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1 Department of Medicine, Allegheny General Hospital, MCP-Hahnemann University School of Medicine, Pittsburgh 15212; and 2 Merck Research Laboratories, West Point, Pennsylvania 19486
Incessant tachycardia
induces dilated cardiomyopathy in humans and experimental models;
mechanisms are incompletely understood. We hypothesized that excessive
chronotropic demands require compensatory contractility reductions to
balance metabolic requirements. We studied 24 conscious dogs during
rapid right ventricular (RV) pacing over 4 wk. We measured hemodynamic,
coronary blood flow (CBF), myocardial O2 consumption
(M
O2) responses, myocardial nitric oxide
(NO) production, and substrate utilization. Early pacing (6 h) resulted
in decreased heart rate (HR)-adjusted coronary blood flow (CBF),
MO2 (CBF/beat: 0.33 ± 0.02 to
0.19 ± 0.01 ml, P < 0.001, MO2/beat: 0.031 ± 0.002 to
0.016 ± 0.001 ml O2, P < 0.001), and
contractility [left ventricular (LV) first derivative pressure
(dP/dt)/LV end-diastolic diameter (EDD): 65 ± 4 to
44 ± 3 mmHg · s
1 · mm1,
P < 0.01], consistent with flow-metabolism-function
coupling, which persisted over the first 72 h of pacing (CBF/beat:
0.15 ± 0.01 ml, MO2/beat:
0.013 ± 0.001 ml O2, P < 0.001).
Thereafter, CBF per beat and MO2 per
beat increased (CBF/beat: 0.25 ± 0.01 ml,
MO2/beat: 0.021 ± 0.001 ml
O2 at 28 days, P < 0.01 vs. 72 h).
Contractility declined [(LV dP/dt)/LVEDD: 19 ± 2 mmHg · s1 · mm1,
P < 0.0001], signifying flow-function mismatch.
Cardiac NO production, endothelial NO synthase expression, and fatty
acid utilization decreased in late phase, whereas glycogen content and
lactate uptake increased. Incessant tachycardia induces contractile,
metabolic, and flow abnormalities reflecting flow-function matching
early, but progresses to LV dysfunction late, despite restoration of flow and metabolism. The shift to flow-function mismatch is associated with impaired myocardial NO production.
nitric oxide; cardiomyopathy; stunning; hibernation; myocardial metabolism
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