Pathobiology of cardiac dyssynchrony and resynchronization

Abstract

Cardiac resynchronization therapy (CRT) represents the major new advance for the treatment of heart failure since the new millennium. With this therapy, failing hearts with discoordinate contraction due to conduction delay are subjected to bi-ventricular stimulation to “resynchronize” contraction and improve chamber function. Remarkably, CRT was mostly developed and tested in patients first, and the speed at which the concept became translated to an approved clinical therapy was unusually quick. To date, CRT is the only treatment for heart failure that can both acutely and chronically improve the systolic pump performance of the human failing heart, yet also enhances long term survival. This raises the importance of understanding how CRT works at the molecular and cellular level, as these insights might shed light on new approaches to treating heart failure more generally. Over the past 7 years, my laboratory and others at Johns Hopkins developed novel animal models to start to address this question, and new results are revealing intriguing insights into the mechanisms of CRT. This review, presented on the occasion of the 4th Annual Douglas Zipes Lecture at the 2009 Scientific Sessions of the Heart Rhythm Society, highlights these advances and new directions in CRT research.

A new score system for predicting response to cardiac resynchronization therapy

“…One of the key mechanisms of benefit from CRT is to correct mechanical dyssynchrony [3,4]. However, in order to restore mechanical dyssynchrony, dyssynchronous segments must be viable in order to recruit their "wasted work" toward cardiac output.…”

“…Correcting mechanical dyssynchrony within the left ventricular (LV) was proposed as one of the key mechanisms of benefit from CRT [3,4]. However, the PROSPECT trial demonstrated that no single echocardiographic measurement of dyssynchrony may be recommended to improve patient selection for CRT [5].…”

Cardiac ‘resynchronization’ by a left lateral accessory pathway

“…However, there are some epidemiological studies that provide evidence of a worse outcome in a population affected with LBBB [2]. Perhaps in this case biventricular depolarization will prevent mechanical dyssynchrony and in the future an evolution to a dilated cardiomyopathy by ventricular remodeling [3][4][5].…”

Cellular and Molecular Aspects of Dyssynchrony and Resynchronization

“…Recently, however, there have been efforts to "reverse-engineer" CRT, exploring the cellular and molecular mechanisms that are involved. Indeed, dyssynchrony and resynchronization therapy induce a wide range of changes beyond the mechanical effects, many which are unique to both the disease and the treatment [15][16][17][18][19]. Interestingly, in some instances, CRT does not simply reverse the damage done by dyssynchrony, but acts in entirely novel ways to improve function.…”