Anthony F. Graham

Dose response effectiveness of propranolol for the treatment of angina pectoris.

Seventeen patients received placebo medication during a 12-week run-in period, followed by four double-blind study periods of six weeks each, during which time placebo, 80 mg, 160 mg and 320 mg propranolol dosages were administered. Examination of the frequency of angina episodes and nonprophylactic nitroglycerin consumption revealed significant beneficial clinical responses for both the 160 and 320 mg dosages. Exercise testing also demonstrated increased exercise tolerance (320 mg dose) with a shift of the exercise end point from pain to fatigue in seven of 17 patients. The interrelationships between propranolol daily dosage, clinical response assessed by percent reduction in anginal episodes, beta-adrenergic blockade measured by percent reduction in exercise heart rate and serum levels were examined. In general, serum levels of 30 ng/ml, when drawn 90 to 180 minutes following the last oral dose, were required to achieve a 25% or greater reduction in angina frequency. Serum levels above 30 ng/ml were similarly correlated with a 20% or greater reduction in exercise heart rate at equivalent levels of exercise. Detailed examination of different patterns of clinical response with respect to beta-blockade, serum levels and oral doses are presented.

Hemodynamic Effects of Morphine and Pentazocine Differ in Cardiac Patients

Abstract The hemodynamic effects of 8 mg of morphine given intravenously to eight patients were compared in a randomized, double-blind protocol with the effects of 48 mg of intravenous pentazocine ...

Arrhythmias after cardiac transplantation

Abstract To determine the nature and frequency of arrhythmias that affect the denervated transplanted human heart, we examined sequential electrocardiograms in 45 of the first 47 cardiac allograft recipients at Stanford University Hospital. Atrial arrhythmias were detected in 72 percent of patients and were frequently associated with acute or chronic rejection episodes. Ventricular premature beats were noted in 57 percent of patients. Two patients had electrocardiographically documented ventricular fibrillation, and two additional patients died suddenly from presumed ventricular arrhythmias. Preliminary data indicate that these arrhythmias can be treated successfully with antiarrhythmic drugs, cardioversion or treatment of the underlying rejection process. Our experience suggests that autonomic innervation of the heart is not a prerequisite for the development of cardiac arrhythmias and is not required for response to antiarrhythmic therapy.

Electrophysiological Studies in the Denervated Transplanted Human Heart: Response to Atrial Pacing and Atropine

To date, no studies have documented the conduction characteristics of the atrioventricular conduction system in the transplanted human heart. Three patients who had undergone cardiac transplantation 1–2 years previously formed the basis of this study. All were functional class I symptomatically and had normal hemodynamics and coronary arteriograms at the time of study. Each patient was in sinus rhythm with a normal P-R interval and QRS configuration. None was taking medications known to affect the atrioventricular conduction system. Using the His bundle technique, all were shown to have normal base-line atrium-His bundle (AH) and His bundle-ventricle (HV) conduction times. Recordings were made of both the donor (AD) and the recipient (AR) electrograms. The AD rate was more rapid than the AR rate by an average of 24 beats/min. Right atrial pacing to a rate of 170 beats/min resulted in a progressive lengthening of the AH interval to an average of 205 msec, a result comparable to that in normal patients. At the cessation of rapid pacing, AD recovery time averaged 770 msec, which is normal. The administration of 1–2 mg of atropine increased the AR rate by an average of 28% but did not alter the AD rate; the AH intervals did not change. We conclude that (1) the normal AH intervals at rest and the increased AH intervals during pacing demonstrate the inherent conduction delay imposed by the atrioventricular node independent of autonomic influence, (2) the AD recovery time after overdrive is an inherent property of the AD sinus node, and (3) the absence of change in the AD rate or the AH interval after administration of atropine suggests that parasympathetic reinnervation has not occurred in these patients.

Surgical treatment of refractory life-threatening ventricular tachycardia

Aortocoronary bypass, with or without myocardial resection, was used to treat eight patients with refractory life-threatening ventricular tachycardia. All patients had documented evidence of coronary artery disease without recent myocardial infarction and were totally disabled by recurrent ventricular tachycardia while receiving aggressive medical treatment. Angiographic studies showed abnormalities of left ventricular contractions in all patients, including aneurysms in four, localized hypokinetic areas in two and diffusely poor contractility in two. Operative treatment consisted of resection of the aneurysm or localized hypokinetic area in six patients and aortocoronary bypass grafting to at least one major coronary artery in all eight patients. Seven patients are alive an average of 17 months after operation and all are free of major ventricular arrhythmias. We conclude that surgical treatment should be considered in patients with coronary artery disease who have life-threatening ventricular arrhythmias that cannot be prevented or controlled with drug therapy.

Arrhythmias in the Denervated Transplanted Human Heart

Multiple cardiac arrhythmias have been noted following cardiac transplantation, and these observations suggest that denervation does not protect the heart from the initiation of arrhythmias. The sequential electrocardiograms of 45 of 47 cardiac transplant patients at Stanford were reviewed. Currently, 16 patients are alive for periods up to 40 months post-transplantation. Atrial arrhythmias were noted in 72% of patients, and were usually associated with acute rejection episodes. Ventricular premature beats were detected in 57% of patients post-transplantation. Two documented episodes of ventricular fibrillation have occurred during severe acute rejection episodes. Two long-term survivors died suddenly of a presumed ventricular arrhythmia, and at autopsy both showed severe coronary atherosclerosis. This experience suggests that innervation is not necessary in the genesis of cardiac arrhythmias in the transplanted human heart.

