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 erythropoietin receptor expressed in skeletal muscle is essential for mitochondrial biogenesis and physiological exercise.

Erythropoietin (EPO) is a haematopoietic hormone that regulates erythropoiesis, but the EPO-receptor (EpoR) is also expressed in non-haematopoietic tissues. Stimulation of the EpoR in cardiac and skeletal muscle provides protection from various forms of pathological stress, but its relevance for normal muscle physiology remains unclear. We aimed to determine the contribution of the tissue-specific EpoR to exercise-induced remodelling of cardiac and skeletal muscle. Baseline phenotyping was performed on left ventricle and m. gastrocnemius of mice that only express the EpoR in haematopoietic tissues (EpoR-tKO). Subsequently, mice were caged in the presence or absence of a running wheel for 4 weeks and exercise performance, cardiac function and histological and molecular markers for physiological adaptation were assessed. While gross morphology of both muscles was normal in EpoR-tKO mice, mitochondrial content in skeletal muscle was decreased by 50%, associated with similar reductions in mitochondrial biogenesis, while mitophagy was unaltered. When subjected to exercise, EpoR-tKO mice ran slower and covered less distance than wild-type (WT) mice (5.5 ± 0.6 vs. 8.0 ± 0.4 km/day, p < 0.01). The impaired exercise performance was paralleled by reductions in myocyte growth and angiogenesis in both muscle types. Our findings indicate that the endogenous EPO-EpoR system controls mitochondrial biogenesis in skeletal muscle. The reductions in mitochondrial content were associated with reduced exercise capacity in response to voluntary exercise, supporting a critical role for the extra-haematopoietic EpoR in exercise performance.

CRRL269: a novel designer and renal-enhancing pGC-A peptide activator.

The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also investigated. In vitro NP receptor activity was quantified with guanosine 3',5'-cyclic monophosphate generation. In vivo effects were determined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldosterone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor.

Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring via Panx1 hypermethylation.

Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring.

Heart Failure and Obesity: Unraveling Molecular Mechanisms of Excess Adipose Tissue.

Obesity is an ongoing pandemic and is associated with the development of heart failure (HF), and especially HF with preserved ejection fraction. The definition of obesity is currently based on anthropometric measurements but neglects the location and molecular properties of excess fat. Important depots associated with HF development are subcutaneous adipose tissue and visceral adipose tissue, both located in the abdominal region, and epicardial adipose tissue (EAT) surrounding the myocardium. However, mechanisms linking these different adipose tissue depots to HF development are incompletely understood. EAT in particular is of great interest because of its close proximity to the heart. In this review, we therefore focus on the characteristics of different adipose tissue depots and their response to obesity. In addition, we evaluate how different mechanisms associated with EAT expansion potentially contribute to HF and in particular HF with preserved ejection fraction development.

Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.

AIMS: Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint. METHODS AND RESULTS: HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty-four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2. In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2, P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses). CONCLUSIONS: Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

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.

Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF.

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. METHODS AND RESULTS: In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase ß-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61-0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65-0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. CONCLUSION: ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.

The 'peptide for life' initiative in the emergency department study.

AIMS: Natriuretic peptide (NP) uptake varies in Emergency Departments (EDs) across Europe. The 'Peptide for Life' (P4L) initiative, led by Heart Failure Association, aims to enhance NP utilization for early diagnosis of heart failure (HF). We tested the hypothesis that implementing an educational campaign in Western Balkan countries would significantly increase NP adoption rates in the ED. METHODS AND RESULTS: This registry examined NP adoption before and after implementing the P4L-ED study across 10 centres in five countries: Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia. A train-the-trainer programme was implemented to enhance awareness of NP testing in the ED, and centres without access received point-of-care instruments. Differences in NP testing between the pre-P4L-ED and post-P4L-ED phases were evaluated. A total of 2519 patients were enrolled in the study: 1224 (48.6%) in the pre-P4L-ED phase and 1295 (51.4%) in the post-P4L-ED phase. NP testing was performed in the ED on 684 patients (55.9%) during the pre-P4L-ED phase and on 1039 patients (80.3%) during the post-P4L-ED phase, indicating a significant absolute difference of 24.4% (95% CI: 20.8% to 27.9%, P < 0.001). The use of both NPs and echocardiography significantly increased from 37.7% in the pre-P4L-ED phase to 61.3% in the post-P4L-ED phase. There was an increased prescription of diuretics and SGLT2 inhibitors during the post-P4L-ED phase. CONCLUSIONS: By increasing awareness and providing resources, the utilization of NPs increased in the ED, leading to improved diagnostic accuracy and enhanced patient care.

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.

Associations of relative fat mass, a new index of adiposity, with type-2 diabetes in the general population.

BACKGROUND: Relative fat mass (RFM) is a novel sex-specific anthropometric equation (based on height and waist measurements) to estimate whole-body fat percentage. OBJECTIVE: To examine associations of RFM with incident type-2 diabetes (T2D), and to benchmark its performance against body-mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). METHODS: This prospective longitudinal study included data from three Dutch community-based cohorts free of baseline diabetes. First, we examined data from the PREVEND cohort (median age and follow-up duration: 48.0 and 12.5 years, respectively) using Cox regression models. Validation was performed in the Lifelines (median age and follow-up duration: 45.5 and 3.8 years, respectively) and Rotterdam (median age and follow-up duration: 68.0 and 13.9 years, respectively) cohorts. RESULTS: Among 7961 PREVEND participants, 522 (6.6%) developed T2D. In a multivariable model, all adiposity indices were significantly associated with incident T2D (Pall<0.001). While 1 SD increase in BMI, WC and WHR were associated with 68%, 77% and 61% increased risk of developing T2D [Hazard ratio (HR)BMI: 1.68 (95%CI: 1.57-1.80), HRWC: 1.77 (95% CI: 1.63-1.92) and HRWHR: 1.61 (95%CI: 1.48-1.75)], an equivalent increase in RFM was associated with 119% increased risk [HR: 2.19 (95%CI: 1.96-2.44)]. RFM was associated with incident T2D across all age groups, with the largest effect size in the youngest (<40 years) age category [HR: 2.90 (95%CI: 2.15-3.92)]. Results were broadly similar in Lifelines (n = 93,870) and Rotterdam (n = 5279) cohorts. CONCLUSIONS: RFM is strongly associated with new-onset T2D and displays the potential to be used in the general practice setting to estimate the risk of future diabetes.

