The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy

he classic definition of hypertrophic cardiomyopathy (HCM) as originally described by Teare 1 is deceptively simple: "left ventricular hypertrophy in the absence of any identifiable cause." This definition fits the majority of referral patients who are identified by either their symptoms or incidental findings on noninvasive testing. Longitudinal studies, however, including a seminal study performed by Frank and Braunwald 2 in 1964, clearly described the disorder much as we know it today: a complex, progressive, and highly variable cardiomyopathy. Subsequent linkage studies in the early 1990s established mutations in the components of the cardiac sarcomere as the molecular cause of the familial form of HCM. Since then, the growing accessibility of genetic screening and advent of specialized centers of care have greatly expanded our understanding of what is now considered to be a genetic cardiomyopathy until proven otherwise. ven with this sophisticated understanding of the genetic etiology of the disorder, many clinically relevant questions remain regarding the basic mechanisms whereby mutations in sarcomeric proteins lead to the variable degrees of myocardial remodeling that define HCM. In other words, how does disrupted myofilament function trigger a myocellular response that alters the geometry of the heart leading to arrhythmias, impaired relaxation, hyperdynamics, and, in some cases, left ventricular outflow tract obstruction? Recent longitudinal studies and a pilot clinical trial of genotyped HCM cohorts have helped to refine and integrate these important questions. In particular, the observation that patients carrying sarcomeric mutations (sarc-positive HCM) have worse outcomes that may not necessarily be defined by the degree of hypertophy has refocused research efforts on both the preclinical state and temporal development of the disorder. 6 Thus, we now know that sarc-positive patients may exhibit impaired relaxation before the onset of symptoms or overt left ventricular hypertrophy, that they exhibit a nonlinear trajectory and focal patterns of ventricular remodeling, and, finally, that diltiazem can slow the initial development of left ventricular hypertrophy in some cohorts. This far more nuanced clinical understanding of sarc-positive HCM establishes a framework for testable hypotheses that will finally allow for proactive management and perhaps even genotype-driven care instead of the current symptom palliation.