The goal of these studies is to define the role of altered Ca and Na transport in the development of ventricular tachycardia (VT) in heart failure (HF). We have recently shown that VT in the failing rabbit & human heart initiates by a nonreentrant" mechanism that may be due to triggered activity from delayed afterdepolarizations (DADs) (or early afterdepolarizations, EADs). We also find upregulation of Na/Ca exchange (NaCaX) mRNA, protein and current in HF which could underlie the transient inward current (I-ti) responsible for DADs. We hypothesize that in HF, prolongation of the action potential duration (APD) and increased [Na]1 (due to decreased Na/K ATPase activity) contribute to SR Ca overload and spontaneous SR Ca release. Further, a given SR Ca release in HF will produce greater I-ti (due to increased NaCaX) and larger DADs (due to increased I-ti and reduced 1-K1), resulting in more triggered APs and nonreentrant arrhythmias in HF. Specific Aims will focus on: l. The role of altered APD & ionic currents on both SR Ca load and DAD induction in HF. 2. The alterations in intracellular [Na] and Na/K-ATPase activity & expression in HF. 3. The relationship of SR Ca release to the genesis of arrhythmogenic I- ti's, DADs and triggered APs. 4. The possible contribution of spontaneous SR Ca release to EADs in HF. 5. The effects of blocking Ca influx via NaCaX (with KB-R7943) on E-C coupling, on prevention of I-ti and DADs in myocytes, and on prevention of VT in the intact failing heart in situ. The experimental approaches will include: in vitro patch clamping (voltage, AP & current clamp); fluorescence measurements of [Ca]i and [Na]i; measurement of mRNA & protein (of Ca transporters & Na/K ATPase subunit isoforms) and Na/K ATPase activity; and 3-dimensional cardiac mapping in vivo. Detailed studies in a novel arrhythmogenic rabbit model of nonischemic HF will be extended to include studies in isolated ventricular myocytes from failing and nonfailing human hearts. The results of these studies will provide the foundation for the development of effective therapeutic approaches to modulate nonreentrant initiation of VT and to decrease the high incidence of sudden death in patients with heart failure.
|Effective start/end date||7/5/00 → 6/30/10|
- National Institutes of Health: $487,236.00
- National Institutes of Health: $514,818.00
- National Institutes of Health: $470,102.00
- National Institutes of Health: $498,251.00
- National Institutes of Health: $486,274.00
- National Institutes of Health: $485,490.00
- National Institutes of Health: $484,586.00
- National Institutes of Health: $504,148.00
- National Institutes of Health: $493,792.00
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