Associations of relative fat mass and BMI with all-cause mortality: Confounding effect of muscle mass.

OBJECTIVE: The study objective was to examine associations of relative fat mass (RFM) and BMI with all-cause mortality in the Dutch general population and to investigate whether additional adjustment for muscle mass strengthened these associations. METHODS: A total of 8433 community-dwelling adults from the PREVEND general population cohort (1997-1998) were included. Linear regression models were used to examine associations of RFM and BMI with 24-h urinary creatinine excretion, a marker of total muscle mass. Cox regression models were used to examine associations of RFM and BMI with all-cause mortality. RESULTS: The mean age of the cohort was 49.8 years (range: 28.8-75.7 years), and 49.9% (n = 4209) were women. In age- and sex-adjusted models, both RFM and BMI were associated with total muscle mass (24-h urinary creatinine excretion), and these associations were stronger with BMI (standardized beta [Sß]RFM : 0.29; 95% CI: 0.27-0.31 vs. SßBMI : 0.38; 95% CI: 0.36-0.40; pdifference < 0.001). During a median follow-up period of 18.4 years, 1640 deaths (19.4%) occurred. In age- and sex-adjusted models, RFM was significantly associated with all-cause mortality (hazard ratio per 1-SD [HRRFM ]: 1.16; 95% CI: 1.09-1.24), whereas BMI was not (HRBMI : 1.04; 95% CI: 0.99-1.10). After additional adjustment for muscle mass, associations of both RFM and BMI with all-cause mortality increased in magnitude (HRRFM : 1.24; 95% CI: 1.16-1.32 and HRBMI : 1.12; 95% CI: 1.06-1.19). Results were broadly similar in multivariable adjusted models. CONCLUSIONS: In the general population, a higher RFM was significantly associated with mortality risk, whereas a higher BMI was not. Adjusting for total muscle mass increased the strength of associations of both RFM and BMI with all-cause mortality.

The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF.

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

Relative fat mass, a new index of adiposity, is strongly associated with incident heart failure: data from PREVEND.

Body-mass index (BMI), waist circumference, and waist-hip ratio are commonly used anthropometric indices of adiposity. However, over the past 10 years, several new anthropometric indices were developed, that more accurately correlated with body fat distribution and total fat mass. They include relative fat mass (RFM), body-roundness index (BRI), weight-adjusted-waist index and body-shape index (BSI). In the current study, we included 8295 adults from the PREVEND (Prevention of Renal and Vascular End-Stage Disease) observational cohort (the Netherlands), and sought to examine associations of novel as well as established adiposity indices with incident heart failure (HF). The mean age of study population was 50 ± 13 years, and approximately 50% (n = 4134) were women. Over a 11 year period, 363 HF events occurred, resulting in an overall incidence rate of 3.88 per 1000 person-years. We found that all indices of adiposity (except BSI) were significantly associated with incident HF in the total population (P < 0.001); these associations were not modified by sex (P interaction > 0.1). Amongst adiposity indices, the strongest association was observed with RFM [hazard ratio (HR) 1.67 per 1 SD increase; 95% confidence interval (CI) 1.37-2.04]. This trend persisted across multiple age groups and BMI categories, and across HF subtypes [HR: 1.76, 95% CI 1.26-2.45 for HF with preserved ejection fraction; HR 1.61, 95% CI 1.25-2.06 for HF with reduced ejection fraction]. We also found that all adiposity indices (except BSI) improved the fit of a clinical HF model; improvements were, however, most evident after adding RFM and BRI (reduction in Akaike information criteria: 24.4 and 26.5 respectively). In conclusion, we report that amongst multiple anthropometric indicators of adiposity, RFM displayed the strongest association with HF risk in Dutch community dwellers. Future studies should examine the value of including RFM in HF risk prediction models.

Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.

The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa). METHODS AND RESULTS: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype. CONCLUSIONS: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.

Autoantibodies against citrullinated histone H3 in rheumatoid arthritis and periodontitis patients.

AIM: To determine the presence of citrullinated histones in inflamed periodontal tissue and to determine the presence of anti-citrullinated histone autoantibodies in sera from patients with rheumatoid arthritis (RA) and periodontitis (PD) patients. METHODS: The presence of citrullinated histone H3, PAD4 and CD68 was determined in 15 periodontal tissue biopsies from PD patients by immunohistochemistry. Sera from 36 healthy controls (HC), 113 PD patients and 84 patients with RA were assessed on presence of autoantibodies against citrullinated histones by Western blot and against citrullinated histone H3 by ELISA. RESULTS: Citrullinated histone H3, PAD4 and CD68 were present in periodontal tissue from nine (60%), 14 (93%) and 13 (87%) PD patients, respectively. Anti-citrullinated histone H3 autoantibodies were found in 33 (39%) patients with RA compared to three (8%) HC and 11 (10%) PD patients. Anti-citrullinated histone H3 levels were higher in anti-cyclic citrullinated peptide (anti-CCP)-positive compared to anti-CCP-negative patients with RA (p = .0008) and correlated moderately with anti-CCP levels (ρ = .22). No associations were found between anti-citrullinated histone H3 levels and periodontal status or smoking behaviour of patients with RA. CONCLUSION: PD patients are exposed to citrullinated histone H3 in inflamed periodontal tissue. Citrullinated histone H3 is targeted by autoantibodies present in RA sera. This supports a role for periodontitis in generation of antigens targeted by autoantibodies directed against citrullinated proteins.