Responses of coronary arteries of cardiac transplant patients to acetylcholine.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition.

We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.

Efficacy of propafenone in Wolff-Parkinson-White syndrome: electrophysiologic findings and long-term follow-up.

The efficacy and safety of intravenous propafenone was studied in 10 patients with Wolff-Parkinson-White syndrome and in 2 patients with a concealed accessory pathway. During electrophysiologic study, the effect of propafenone on the effective refractory period of the accessory pathway was determined, as well as its effect during orthodromic atrioventricular (AV) reentrant tachycardia and atrial fibrillation. Propafenone caused significant increases in the accessory pathway refractory period, both in the anterograde direction (290 +/- 19 versus 474 +/- 50 ms, p less than 0.05) and in the retrograde direction (238 +/- 15 versus 408 +/- 44 ms, p less than 0.05). Complete anterograde accessory pathway conduction block occurred in four patients. Sustained AV reentrant tachycardia was inducible in 11 patients before administration of propafenone. Drug infusion during AV reentrant tachycardia promptly terminated arrhythmia in 10 of these 11 patients and caused slowing of AV reentrant tachycardia in the remaining patient. Before propafenone, sustained atrial fibrillation was inducible in six patients and nonsustained atrial fibrillation in four patients. After propafenone, no patient had inducible sustained atrial fibrillation. Furthermore, propafenone caused a marked decrease in peak ventricular rate during atrial fibrillation. Eight patients have been treated with oral propafenone and followed up for 12 +/- 2 months. All have remained virtually free of recurrent arrhythmia and none has developed significant side effects. Propafenone is a very promising agent for emergency intravenous therapy as well as long-term oral therapy in patients with Wolff-Parkinson-White syndrome.

Role of reflex sympathetic withdrawal in the hemodynamic response to an increased inotropic state in patients with severe heart failure.

Newer positive inotropic agents used in the treatment of severe heart failure not only increase cardiac contractility, but also cause peripheral vasodilation. It is not known to what extent this vasodilation is due to a direct peripheral action of the drug, as opposed to reflex withdrawal of sympathetic tone secondary to an augmented inotropic state. In 16 patients with severe heart failure, a 48 hour intravenous infusion of milrinone, a positive inotropic vasodilator drug, resulted in an increase in stroke volume index from 26 +/- 2 to 34 +/- 3 ml/m2 (p less than 0.001), a reduction in forearm vascular resistance measured by venous plethysmography from 43 +/- 5 to 27 +/- 3 U (p less than 0.003) and an increase in forearm venous capacitance from 2.1 +/- 0.2 to 2.9 +/- 0.2 ml/100 ml (p less than 0.001). To determine whether a withdrawal of sympathetic tone contributed to this vasodilation, milrinone was infused directly into the left main coronary artery in eight of the patients, thereby eliminating any direct vascular effects of the drug. Intracoronary milrinone (50 micrograms/min) caused an increase in peak positive first derivative of pressure (658 +/- 49 to 784 +/- 68 mm Hg/s; p less than 0.01) and stroke volume index (20 +/- 2 to 25 +/- 3 ml/m2; p less than 0.0001), which was associated with a reduction in plasma norepinephrine from 540 +/- 101 to 423 +/- 90 pg/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Transtelephonic electrocardiographic transmission for management of cardiac arrhythmias.

Brief periods of transtelephonic electrocardiographic transmission conducted at periodic intervals or during sporadic symptoms may provide an inexpensive and reliable alternative to extended ambulatory electrocardiographic tape recordings. Sixty-one patients were enrolled in a transtelephonic electrocardiographic transmissions program. In 51 patients with documented arrhythmias (group I), telephone electrocardiographic transmissions were used to monitor antiarrhythmic drug therapy. In 10 patients, telephone electrocardiographic transmission was used in an attempt to diagnose infrequent symptoms suggestive of arrhythmia (group II). Of the 650 telephone electrocardiographic transmissions received, 73 (11%) revealed a clinically significant event, whereas 577 (89%) did not show any significant disturbances of cardiac rhythm. Of the 61 patients entered into the program, 29 (48%) had a clinically significant event identified during 1 or more transmissions. In group I, transtelephonic electrocardiographic transmission prompted a change in therapy in 37% of the patients. Of the 10 patients in group II, clinically significant events were noted during telephone electrocardiographic transmissions in each patient. Assuming a yield of 1 clinically significant event detected per 10 telephone electrocardiographic transmissions and a similar yield on long-term ambulatory electrocardiographic recordings, use of telephone electrocardiographic transmissions offers a cost-effective means of following patients with significant cardiac arrhythmias who are receiving potent antiarrhythmic drugs. In addition, telephone electrocardiographic transmission is a suitable diagnostic technique for patients with infrequent symptoms suggestive of cardiac arrhythmias.

