Cellular and Molecular Aspects of Dyssynchrony and Resynchronization

Abstract

Dyssynchronous contraction of the ventricle significantly worsens morbidity and mortality in patients with heart failure (HF). Approximately one-third of patients with HF have cardiac dyssynchrony and are candidates for cardiac resynchronization therapy (CRT). The initial understanding of dyssynchrony and CRT was in terms of global mechanics and hemodynamics, but lack of clinical benefit in a sizable subgroup of recipients who appear otherwise appropriate has challenged this paradigm. This article reviews current understanding of these cellular and subcellular mechanisms, arguing that these aspects are key to improving CRT use, as well as translating its benefits to a wider HF population.

Keywords: Animal models; Cardiac resynchronization therapy; Dyssynchrony; Myocyte; Myofilament.

Figure 1

Immediate LV resynchronization with cardiac resynchronization therapy (CRT) and change in LV end-systolic volume at 6-month follow-up from Bleeker et al. [25] with permission. An acute response to CRT (>20% LV resynchronization) is necessary for a positive chronic response (>10% LV reverse remodelling), but among these “responders” there is almost no relationship between acute and chronic response. Therefore, acute hemodynamic response to CRT has little ability to predict long-term benefit.

Figure 2

Dyssynchrony reduced baseline cellular function, which is restored by CRT. (A) Myocyte sarcomere shortening and corresponding whole cell calcium transients in myocytes taken from control (Con), dyssynchronous heart failure (Dys HF), synchronous heart failure (Sync HF), and CRT. Adapted from Chakir et al. [35]. (B) Western blots for calcium handling proteins. Arrows show the direction of change in Dys HF and CRT groups as compared to control. Adapted from Aiba et al. [33]. (C) Three-dimensional reconstructions from confocal microscopic images showing t-tubule structure (blue) and ryanodine receptors (red). Adapted from Sachse et al. [34]. (D) In response to isoproterenol, Dys HF exhibited a much smaller augmentation in sarcomere shortening and calcium transient amplitude, which was reversed by CRT. (E) Cell fluorescence ratio-encoded images from myocytes from Con, Dys HF, and CRT. The CRT myocytes exhibited elevated cyclic AMP generation when stimulated with zinterol (β2 adrenergic receptor stimulation) (F) RGS2/3 can inhibit Gαi, and were significantly up-regulated in CRT. Adapted from K. Chakir, et al. Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart. Sci Transl Med 2011;3:100ra88; with permission.

Figure 3

Action potential duration and its modulation by the late sodium current. (A) Action potentials from myocytes isolated from the lateral wall in Con, Dys HF, and CRT, exhibiting a significantly longer Action potential duration (APD) in Dys HF that is mostly reversed with CRT. Using ranolazine to block the late sodium current (I_Na-L) shortened APD in Dys HF, but had no affect in Con or CRT myocytes. (B) APD duration at 90% repolarization at baseline and after ranolazine. Adapted from T. Aiba, et al. Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. Circ Arrhythm Electrophysiol 2013;6:546–54; with permission.

Figure 3

Action potential duration and its modulation by the late sodium current. (A) Action potentials from myocytes isolated from the lateral wall in Con, Dys HF, and CRT, exhibiting a significantly longer Action potential duration (APD) in Dys HF that is mostly reversed with CRT. Using ranolazine to block the late sodium current (I_Na-L) shortened APD in Dys HF, but had no affect in Con or CRT myocytes. (B) APD duration at 90% repolarization at baseline and after ranolazine. Adapted from T. Aiba, et al. Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. Circ Arrhythm Electrophysiol 2013;6:546–54; with permission.

Figure 4

Myofilament function is affected by heart failure, dyssynchrony, and CRT in different ways. (A) Compared to healthy myocytes (black) calcium sensitivity is increased in HF (Sync HF, dark red) and decreased in dyssynchronous HF (Dys HF, red). This is due to de-activation of the kinase glycogen synthase kinase 3β (GSK-3β) in dyssynchronous HF, but not in synchronous HF (inset). (B) CRT (blue) restores calcium sensitivity to normal levels, via re-activation of GSK-3β. If Dys HF myocytes are treated with active GSK-3β, the recovery with CRT is recapitulated. However, treating CRT myocytes with GSK-3β had no effect, since the myofilament is already re-sensitized via this mechanism (inset). (C) Both Dys HF and Sync HF see a decrease in maximal calcium activated force (F_max), and this is due to an increase in myocyte size (inset). (D) CRT restores F_max, by reversing the change in cell size (inset). Adapted from J. A. Kirk, et al. Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3beta. J Clin Invest 2014;124:129–38; with permission.

Figure 5

Summary of molecular alterations in dyssynchronous HF (Dys HF) and CRT.