Re-evaluating sarcoplasmic reticulum function in heart failure

To the editor

Heart failure presently afflicts an estimated 5 million Americans with a 4 year mortality rate approaching 50% (ref. 1). The failing human heart transitions into a dilated state characterized by ventricular remodeling, collagen deposition and reduced contractility. The molecular etiology of this phenotype is closely associated with reduced calcium transients and prolongation of diastolic calcium re-sequestration leading to decreased cardiac contractility². Critical intracellular regulators of calcium cycling within cardiac myocytes are the sarcoplasmic reticulum associated calcium ATPase pump, SERCA2, and its negative regulator phospholamban (PLB). The deterioration in calcium cycling characteristic of the failing human heart has been largely associated with a reduction in SERCA2 activity resulting from reduced protein concentrations or from enhanced inhibition mediated by PLB (ref. 2). Indeed, targeted ablation of PLB in the mouse allows unrestricted SERCA2 activity resulting in a dramatic increase in baseline calcium cycling and enhanced contractility in the unstimulated state².

A recent study by Minamisawa et al. used PLB knockout mice to investigate the causality between reduced SERCA2 activity and the initiation and propagation of dilated cardiomyopathy³. Ablation of the PLB gene was sufficient to rescue the dilated cardiomyopathic phenotype of the muscle lim protein (MLP) knockout mouse³. This observation suggested that dilated cardiomyopathy can be rescued by enhancing intracellular calcium cycling and that deterioration in calcium handling kinetics play a primary role in the pathogenesis of heart failure.

In contrast, our recent studies indicate that this postulate may not extend to all forms of dilated cardiomyopathy. Using a similar approach, we crossed PLB knockout mice with transgenic mice over-expressing the sarcomeric structural protein tropomodulin⁴. The tropomodulin over-expressing transgenic (TOT) mouse model of dilated cardiomyopathy shows many characteristics of human heart failure^4,5. We observed that disruption of the PLB gene failed to rescue the overt dilated phenotype of TOT mice (Fig. 1a), nor did it rescue the increase in heart-to-body weight ratio characteristic of the TOT phenotype (Fig. 1b). Last, ablation of the PLB gene also failed to rescue juvenile lethality associated with tropomodulin over-expression, as 9 of 21 mice died by 28 days of life, comparable with reported levels of TOT mortality⁵.

Figure 1: a, Hematoxylin and eosin-stained histological sections demonstrate dilated cardiomyopathy induced by the tropomodulin transgene (TOT) which is not rescued by phospholamban ablation (PLB).

Animals were analyzed at 22 days after birth, although phenotypic analysis at day 18 or 28 also failed to demonstrate any protective effect of PLB ablation. b, PLB ablation failed to protect TOT mouse hearts from increased heart-to-body weight ratio associated with the dilated cardiomyopathy. ^*P< 0.05 versus PLB^+/+

These data indicate that augmented calcium cycling may not benefit all forms of heart failure, especially if impaired intracellular calcium cycling is not associated with the end phenotype. Indeed, cardiac myocytes from TOT mice are actually characterized by enhanced calcium transients, despite the dilated cardiomyopathic state⁵. Minamisawa et al. proposed that PLB ablation rescued the pathology associated with the MLP gene disruption by a mechanism involving augmented calcium cycling resulting in greater cardiac contractility and reduced ventricular wall stress. This interpretation is further supported by the results of Rockman et al. in which enhanced contractility mediated by the βARKct transgene rescued certain aspects of the cardiomyopathic MLP phenotype⁶. Collectively, these data suggest that enhanced intracellular calcium cycling and the associated increase in cardiac contractility may benefit certain forms of heart failure. Our results, however, suggest that augmentation of cardiac calcium cycling may not benefit all forms of dilated heart failure. These results also underscore the potential complexity of associated molecular defects that may underlie human heart failure.