Systemic delivery of extracellular vesicles reduces AF in heart failure with preserved ejection fraction


AFA recent study has provided new mechanistic insights identifying distinct atrial electrophysiological remodelling and fibrosis-associated conduction abnormalities favouring atrial fibrillation (AF) susceptibility in heart failure with preserved ejection fraction (HFpEF). The results from this proof-of-concept study support a correlation between immortalised cardiosphere-derived extracellular vesicles (imCDCevs) reduction of AF burden, improving arrhythmogenic substrate in rats with HFpEF.

Published in JACC: Clinical Electrophysiology the study authors led by Rui Zhang (The Chinese University of Hong Kong, Shenzhen, China) observed dahl salt-sensitive rats who were fed a high-salt diet for seven weeks, inducing HFpEF and randomised to receive imCDCevs (n=18) or vehicle intravenously (n=14). They also included rats that were fed a normal salt diet as control animals (n=26).

In their results, Zhang et al observed that the HFpEF-verified animals displayed significantly higher AF inducibility (84%) when compared with the control animals (15%). The authors note that these changes were associated with prolonged action potential duration, slowed conduction velocity (connexin 43 lateralisation), and fibrotic remodelling in the left atrium of HFpEF in comparison with the control animals. In addition, they observed imCDCevs reduction of adverse electrical remodelling and reduced AF inducibility (33%).

The study authors add that, importantly, fibrosis, inflammation and oxidative stress­—which are known to be major pathological AF drivers—were “markedly” attenuated in imCDCevs-treated animals and occurred without altering blood pressure and diastolic function.

Commenting on their findings, Zhang et al assert that the “unique” electrophysiological changes in HFpEF-related AF, as shown in their study, contrast those that have been previously reported and may help “rationalise” why the condition has proven to be refractory to therapies. Setting their research apart, they note that “classic” changes favouring re-entry circuits, such as shortening of atrial action potential duration (APD), with associated abbreviated atrial refractoriness, were not seen in their study.

Noting a prominent  limitation of their study, the investigators refer to the cardioprotective effects CDCs have on various diseases, including HFpEF. Although most salutary effects of CDCs are mediated by EVs (CDC EVs), the authors assert EVs have potential to reverse disease phenotypes affecting fibrosis, angiogenesis, oxidative stress, and inflammation signalling pathways, overcoming “major limitations of cell therapy”.

Zhang and colleagues note: “We recently characterised the RNA and protein content in imCDCevs. These EVs from an engineered cell source have shown disease-modifying bioactivity while optimising the manufacturing and scalability process. ImCDCevs are enriched with small RNAs (e.g. miR-4488 and miR92a), which have been shown to be therapeutically active microRNA in arrhythmogenic cardiomyopathy and HF.”  However, Zhang et al posit the exact mechanism by which imCDCevs alleviate AF in HFpEF remains to be determined and further investigation is needed to define this.


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