Peter R. Kowey

Influence of intracoronary platelet aggregation on ventricular electrical properties during partial coronary artery stenosis

Several clinical studies suggest that drugs which interfere with platelet function may protect persons at risk for sudden death. However, there is no direct evidence that intracoronary platelet aggregation produces cardiac arrhythmias. Induction of fixed partial coronary stenoses in dogs resulted in spontaneous cyclical reductions in coronary blood flow of 21 to 81% (p less than 0.01). These changes are known to be associated with the formation and distal embolization of platelet aggregates. These reductions in coronary blood flow were accompanied by significant decreases in the repetitive extrasystole (-40%) and ventricular fibrillation (-38%) thresholds. Prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet activation, in increasing doses of from 25 to 100 ng/kg/min caused a stepwise decrease in the frequency and magnitude of coronary blood flow fluctuations and restored the vulnerable period thresholds to control levels. Indomethacin (5 mg/kg), an inhibitor of cyclo-oxygenase activation and platelet thromboxane A2 production, produced similar results. The mechanism of coronary blood flow reduction appears to be mechanical blockade of the vessel lumen by platelet thrombi and production of myocardial ischemia. These results suggest that intracoronary platelet aggregation contributes to electrical destabilization of the myocardium and may predispose to ventricular fibrillation. A model is thus available for further investigating the role of platelets and antiplatelet drugs in modulating ventricular electrical stability.

Effect of alpha-adrenergic receptor stimulation on ventricular electrical properties in the normal canine heart☆

We examined the effects of alpha-adrenergic stimulation on ventricular excitability, refractoriness, and vulnerability to fibrillation. Methoxamine or phenylephrine was infused in five dogs each before and after aortic arch and carotid sinus baroreceptor denervation, in doses which increased mean arterial blood pressure by 20 to 30 mm Hg. Methoxamine or phenylephrine caused an increase in the ventricular fibrillation threshold (VFT) (from 27% to 41%) and in the repetitive extrasystole threshold (RET) (from 28% to 39%). This effect was abolished by baroreceptor denervation. Neither drug altered mid-diastolic threshold or effective refractory period duration either before or after denervation. We conclude that alpha-receptor activation exerts no direct effect on ventricular excitability or refractoriness in the normal intact heart.

Use of radionuclide ventriculography for assessment of changes in myocardial performance induced by disopyramide phosphate

Disopyramide phosphate may precipitate heart failure in susceptible patients with cardiomegaly. To identify those at risk, gated radionuclide ventriculography (RVG) was performed in two groups. Eleven patients without evidence of structural heart disease constituted group 1, and 12 with impaired ventricular function made up group 2. RVG was carried out before and 2 hours after administration of a single 300-mg dose of disopyramide orally. After disopyramide mean left ventricular ejection fraction (EF) decreased in the 12 patients in group 2 (35% to 26%) (p less than 0.01); depression of function was most pronounced in regions with the poorest baseline value. Of the 11 patients in group 1 (mean EF 60%), EF was reduced after disopyramide in only one. Serum levels of drugs were comparable in patients in both groups (3.1 vs. 3.7 micrograms/ml). We conclude that (1) patients with left ventricular dysfunction are particularly susceptible to the depressant effects of disopyramide; (2) RVG is a sensitive technique for detecting disopyramide-induced changes in ventricular performance; and (3) RVG before and shortly after a dose of disopyramide orally may help to identify those patients at high risk.

