of the 250 older adult patients, the prevalence rates of coexisting AF between male and female HF patients were 46.0% and 31.0%, respectively. In both male and female older patients, patients with AF have a significantly higher readmission rate (male 46.0%, and female 34.3%) than those without AF (male 6.8%, and female 12.8%). However, there are no significant differences in the association between AF and ER visits in both male and female older HF patients. The multivariate logistic analysis showed that coexisting AF significantly increased the risk of 90-day hospital readmission in both male and female older patients. In addition, older age in males and longer periods of time after an HF diagnosis in females were associated with an increased risk of hospital readmission. Consequently, prospective cohort studies are needed to identify the impact of coexisting AF on short- and long-term outcomes in older adult HF patients by sex.

Causes and associated risk factors of heart failure patients in Aljouf region of Saudi Arabia

Background: Heart failure (HF) is a major and growing public health problem across the world for both males and females in all ethnic groups. Therefore, this study aimed to evaluate the causes and associated risk factors of HF patients in Aljouf, Saudi Arabia. Methodology: Total 274 consecutive patients including 165 males and 109 females who were diagnosed with HF and admitted to Cardiac center of King Abdul Aziz Specialized Hospital (KAASH) over a period of January 2019 to December 2019, were enrolled in this retrospective study. All information was collected from the hospital records including medical history, age, causative factors and associated risk factors. Result: It was found that majority of female (31.1%) and male (45.4%) HF patients were over 65 years of age and between 55 to 64 years, respectively. The common causes were ischemic heart diseases (47.4%), hypertensive heart disease (30.2%), and dilated cardiomyopathy (22.2%) among HF patients. Furthermore, risk factors included diabetes (88%) and obesity (80.7%) which were higher in female as compared to males (p < 0.05). Besides, the family history of coronary artery disease and cardiovascular diseases (71.5%), and hypertension (32.7%) were significantly higher in male HF patients than female HF patients (p < 0.05). Smoking (58.39%) was considered as a major risk factor for male HF patient. Conclusion: The HF patient’s incidence as well as its complications might be reduced remarkably by early prevention with proper management of its associated risk factors and major causes.

Temporal trends, sex-differences and outcomes of patients hospitalized for heart failure in Germany

Abstract Background Despite remarkable improvements in treatment of cardiovascular disease, heart failure (HF) is still characterized by a high mortality rate. Sex-specific differences in HF have been described, but underlying reasons are widely unexplored. Thus, we aimed to investigate sex differences of patients hospitalized for HF in a nationwide cohort. Methods The nationwide German inpatient sample (2005–2016) was used for this sex-specific analyses. Temporal trends on hospitalizations, mortality, and treatments were analyzed and independent predictors of adverse outcomes identified. Results The present analysis comprises 4,538,977 hospitalizations due to HF (52.0%women) in Germany (2005–2016). Although women were older (median 82 (IQR75–87) vs. 76 (69–82), P&amp;lt;0.001), coronary artery disease (CAD, 50.3% vs. 30.7%, P&amp;lt;0.001) was more prevalent in men, who were more often treated with PCI (3.4% vs. 1.4%, P&amp;lt;0.001) and implantable cardioverter-defibrillator (2.2% vs. 0.5%, P&amp;lt;0.001). In-hospital mortality was significantly lower in men than in women (8.9% vs. 10.2, P=0.001) and was reduced in patients who received PCI or implantation of an ICD. While total numbers of hospitalizations between 2005 and 2016 increased in both men (β-estimate 7185.71 (95% CI 6502.23 to 7869.18), P&amp;lt;0.001) and women (β-estimate 5297.60 (95% CI 4557.37 to 6037.83), P&amp;lt;0.001) as well as almost all comorbid co-conditions, in-hospital mortality rate decreased more distinctly in women (β-estimate −0.41 (95% CI: −0.42 to −0.39), P&amp;lt;0.001) compared to men (β-estimate −0.29 (95% CI: −0.30 to −0.27), P&amp;lt;0.001). Conclusions Interventional treatments of HF were associated with improved outcomes and equally beneficial for both sexes. However, they were more often used in male HF patients, in which CAD is significantly more frequent than in female HF patients. This may explain the higher case fatality rate of HF in females. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Federal Ministry of Education and Research (BMBF)

3069Epigenetic changes in heart failure cohorts: novel insights into methylation changes of protein and RNA coding genes in human cardiac tissue

