Abstract 15877: Abnormal T-Tubules, Calcium Cycling, and Cardiac Function During the Transition From Hypertension to Heart Failure: A Cell Attrition Model
INTRODUCTION: The cellular basis for the development of heart failure (HF) is not well understood. Disorganized t-tubules and the associated defects in Ca cycling are present in all types of HF. However, it is not known if t-tubule disruption occurs and contributes to altered cardiac function before the development of overt HF.
HYPOTHESIS: We hypothesized that in the spontaneously hypertensive rat (SHR), disorganization of t-tubules (1) precedes the development of HF, (2) is associated with Ca2+i cycling defects, and (3) correlates with abnormal cardiac function.
METHODS: SHR (n = 23) and control WKY rats (n = 15), age range 2-16 months, underwent conventional and speckle tracking echocardiography, followed by confocal laser microscopy of intact mid wall subepicardial left ventricular cardiomyocytes. T-tubule organizational index (OI) utilizing di-4-ANEPPS and Ca2+i cycling via fluo-4AM were assessed.
RESULTS: In the SHR, during the transition from hypertension (HTN) to left ventricular hypertrophy (LVH) and prior to the onset of HF, t-tubule OI declined (HTN OI = 0.89 vs. LVH OI = 0.77, p = 0.0001). Defects in Ca cycling matched the observed disruptions in t-tubule organization. Changes in peak radial systolic strain correlated with the degree of t-tubule organization (r = 0.51, p = 0.004). Finally, these pathologic changes preceded a decline in ejection fraction (HTN EF 85% vs. LVH EF 82%, p = 0.21).
CONCLUSIONS: In the SHR, disorganization of t-tubules and defective Ca2+i cycling occur during the course of HTN heart disease, prior to a decline in EF or onset of overt HF. Slowed Ca release and removal leads to systolic and diastolic dysfunction, respectively. Our findings, for the first time, relate disorganization of t-tubules and defects in calcium cycling with abnormalities in contractility as assessed by speckle tracking echocardiography. These data support a cellular basis for the development of HF, namely the progressive attrition of normal cardiomyocytes leads to the loss of cardiac reserve and the onset of HF. Importantly, this research examined the subclinical vulnerable stage of hypertensive heart disease, before the development of overt HF, which represents a window for the implementation of HF prevention strategies.
- © 2011 by American Heart Association, Inc.