Modelling cardiomyopathy in inflammatory arthritis to define mechanisms and guide therapeutic strategies

Cardiovascular comorbidities contribute to around half of all deaths in patients with rheumatoid arthritis (RA), among which non-ischaemic heart failure plays a predominant role.

RA patients are particularly susceptible to a type of heart failure with preserved ejection fraction (HFpEF), which is accompanied by diastolic dysfunction.

The causes of diastolic dysfunction in RA are unknown and current medications for RA do not produce marked cardioprotective effects.

To address this unmet clinical need, I have identified a mouse model of arthritis, K/BxN F1 progeny, which recapitulates the specific diastolic dysfunction reported in RA patients; this is the first mouse model of inflammatory arthritis which shows diastolic dysfunction.

Based on my preliminary data, I hypothesise that the observed diastolic dysfunction in arthritic mice is due to 1) cardiac fibrosis/hypertrophy contributed by systemic and local inflammation indicated by elevations in multiple circulating inflammatory cytokines and dysregulated infiltration of cardiac immune cells; and 2) substantial metabolic alterations, with uncoupled glycolysis and mitochondrial oxidative metabolism.

I have identified a separate second model of inflammatory arthritis also coupled to diastolic dysfunction: hyper-homocysteinaemic mice subjected to injection of arthritogenic KBN serum.

In this fellowship, I will address the following key goals: I will utilise K/BxN F1 progeny to elucidate how cellular/molecular dysregulation contributes to the development of cardiac dysfunction by defining time-courses for immune cell infiltration, glycolysis and mitochondrial oxidative metabolism.

I will also test the impact of both established anti-inflammatory as well as innovative pro-resolving therapeutic strategies on cardiac function and joint symptoms in K/BxN F1 mice. I will validate discoveries in a second model of arthritic mice with hyper-homocysteinaemia.

Finally, I will access RA patients’ data and blood samples from Barts NHS Bioresource to investigate whether diastolic dysfunction/ HFpEF is associated with cardiac fibrosis, and whether systemic inflammation contributes to cardiac fibrosis and/or dysfunction.