Abstract Background Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in Heart Failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and non-coding RNA across different etiological sub-types of HF. Methods and results A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing etiologies including Hypertrophic Obstructive Cardiomyopathy (HOCM, n=12), Ischemic Cardiomyopathy (ISCM, n=9), Dilated Cardiomyopathy (DCM, n=9), and 9 control patients with non-failing hearts (NF). We detected 62,678 differentially methylated regions (DMR) in the studied HF cohort. By comparing each HF sub-group to the NF control group we identified 195 unique DMRs: 5 in HOCM, 151 in DCM, and 55 in ISCM. These translated to 4 genes/1 non-coding RNA (ncRNA) in HOCM, 131 genes/17 ncRNA in DCM, and 51 genes/5 ncRNA in ISCM. Subsequent gene/ncRNA expression analysis was assessed using qRT-PCR and revealed 6 genes: 4 hypermethylated (HEY2, MSR1, MYOM3, COX17), 2 hypomethylated (CTGF, MMP2); and 2 microRNA: 1 hypermethylated (miR-24–1), 1 hypomethylated (miR-155) with significantly up- or down-regulated expression levels consistent with the direction of methylation in the particular HF sub-group. Conclusions For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically-variant pathological heart failure tissue. The methylation-sensitive and disease-associated genes/non-coding RNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and/or therapeutic target in HF and warrant further investigation. Acknowledgement/Funding Enterprise Ireland; European Regional Development Fund under Ireland's European Structural and Investment Funds Programmes 2014-2020

Modeling of Transport Mechanisms in the Respiratory System: Validation via Congestive Heart Failure Patients.

The heart and lungs are intricately related. For congestive heart failure patients, fluid (plasma) backs up into the pulmonary system. As a result, pulmonary capillary pressure increases, causing fluid to seep into the lungs (pulmonary edema) within minutes. This excess fluid induces extra stress during breathing that affects respiratory health. In this paper, we focus on the effect that high pulmonary capillary pressure has on the development of this extravascular lung water (EVLW). A mathematical model of pulmonary fluid and mass transport mechanisms is developed in order to quantitatively analyze the transport phenomena in the pulmonary system. The model is then validated on 15 male heart failure patients from published literature [1]. The model shows reasonable estimation of EVLW in heart failure patients, which is useful in assessing the severity of pulmonary edema.

Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes.

Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in heart failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and noncoding RNA (ncRNA) across different etiological subtypes of HF. A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing causes including hypertrophic obstructive cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and 9 control patients with nonfailing hearts. We detected 62 678 differentially methylated regions in the studied HF cohort. By comparing each HF subgroup to the nonfailing control group, we identified 195 unique differentially methylated regions: 5 in hypertrophic obstructive cardiomyopathy, 151 in dilated cardiomyopathy, and 55 in ischemic cardiomyopathy. These translated to 4 genes/1 ncRNA in hypertrophic obstructive cardiomyopathy, 131 genes/17 ncRNA in dilated cardiomyopathy, and 51 genes/5 ncRNA in ischemic cardiomyopathy. Subsequent gene/ncRNA expression analysis was assessed using quantitative reverse transcription polymerase chain reaction and revealed 6 genes: 4 hypermethylated ( HEY2, MSR1, MYOM3, and COX17), 2 hypomethylated ( CTGF and MMP2); and 2 microRNA: 1 hypermethylated (miR-24-1), 1 hypomethylated (miR-155) with significantly upregulated or downregulated expression levels consistent with the direction of methylation in the particular HF subgroup. For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically variant pathological HF tissue. The methylation-sensitive and disease-associated genes/ncRNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and therapeutic target in HF and warrant further investigation.

Sleep quality and daytime sleepiness are not associated with cognition in heart failure

BackgroundIndividuals with heart failure (HF) exhibit comorbid impairments in both sleep and cognitive performance. Sleep quality has been associated with impaired cognitive performance in HF patients, but reports are inconsistent. In this study, we examined associations between sleep quality, daytime sleepiness, and cognitive function in HF. Methods and resultsParticipants were 267 (age = 69.1 ± 9.3) mostly Caucasian (74.9%), male (59.6%) stable HF patients recruited from outpatient settings. This cross-sectional study was a secondary analysis of a prospective observational study. Cognitive function domains assessed included: global cognitive function, attention, memory, and executive function. Sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS), respectively. Separate multiple hierarchical linear regressions were conducted to determine associations between cognitive function and sleep quality and daytime sleepiness, after controlling for sex, New York Heart Association (NYHA) class, education, depressive symptoms, and medical comorbidities. Cognitive function was not associated with sleep quality or daytime sleepiness after alpha inflation corrections were applied. ConclusionsCognitive function in HF is not associated with sleep quality or daytime sleepiness; other factors may exert greater influence on cognitive performance.

Waist-to-hip ratio and mortality in heart failure.

A higher body mass index (BMI) is associated with better survival in heart failure (HF) patients, also known as the obesity paradox. However, BMI does not account for body composition. We therefore analysed the association between abdominal fat, measured via waist-to-hip ratio (WHR), BMI and all-cause mortality in patients with HF. For this analysis, 1738 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) validation study were included. Patients without waist and hip measurements were excluded. WHR was defined as waist circumference/hip circumference, divided into tertiles and split for sex. A linear regression of principal components from an extensive panel of biomarkers was performed to provide insight in the pathophysiology behind a higher WHR. In total, 1479 patients were included, of which 33% were female and mean age was 75 ±11 years. A higher WHR was independently associated with a higher BMI, a higher prevalence of diabetes and higher New York Heart Association functional class. There was a significant interaction between sex and WHR on its association with mortality (P <0.001). In women, a higher WHR was associated with a higher mortality risk [hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.37-3.63; P =0.001], whereas no significant association was found in men (HR 0.87, 95% CI 0.63-1.20; P = 0.409). We found a strong association between a higher WHR and elevated markers of inflammation and MAPK cascade in women, while these associations were less profound in men. A higher WHR was associated with a higher risk of death in female but not in male HF patients. These findings challenge the obesity paradox, and suggest that fat deposition is pathophysiologically harmful and may be a target for therapy in female patients with HF.

