Introduction and objective

About 64.3 million people are living with heart failure (HF) worldwide and almost half of these cases are HFpEF. With the current global demographic heading towards aging and the increasing rate of metabolic disorders, HFpEF is poised to be an imminent epidemic and the lack of evidence based interventions makes us ill-equipped to deal with it. There is an urgent need for clinically relevant animal models but, it is further complicated by multiple and simultaneous comorbid conditions that are often present with HFpEF. We attempt to fill this gap by creating mouse models of HFpEF by mimicking common causal factors in separate models and stratifying them based on their key differences.

Methods

Two models of HFpEF were created: A combination of Low grade Transverse Aortic Constriction  + 8 weeks of High Fat Diet consisting 60% fat/kCal (LG-TAC+HFD), and natural aging. A model was considered HFpEF when there was diastolic dysfunction and systolic function was preserved. They were then characterised using different levels of analysis. Echocardiography, broad range morphometry, real time Pressure volume (PV) loop, histopathology, protein and gene expression analysis was employed to unravel a snapshot of the intrinsic patho-mechanisms.

Results

Characteristic differences were seen in the mechanistic profile of the two models. While LG-TAC+HFD showed high levels of hypertrophy both on organ and cellular level, aging model did not exhibit significant hypertrophy. The difference between the two models was also reflected in the molecular profiles of common hypertrophic A type and B type natriuretic peptides.  Interestingly, it was also observed that the mice on a combination of HFD + TAC exhibited a HFpEF profile while simultaneous Normal diet + TAC controls showed HFrEF, that is a reduction in Left ventricular Ejection Fraction. This shows that the metabolic mechanisms driven by the HFD are an important component in shifting the HF spectrum towards HFpEF. Moreover, elements of calcium signalling cascade, apoptosis, fibrosis and inflammation were also differentially regulated in the two models. These differences highlight the heterogeneity of HFpEF and its mechanisms.

Clinical Relevance

In the present clinical scenario, a ‘one-size-fits-all’ approach to treating HFpEF is not sufficient. We need tailor made therapies and interventions based on the specific phenotype of the patient i.e. the HFpEF subtype that they exhibit. For this, a pre-requisite is to establish well-defined and well-characterised animal models that are not only able to capture the intrinsic pathophysiology of HFpEF but also highlight mechanistic differences. Such models can provide us with valuable insights to guide evidence based therapies in the clinic. The ultimate goal of such endeavours would be to have animal models matching various possible subtypes of HFpEF through which mechanistic data can be gathered and therapeutic interventions could be tested.