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.

Sex differences in associations of comorbidities with incident cardiovascular disease: focus on absolute risk.

Aim: To examine sex differences in associations of obesity, type-2 diabetes, hypertension, and atrial fibrillation (AF) with incident cardiovascular disease (CVD), focusing on absolute risk measures. Methods and results: We included a total of 7994 individuals (mean age 49.1 years; 51.2% women) without prior CVD from the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort with a median follow-up of 12.5 years. Using Poisson regression, we calculated the increase in absolute as well as relative CVD risk associated with a comorbidity using incidence rate differences (IRD = IRcomorbidity-IRno-comorbidity) and incidence rate ratios (IRR = IRcomorbidity/IRno-comorbidity), respectively. Sex differences were presented as women-to-men differences (WMD = IRDwomen-IRDmen) and women-to-men ratios (WMR = IRRwomen/IRRmen). Absolute CVD risk was lower in women than in men (IRwomen: 6.73 vs. IRmen: 14.58 per 1000 person-years). While increase in absolute CVD risk associated with prevalent hypertension was lower in women than in men [WMD: -6.12, 95% confidence interval: (-9.84 to -2.40), P = 0.001], increase in absolute CVD risk associated with prevalent obesity [WMD: -4.25 (-9.11 to 0.61), P = 0.087], type-2 diabetes [WMD: -1.04 (-14.36 to 12.29), P = 0.879] and AF [WMD: 18.39 (-39.65 to 76.43), P = 0.535] did not significantly differ between the sexes. Using relative risk measures, prevalent hypertension [WMR: 1.49%, 95% confidence interval: (1.12-1.99), P = 0.006], type-2 diabetes [WMR: 1.73 (1.09-2.73), P = 0.019], and AF [WMR: 2.53 (1.12-5.70), P = 0.025] were all associated with higher CVD risk in women than in men. Conclusion: Increase in absolute risk of developing CVD is higher in hypertensive men than in hypertensive women, but no substantial sex-related differences were observed among individuals with obesity, type-2 diabetes and AF. On a relative risk scale, comorbidities, in general, confer a higher CVD risk in women than in men.

Sex-specific aspects of phospholamban cardiomyopathy: The importance and prognostic value of low-voltage electrocardiograms.

BACKGROUND: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization. Whether sex-specific differences in PLN cardiomyopathy exist is unknown. OBJECTIVE: The purpose of this study was to improve the accuracy of PLN cardiomyopathy diagnosis and risk assessment by investigating sex-specific aspects. METHODS: We analyzed a multicenter cohort of 933 patients (412 male, 521 female) with the PLN p.(Arg14del) pathogenic variant following up on a recently developed PLN risk model. Sex-specific differences in the incidence of risk model components were investigated: low-voltage electrocardiogram (ECG), premature ventricular contractions, negative T waves, and left ventricular ejection fraction. RESULTS: Sustained ventricular arrhythmias (VAs) occurred in 77 males (18.7%) and 61 females (11.7%) (P = .004). Of the 933 cohort members, 287 (31%) had ≥1 low-voltage ECG during follow-up (180 females [63%], 107 males [37%]; P = .006). Female sex, age, age at clinical presentation, and proband status predicted low-voltage ECG during follow-up (area under the curve: 0.78). Sustained VA-free survival was lowest in males with low-voltage ECG (P <.001). CONCLUSION: Low-voltage ECGs predict sustained VA and are a component of the PLN risk model. Low-voltage ECGs are more common in females, yet prognostic value is greater in males. Future studies should determine the impact of this difference on the risk prediction of PLN cardiomyopathy and possibly other cardiomyopathies.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, 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, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 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-cTnT (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 with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Relationship between body mass index, cardiovascular biomarkers and incident heart failure.

AIMS: There are limited data examining whether body mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF). METHODS AND RESULTS: Thirteen biomarkers representing key HF domains were measured: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), cardiac troponin T (cTnT), C-reactive protein, procalcitonin, galectin-3, C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin, plasminogen activator inhibitor-1, copeptin, renin, aldosterone, and cystatin-C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations. Among 8202 individuals, 41% were overweight (BMI 25-30 kg/m2 ), and 16% were obese (BMI ≥30 kg/m2 ). Mean age of the cohort was 49 years (range 28-75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT-proBNP, MR-proANP, CT-proET-1 and aldosterone whereas positive associations were observed with the remaining biomarkers (all P ≤ 0.001). During 11.3 ± 3.1 years of follow-up, 357 HF events were recorded. Only NT-proBNP, MR-proANP and cTnT remained associated with incident HF (P < 0.001), and a significant biomarker*BMI interaction was not observed (interaction P > 0.1). Combined NT-proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC-statistic = 0.024; likelihood ratio χ2  = 38; P < 0.001) and obese (ΔC-statistic = 0.020; likelihood ratio χ2  = 32; P < 0.001) individuals. CONCLUSIONS: Plasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT-proBNP, MR-proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT-proBNP and cTnT improves HF risk prediction in overweight and obese individuals.

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.