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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., Graphical Abstract An in-depth review of existing pre-clinical HFpEF mouse models with validation of their translational value using the HFA-PEFF and H2FPEF scores.

Purpose To examine whether cardiovascular risk factor development over time would associate differently with incident heart failure (HF) in women and men. Methods In the PREVEND (Prevention of Renal and Vascular End-stage Disease) cohort, we calculated the incidence rates (IR) of HF and cardiovascular risk factors using Poisson regression. We examined sex-related differences in relative rates of HF according to cardiovascular risk factor development using IR-ratio (IRR=IRrisk-factor/IRno-risk-factor) and Cox regression models. Results Among 8592 participants (mean age 49.8 years; 50.1% women), 241 men and 133 women developed HF over 12.5 (12.2–12.9) years, resulting in an overall HF incidence rate of 5.12 (per 1000 person-years) in men versus 2.69 in women. Men also had higher incidence rates of diabetes (IRmen: 7.23 vs IRwomen: 4.46), hypertension (IRmen: 27.93 vs IRwomen: 21.35) and myocardial infarction (IRmen: 3.73 vs IRwomen: 1.33). Relative rates of HF in individuals developing obesity, diabetes and MI were comparable in both sexes (P>0.05), but development of hypertension more strongly associated with incident HF in women (IRRwomen: 6.49; 95% CI: 3.04–13.87 vs IRRmen: 2.34; 95% CI: 1.38–3.95, P=0.030). Similar trends were observed in an adjusted Cox-regression model (women:men HR: 2.93; 95% CI: 1.15–7.45; p=0.024). Conclusions Cardiovascular risk factors develop more often in men and associate with higher absolute rates of HF in men. However, in individuals developing hypertension, the relative rate of HF is higher in women compared to men. Our results suggest that aggressive and sex-specific risk factor management may be helpful to prevent incident HF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Netherlands Heart Foundation;Public EU grant - European Research Council