Breathing With Heart Failure

The syndrome of heart failure (HF) is often accompanied by numerous derangements in ventilatory function. These pathophysiological changes in ventilatory function are believed to augment the mechanical work required to breathe during exercise (Wb). However, the precise contributions of resistive and elastic work to this overall higher Wb in HF remain unclear. PURPOSE: To quantify the resistive and elastic components of Wb during exercise in HF patients and age-matched, healthy controls at standardized levels of minute ventilation ( ). METHODS: The elastic and resistive Wb were assessed in 9 male HF patients (NYHA class I-III) and 9 age-matched, healthy male controls at minute ventilations of 20, 40, 60 and 80 L[BULLET OPERATOR]min-1 during graded exercise. The components of Wb were quantified using oesophageal manometry and modified Campbell diagrams. RESULTS: Dynamic lung compliance was lower across all minute ventilations in HF patients (P<0.05). Moreover, the inspiratory and expiratory resistive Wb was higher in HF patients compared with controls at any given (P<0.05). The inspiratory elastic Wb was higher at minute ventilations of 40-60 L[BULLET OPERATOR]min-1 during exercise in HF patients. (P<0.05). CONCLUSIONS: The findings of this study indicate that the overall higher Wb in HF patients may be more so related to greater amounts of resistive than elastic Wb during exercise.

Vitamin D supplementation and bone turnover in advanced heart failure: the EVITA trial

Low vitamin D status is common in patients with heart failure (HF) and has been related to disturbed bone turnover. The present study investigated the effect of a daily vitamin D3 dose of 4000IU on bone turnover markers (BTMs) in patients with advanced HF and 25-hydroxyvitamin D (25OHD) concentrations < 75nmol/L. In this pre-specified secondary analysis of a randomized controlled trial, we assessed in 158 male HF patients (vitamin D group: n = 80; placebo group: n = 78) between-group differences in calciotropic hormones (25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone [iPTH]), and BTMs (cross-linked C-telopeptide of type I collagen, bone-specific alkaline phosphatase, undercarboxylated osteocalcin). Comparisons were performed at the end of a 3-year vitamin D supplementation period with adjustments for baseline values. Compared with placebo, vitamin D increased 25OHD on average by 54.3nmol/L. At study termination, 25OHD and 1,25(OH)2D were significantly higher (P < 0.001 and P = 0.007, respectively), whereas iPTH tended to be lower in the vitamin D group than in the placebo group (P = 0.083). BTMs were initially within their reference ranges and did not differ significantly between groups at study termination, neither in the entire study cohort nor when data analysis was restricted to the subgroup of patients with initial 25OHD concentrations < 30nmol/L (n = 54) or to patients with initial hyperparathyroidism (n = 65) (all P values > 0.05). A daily vitamin D3 dose of 4000IU did not influence BTMs. Data indicate that vitamin D supplementation will not lower bone turnover in male patients with heart failure.

Early and asymptomatic cardiac dysfunction in chronic kidney disease.

Heart failure (HF) is highly prevalent and associated with high mortality in chronic kidney disease (CKD). However, the pathophysiology of cardiac dysfunction in CKD, especially in the early asymptomatic stage, is not well understood. We studied subclinical cardiac dysfunction in asymptomatic CKD patients without comorbid cardiac disease or diabetes mellitus by evaluating peak cardiac performance. In a cross-sectional study (n = 130) we investigated 70 male non-diabetic CKD patients (21 CKD stage 2-3a, 27 CKD stage 3b-4 and 22 CKD stage 5) employing specialized cardiopulmonary exercise testing to measure peak cardiac output and cardiac power output non-invasively. Data from 35 age-matched healthy male volunteers were obtained for comparison. In addition, as a positive control, data from 25 age-matched male HF patients in New York Heart Association class II and III were also obtained. The study subjects showed a graded reduction in peak cardiac power, with 6.13 ± 1.11 W in controls, 5.02 ± 0.78 W in CKD 2-3a, 4.59 ± 0.53 W in CKD 3b-4 and 4.02 ± 0.73 W in CKD 5, although not as impaired as in HF, with 2.34 ± 0.63 W (all P < 0.005 versus control). The central haemodynamic characteristics of the cardiac impairment in CKD mirrored that of HF, with reduced flow and pressure-generating capacities, reduced chronotropic reserve and impaired contractility. The study demonstrates for the first time impaired peak cardiac performance and cardiac functional reserve in asymptomatic CKD patients. The evidence of myocardial dysfunction in the absence of comorbid cardiac disease and diabetes warrants further evaluation of current pathophysiological concepts of cardiovascular disease in CKD.