The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy
Authors: Jil C. Tardiff
Journal: Circulation (2016)

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. 3ven 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. 4,5In 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. 6Thus, 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. 4,5,7This 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.Building on these central observations and previous results from transgenic animal models of HCM demonstrating early activation of calcium/calmodulin-dependent protein kinase II (CaMKIIδ) activity, in the current issue of Circulation, Helms et al 8 utilized a robust set of myomectomy samples from patients with extensively phenotyped and fully genotyped hypertrophic cardiomyopathy to delineate the potential role of CaMKIIδ activation in disease pathogenesis.The study is specifically focused on identifying pathways known to be involved in the regulation of myocellular calcium homeostasis that may distinguish the natural history of HCM patients with sarcomeric gene mutations (sarc-positive HCM) from those who do not carry sarcomeric mutations (sarc-negative the role of Calcium/Calmodulin-dependent Protein Kinase ii activation in Hypertrophic Cardiomyopathy