Holy Grail: Reversal of pathological atrial remodelling

Professor Julie McMullen

The underlying mechanisms responsible for atrial enlargement from physiological causes must be different from pathological causes. But can insights from atrial enlargement in athletes and pregnant women help prevent or reverse pathological remodelling of the heart and its complications such as atrial fibrillation?

The limbic asked Professor Julie McMullen, head of the Discovery and Preclinical Domain at the Baker Heart and Diabetes Institute where she also leads the Cardiac Hypertrophy laboratory.

Professor Julie McMullen is coauthor on a Journal of the American College of Cardiology State-of-the-Art Review: Prevention of Pathological Atrial Remodeling and Atrial Fibrillation.

Chronic oxidative stress, inflammation and fibrosis are common features in pathological rather than physiological atrial enlargement. What can we learn from this?

These distinct features are indicative of different cellular and molecular mechanisms underpinning pathological and physiological atrial enlargement. This provides an opportunity to distinguish these different forms of enlargement with imaging e.g. late gadolinium enhancement cardiac magnetic resonance imaging, or biomarker approaches e.g. gene or lipid signatures. The ultimate goal is to differentiate atrial enlargement which is likely to progress to severe pathology and atrial fibrillation from atrial enlargement that is benign and potentially protective.

Pathological atrial enlargement is largely irreversible, the impact of extreme exercise and preeclampsia on the heart is partially reversible, while the impact of endurance exercise and normal pregnancy may be fully reversible. What explains this differential?

This is a really good question. Our knowledge in this area is currently very limited, and further studies are required. Current evidence suggests that atrial myocyte enlargement – as occurs in all three settings – is reversible, but in combination with chronic inflammation and fibrosis – as can occur with extreme exercise, preeclampsia, pathological enlargement – the process has limited capacity to reverse. However, if we can understand the underlying cellular and molecular changes that occur with pathological atrial enlargement versus exercise or pregnancy-induced atrial enlargement, we can then target these mechanisms with new therapeutic approaches.

Exercise can be a physiologic stimuli for atrial enlargement but in different forms or intensity might also help with reversal of pathological atrial enlargement. How do you explain – or can we harness – this dichotomy?

We think this occurs because there are unique sets of genes which are critical for physiological and pathological cardiac enlargement. Studies in the ventricle suggest that targeting genes which play a critical role for exercise-induced physiological enlargement can inhibit fibrotic and inflammatory pathways activated in settings of cardiac stress. The result is prevention or reversal of pathological ventricular enlargement. Further work is required to assess whether this can be harnessed in the atria.

None of our current surgical or medical strategies for pathological atrial enlargement are fully effective. What are the shiny new things on the horizon and how long before they impact patient care?

Identifying atrial stress as early as possible is critical i.e. before there is significant pathological atrial enlargement and dysfunction. It is hoped this can be achieved with improved imaging techniques and profiling studies as we describe in our review. For example there are significant advancements in the areas of molecular imaging and profiling hundred to thousands of genes, proteins and lipids. These techniques are already being used in other research fields, so it is hoped these approaches are not too far away for patients at risk of pathological atrial enlargement.

What aspect of this research interests you the most? Are you optimistic there is a way forward?

Yes, I am optimistic. Over the last decade, researchers have identified key differences between pathological and physiological ventricular enlargement. This has led to preclinical studies which have identified new drug targets and approaches for treating the failing heart. By identifying key differences between pathological and physiological atrial enlargement we have an opportunity to identify new targets for treating pathological atrial enlargement and atrial fibrillation. Understanding the process of reverse atrial remodelling is also an exciting and understudied area. It will be fascinating to test new targets in preclinical models and hopefully see this work translated into the clinic for patients with atrial fibrillation.


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