Programmed electrical stimulation of the heart in coronary artery disease

The induction of ventricular arrhythmia in patients with a history of malignant ventricular arrhythmia by programmed electrical stimulation (PES) is associated with a poor prognosis. However, the incidence and significance of inducible arrhythmia in patients with stable coronary artery disease (CAD) who do not have a history of serious arrhythmia are unknown. We studied 32 such patients (31 men, mean age 55 years) with PES at the time of cardiac catheterization. Fourteen patients (Group I) manifested greater than or equal to 3 extraventricular responses when challenged with 1 to 3 propagated right ventricular extrastimuli during ventricular pacing. Twelve (86%) of these 14 had evidence of left ventricular dysfunction (LVD), defined by a global ejection fraction of less than 50% or regional wall motion abnormalities. The remaining 18 patients (Group II) manifested less than or equal to 2 responses to extrastimulation. Only 4 (22%) of these 18 had LVD. Proximal 3-vessel CAD was more frequent in Group I patients (10 of 14, 71%) than in Group II (7 of 18, 39%). Only 5 patients (4 from Group I and 1 from Group II) demonstrated complex arrhythmia during exercise testing or ambulatory monitoring. The induction of extraventricular responses during PES may serve as an independent marker of electrical instability in the coronary population and is a much more common finding in those with LVD.

The repetitive extrasystole as an index of vulnerability to ventricular fibrillation during myocardial ischemia in the canine heart

The repetitive extrasystole threshold (RET) is a reliable measure of vulnerability to ventricular fibrillation (VF) during diverse interventions in the normal heart. Whether this relationship also holds during varying degrees of myocardial ischemia has not been adequately explored. In 15 chloralose-anesthetized dogs, circumflex coronary blood flow (CBF) was decreased progressively with the use of an externally applied balloon occluder. There was a statistically significant correlation between the RET and ventricular fibrillation threshold (VFT) until left circumflex coronary artery flow was reduced by 90% of control values (r = 0.92). During reductions of CBF of 90% or greater, the VFT fell more than the RET and the RET/VFT ratio was disrupted. Total coronary occlusion, whether performed abruptly or gradually (5 minutes), likewise resulted in a disproportionate decline in VFT. During sustained total coronary occlusion, the VFT recovered to control values within 15 minutes, and the relationship between the RE and VF thresholds was restored. We conclude that the vulnerable period threshold for provoking repetitive extrasystole is a reliable index of vulnerability to VF during myocardial ischemia and remains so until nearly total occlusion of a major coronary vessel.

Vulnerability to ventricular fibrillation in patients with clinically manifest ventricular tachycardia

Ventricular vulnerability may be assessed by measuring the threshold current for the induction of ventricular fibrillation (VF). This technique has been widely utilized in animal experimentation and has been safely applied in a small number of clinical studies. We measured the VF threshold (VFT), using the single stimulus technique in 10 patients with coronary artery disease just prior to the institution of cardiopulmonary bypass. There were no adverse effects of VFT measurement. Three patients had nonsustained ventricular tachycardia (VT) on 24-hour ambulatory monitoring and had VFTs of 10, 14, and 16 mA. In this group VF was induced without any preceding repetitive ventricular responses. Seven patients had no repetitive forms on ambulatory monitoring. Their VFTs ranged from 30 to greater than 40 mA (mean greater than 37). Repetitive extrasystoles were regularly observed in this group at current intensities which ranged from 53% to 80% of the VFT. Thus patients with manifest VT appear to have an enhanced vulnerability to VF. Single or multiple responses were not observed in these patients but appeared to be present in patients with coronary disease and no demonstrable rhythm disorder.

Effects of prostacyclin (PGI2) on vulnerability to ventricular fibrillation in the normal and ischemic canine heart

Prostacyclin (PGI2) has been shown to have a number of beneficial effects on the cardiovascular system. However, its effects on ventricular electrical properties remain unexplored. We studied the effects of this naturally occurring humoral agent on ventricular vulnerability in the normal heart and in two models of myocardial ischemia: coronary artery occlusion and release and ergonovine-induced coronary vasoconstriction. Prostacyclin lowered the vulnerable period threshold in the normal animal. PGI2 had no effect on ventricular vulnerability when the blood pressure was controlled with phenylephrine and was not protective during either occlusion or release. However, when blood pressure was controlled, PGI2 did not reverse the vasoconstrictor and profibrillatory effects of ergonovine.