Abstract 3890: Resting and Tachycardia-Induced Contracture in Human Myocardium From Patients With Left Ventricular Hypertrophy: A Mechanism for Acute Diastolic Decompensation
Background: Concentric left ventricular hypertrophy (LVH) is known to cause diastolic dysfunction (DD) and is present in the majority of patients with heart failure with normal ejection fraction (HFNEF). Tachycardia can induce HF symptoms in these patients. In order to elucidate the pathophysiology of DD in LVH we evaluated the effects of increasing stimulation rates in myocardial strip preparations from patients with or without LVH.
Methods: Epicardial biopsies were obtained from 14 patients during coronary bypass surgery. All had normal EF and regional wall motion ± LVH. Isometrically contracting strips prepared from the biopsies were paced at rates from 60 –180/min. The active component of diastolic resting tone was assessed by pharmacological cross-bridge deactivation, sarcoplasmic reticulum (SR) Ca load was examined by rapid-cooling contractures (RCC’s), and myofilament Ca sensitivity was studied after demembranation.
Results: 7 out of 14 preparations developed an increase in diastolic tension [rate-dependent contracture (RDC+)] due to incomplete relaxation at rates ≤120/min. This was absent in all other preparations (RDC−). Clinical data revealed that RDC+ preparations originated from patients with a higher LV mass (p<0.01) and left atrial volume (p<0.01) compared with RDC- preparations. 7 out of 7 RDC+ patients met criteria for LVH while 6 out of 7 RDC− patients did not. Pharmacologic cross-bridge deactivation revealed that RDC+ but not RDC− preparations have significant resting tone (p<0.001). SR Ca load (RCC) at 180/min was 4.1 fold greater in RDC+ versus RDC− preparations (p<0.05). Myofilament Ca2+ sensitivity was identical in RDC+ and RDC− groups (EC50: RDC+ 6.4±0.4, RDC− 6.4±0.2).
Conclusions: Tachycardia-induced contracture is a common finding in myocardium from CBG patients with LVH and normal EF. This is associated with a rate-dependent increase in SR Ca load but no change in myofilament Ca sensitivity, suggesting that abnormal Ca handling is the underlying mechanism. LVH is also associated with elevated resting tone due to diastolic cross-bridge cycling. Both observations may play a substantial role in the limited exercise tolerance in patients with LVH and the clinical presentation of HFNEF.
This research has received full or partial funding support from the American Heart Association, National Center.