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Cardiac Dyssynchrony - The Heart Out of Beat

    Contraction of the left ventricle is precisely coordinated by the His-Purkinje system, which rapidly conducts electrical excitation to the myocardium. This ensures that shortening throughout the muscle wall occurs synchronously and by a similar magnitude to optimize the pumping efficiency of the heart. Diseases of the conduction system such as a left-bundle branch block (LBBB) lead to a loss of synchrony, and occur in 30-50% of patients with heart failure. As a result, the early-stimulated regions do not generate sufficient pressure to eject blood, but merely stretch the later-activated regions, while the opposite happens later in the cardiac cycle. The “sloshing” of blood within the heart results in a reduction in mechano-energetic performance. In the failing heart, where function is already reduced, dyssynchrony worsens both morbidity and mortality.

    Pioneering studies in the 1990s showed that simultaneous bi-ventricular pacing applied to dyssynchronous hearts improved function and chamber efficiency, while concomitantly lowering morbidity and mortality. This ultimately led to Cardiac Resynchronization Therapy (CRT). To date, CRT remains the singular therapy for heart failure that simultaneously improves both acute and chronic systolic function, increases cardiac work, and yet also prolongs survival.

    Traditionally, CRT has been viewed as a mechanical tuning of the heart. Its relative simplicity and ease of entry into the clinic led to rapid development, testing, and approval – all performed in human subjects. There was very little basic science on CRT reported prior to its clinical adaption. Recently, however, there have been efforts by ourselves and others to “reverse-engineer” CRT, exploring the cellular and molecular mechanisms that are involved. Indeed, dyssynchrony and resynchronization therapy induce a wide range of changes, many unique to both the disease and the treatment. Interestingly, in some instances, CRT does not simply reverse the damage done by dyssynchrony, but acts in entirely novel ways to improve function.

    Our work involves furthering this understanding, with the goal of improving CRT and discovering a way to bring its substantial benefits to the wider heart failure population.