Effects of milrinone on complex ventricular arrhythmias in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To determine whether oral milrinone therapy has an effect on complex ventricular arrhythmias in patients with severe congestive heart failure and, if so, whether a change in the severity of complex ventricular arrhythmias after 1 week of milrinone therapy is associated with a change in the mode or frequency of cardiac mortality, a retrospective analysis was performed to determine the frequency of ventricular tachycardia and the density of ventricular couplets on 24-hour ambulatory electrocardiographic recordings performed before and 1 week after initiation of oral milrinone therapy in 74 consecutive patients with New York Heart Association functional class III or IV congestive heart failure. The endpoints of mortality and mode of death were assessed during a mean follow-up of 6 months. In 91% of the patients, 1 week of oral milrinone therapy was associated with no significant change (85%) or a significant decrease (6%) in the density of ventricular couplets and frequency of ventricular tachycardia. However, in 9% of patients the frequency of complex ventricular arrhythmias increased significantly at the end of 1 week of oral milrinone therapy. In this subgroup, neither total cardiac mortality nor the incidence of sudden cardiac death was significantly higher than that in patients with no change or a decrease in complex ventricular ectopic activity.

Beta-adrenergic inotropic responsiveness of patients with heart failure: studies with intracoronary dobutamine infusion.

Although there is theoretical and indirect evidence to suggest that patients with severe congestive heart failure may have desensitization of myocardial beta-adrenergic responsiveness, there is little direct evidence in patients. The purpose of this study was to determine whether myocardial beta-adrenergic inotropic responsiveness is reduced in patients with severe congestive heart failure and markedly elevated plasma norepinephrine levels. To assess myocardial beta-adrenergic inotropic responsiveness, the beta-adrenergic agonist dobutamine was infused directly into the left main coronary artery, and the change in +dP/dt was measured as an index of change in inotropic state. Eight patients with severe New York Heart Association functional Class III and IV congestive heart failure were compared with 4 patients without significant congestive heart failure. The increase in +dP/dt at an intracoronary dobutamine infusion rate of 25 micrograms/min in patients with severe congestive heart failure was significantly less than in the patients without heart failure (heart failure, 33 +/- 8%; no heart failure, 69 +/- 12%; p less than 0.05). Although the maximum intracoronary dobutamine infusion rate was substantially higher in patients with heart failure (94 +/- 25 micrograms/min) compared with patients without heart failure (38 +/- 7 micrograms/min), the increase in +dP/dt at maximum infusion rates was also significantly less in patients with heart failure (heart failure, 52 +/- 8%; no heart failure, 93 +/- 24%; p less than 0.05). Plasma norepinephrine concentration was normal in the 4 patients without heart failure and was markedly elevated (range, 307-3,967 ng/l) in the patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique.

To determine the relative contributions of milrinone's positive inotropic and vasodilator actions in patients with severe congestive heart failure, the drug was administered by constant infusion directly into the left main coronary artery of 11 patients with New York Heart Association functional class III or IV heart failure. Intracoronary infusion of milrinone at rates up to 50 micrograms/min had no effect on mean arterial pressure or systemic vascular resistance but resulted in dose-related increases in peak positive dP/dt (+21%), stroke volume index (+18%), and stroke work index (+21%) and decreases in heart rate (-3%), mean right atrial pressure (-25%), and left ventricular end-diastolic pressure (-17%). In eight patients, intravenous administration (75 micrograms/kg) after the intracoronary infusion resulted in significant decreases in mean arterial pressure (-14%) and systemic vascular resistance (-40%), further increase in stroke volume index compared with intracoronary administration, and further decreases in mean right atrial and left ventricular end-diastolic pressures compared with intracoronary administration. These data indicate that milrinone exerts both positive inotropic and vasodilator actions that contribute significantly to the drug's overall hemodynamic effect.

Circadian variation in the frequency of sudden cardiac death.

To determine whether sudden cardiac death exhibits a circadian rhythm similar to that recently demonstrated for nonfatal myocardial infarction, we analyzed the time of day of sudden cardiac death as indicated by death certificates of 2203 individuals dying out of the hospital in Massachusetts in 1983. The data reveal a prominent circadian variation of sudden cardiac death, with a low incidence during the night and an increased incidence from 7 to 11 A.M. The pattern is remarkably similar to that reported for nonfatal myocardial infarction and episodes of myocardial ischemia. The finding that the frequency of sudden cardiac death is increased in the morning is compatible with hypotheses that sudden cardiac death results from ischemia or from a primary arrhythmic event. Further study of the physiologic changes occurring in the morning may provide new information supporting or refuting these hypotheses, thereby leading to increased understanding and possible prevention of sudden cardiac death.

Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.