Clinical and Hemodynamic Studies in Patients with Homograft Mitral Valve Replacement

Debate continues regarding the long-term clinical and hemodynamic benefit of homograft replacement of the diseased mitral valve. The results of valve replacement with mitral homografts in the 120 patients who have had operation at the Stanford Medical Center from May 1967 to November 1970 are given. The operative mortality rate has been 5% and the late mortality rate 6%. Anticoagulants were stopped 6 weeks following surgery and there has been only one thromboembolic complication. Ninety percent of the surviving patients are improved clinically. Thirteen of these patients have been restudied 25 to 41 months after receiving homograft mitral valve replacement. Hemodynamic studies showed a 43% decrease in mean left atrial pressure and 42% decrease in mean pulmonary artery pressure with a 10% increase in mean resting cardiac output. Early diastolic gradients between the left atrium and left ventricle averaging 3.0 mm Hg at rest and 6.0 mm Hg during moderate exercise were present. Left ventricular angiography showed a trace of mitral insufficiency in three patients, moderate to severe in three others, and poor contractility in three other patients with normal homograft function. Mitral insufficiency, when present, was thought to result from poor mounting of the homograft on the metal strut rather than primary deterioration of the valve leaflets. These data indicate that fresh homograft replacement of the mitral valve provides good long-term clinical and hemodynamic benefit in most patients.

Coronary Arteriography in Long-Term Human Cardiac Transplantation Survivors

Coronary arterial lesions in survivors of cardiac transplantation result from accelerated coronary atherosclerosis. Clinical recognition of this event is difficult but essential for long-term management and prognostication. Coronary arteriography was performed on 30 occasions in a group of 16 patients 1-4 years after cardiac transplantation. Fifteen patients had normal coronary arteries at one year. Of 10 patients studied at two years, seven showed no change but three others revealed significant coronary arterial lesions which correlated well with clinical signs of coronary artery disease. These three patients subsequently died, two due to coronary artery disease, one due to infection. Three patients have remained normal at three years and one patient is normal at four years as evidenced on yearly coronary arteriograms. A postmortem examination of the patients who died with coronary artery disease confirmed the extent of the luminal narrowing due to atheromatous plaques superimposed on intimal lesions. Coronary arteriography has proven to be a safe, reliable method for assessing the coronary circulation of long-term cardiac transplant survivors.

Acute rejection in the long-term cardiac transplant survivor. Clinical diagnosis, treatment and significance.

Thirty-two of 59 patients undergoing cardiac transplantation at Stanford University Medical Center since January, 1968, have survived longer than three months. In 19 of these long-term survivors 47 episodes of late acute rejection occurred. In the first two months post-transplantation the incidence of acute rejection is one episode per 20.5 patient days, but between four and 12 months post-transplantation decreases to one episode per 200 patient days. Late acute rejection episodes are usually clinically mild and can be detected by electrocardiographic changes, evidence of mild graft dysfunction and characteristic histologic changes in tissue obtained by transvenous endomyocardial biopsy. Out-patient treatment with increased oral prednisone has successfully reversed 70% of these late acute rejection episodes, with the other 30% requiring more aggressive therapy. Late acute rejection or complications related to its treatment have contributed to the death of three long-term survivors and has been implicated as a causative factor in the development of graft coronary atherosclerosis in six patients in the earlier part of our series. However, the occurrence of acute rejection in the long-term cardiac transplant patient does not preclude good graft function and patient survival in the majority of patients.

Studies on circulatory response to hypoxia in the denervated transplanted human heart

Abstract The relative importance of centrally mediated reflex responses versus the release of circulating humoral substances in the hearts response to acute hypoxia was studied in the transplanted human heart with its residual innervated recipient atrium and denervated donor atrium. The sinus node rates of both the donor and recipient atria were compared by monitoring P wave activity on the standard electrocardiogram in six patients during control and hypoxic conditions. Breathing 13 per cent oxygen for 10 minutes resulted in an average oxygen saturation of 75 per cent and an oxygen tension (pO 2 ) of 40 mm Hg, and was associated with a 16 per cent (p 0.05) increase in the recipient sinus node rate, but with no change in the donor sinus node rate. Pretreatment with atropine abolishes this increase in the innervated recipient sinus node. Breathing 10 per cent oxygen resulted in an oxygen saturation of 55 per cent and a pO 2 of 25 mm Hg, with an associated 10 per cent increase in both donor and recipient sinus node rate. These studies indicate that changes in heart rate during mild degrees of hypoxemia are mediated by a central reflex mechanism which leads to the release of normal vagal parasympathetic tone. The increase in heart rate that occurs in both the innervated and denervated sinus node rates during more severe degrees of hypoxia is probably due to the release of circulating humoral substances, since reinnervation has not been documented in the human cardiac allograft.