Evaluation of total artificial heart performance in man

This report describes the method whereby total artificial heart (TAH) performance was evaluated in the first human implantation, the operating characteristics of the TAH and the accompanying circulatory response. The patient survived for 112 days. Weekly averages (+/- standard deviation) for left-heart drive pressure ranged from 146 +/- 5 to 171 +/- 10 mm Hg, right-heart drive pressure from 46 +/- 4 to 79 +/- 17 mm Hg, heart rate from 77 +/- 8 to 98 +/- 3 beats/min, diastolic vacuum from 0 to 7 +/- 0.5 mm Hg and percent systole 40 +/- 1 to 44 +/- 0. Left-sided cardiac output ranged from 3.0 +/- 0.4 to 3.9 +/- 0.2 liters/min/m2, and was consistently greater than right-sided cardiac output, which ranged from 2.6 +/- 0.4 to 3.6 +/- 0.1 liters/min/m2. Drive line air pressure and flow signals and cineradiography of the TAH demonstrated complete filling and ejection for the left ventricle and complete filling but partial ejection for the right ventricle. There was no significant change in cardiac index during variation in right atrial pressure between 4 and 14 mm Hg. During 21 days of invasive hemodynamic monitoring, daily average of mean systemic arterial pressure ranged from 81 +/- 5 to 107 +/- 11 mm Hg, pulmonary artery pressure from 22 +/- 2 to 28 +/- 8 mm Hg and left atrial pressure from 8 +/- 2 to 22 +/- 4 mm Hg. Prominent V waves on the left atrial pressure tracing suggested mitral regurgitation as a cause of the difference between the outputs of the 2 ventricles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical correlates in hypertensive patients with left ventricular hypertrophy diagnosed with echocardiography

Seventy-three hypertensive patients were evaluated with M mode and two dimensional echocardiography. Left ventricular hypertrophy was found in 37 patients (51 percent); 29 had concentric hypertrophy and the remaining 8 had disproportionate septal thickening. Factors that did not influence the distribution of patients in the group with left ventricular hypertrophy and normal subjects included (1) duration of hypertension, (2) level of blood pressure, (3) age, (4) body surface area, and (5) race. More of the patients who had a normal left ventricular mass (32 or 89 percent) than of those who had hypertrophy (22 or 59 percent) were receiving two or more antihypertensive drugs. Electrocardiography was very insensitive in identifying left ventricular hypertrophy in these patients. The presence of increased left ventricular mass was associated with a greater incidence of other target organ disease.     

Characteristics of ventricular tachycardia in ambulatory patients

This study analyzes 94 episodes of the ventricular tachycardia recorded in the ambulatory electrocardiograms of 23 patients with stable cardiac disease. The episodes were asymptomatic in 19 patients, and only one episode resulted in ventricular fibrillation. Eighty-five percent of the episodes occurred when the underlying heart rate was less than 100 beats/min, and 17 percent occurred during sleep. The rate of the ventricular tachycardia was between 120 and 180 beats/min in 78 percent of the episodes and showed a modest correlation with the underlying heart rate (r = 0.59, P less than 0.001). Only 14 of the 94 episodes were initiated by R on T premature ventricular contractions, and the mean prematurity index (+/- standard deviation) (R-R'/Q-T) for all episodes was 1.31 +/- 0.28. Episodes of ventricular tachycardia recorded during ambulatory electrocardiographic monitoring are usually self-limited and asymptomatic. They occur during ordinary nonexertional activity and are frequently initiated by late couples premature ventricular contractions.     

Antiarrhythmic drug effect assessed from ventricular arrhythmia reduction in the ambulatory electrocardiogram and treadmill test: Comparison of propranolol,procainamide and quinidine

A 5 week study was performed in 17 patients with frequent ventricular ectopic complexes. The study design comprised an initial control period, 1 week each of treatment with propranolol (240 mg daily), procainamide (3.0 g daily) and quinidine (1.8 g daily) and a final control period. Twenty-four hour ambulatory electrocardiograms and maximal exercise tests were performed each week. For the group, the total number and qualitative types of ventricular ectopic complexes were similar during the two control periods; however, there were large variations among individual patients. Each drug reduced the total number of ventricular ectopic impulses and the percent of patients with each qualitative type. There was agreement between the ambulatory electrocardiogram and treadmill test in three quarters of the drug evaluations. Although it is possible to determine antiarrhythmic drug effects for a group, spontaneous variability In the occurrence of ventricular arrhythmias makes it difficult to evaluate the effects in individual patients.     

Left ventricular function at high altitude examined by systolic time intervals and M-mode echocardiography

To better understand the effects of high-altitude hypoxia on cardiac performance, healthy lowlandresiding volunteers were studied in 2 groups: 10 subjects after acute ascent to 12,500 ft (3,810 m) (acute group) and 9 subjects after chronic exposure for 6 weeks to 17,600 ft (5,365 m) and 11,000 ft (3,353 m) (chronic group). Systolic time intervals and M-mode echocardiograms were recorded at low and high altitudes. Heart rate was 21% greater at high altitude for all subjects. Preejection period/left ventricular ejection time (PEP/LVET) increased by 16% in the acute group and by 22% in the chronic group. Heart size was smaller at high altitude in both groups, with left atrial and left ventricular (LV) diameters decreasing by 10 to 12%. These changes were statistically significant (p ≤ 0.01). Despite the increase in PEP/LVET, echocardiographic measurements of LV function (percent fractional shortening and mean normalized velocity of circumferential fiber shortening) remained normal. LV isovolumic contraction time was shorter at high altitude, suggesting heightened, rather than depressed, contractility. LV function does not appear to deteriorate at high altitude. Alterations in systolic time intervals probably result from decreased preload, as reflected by smaller heart size, rather than from heart failure or depressed LV contractility.     

Pirmenol for control of ventricular arrhythmias: oral dose-ranging and short-term maintenance study

The antiarrhythmic efficacy and safety of oral pirmenol hydrochloride were assessed during a controlled, dose-ranging and short-term maintenance study in 12 patients with frequent (greater than 480/8 hours) premature ventricular complexes (PVCs). Eleven patients (92%) responded favorably (greater than 70% PVC suppression) to a trial of different doses. Mean interval (8-hour) suppression of PVC frequency was 95% in these 11 and 86% in the entire group. Twenty-four-hour suppression was similar in responders (88%). Repetitive PVCs were essentially eliminated. The mean effective dose was 316 mg/day (105 mg/8 hours). The average predose (trough) plasma concentration at the end of dose ranging was 1.4 micrograms/ml and the drug elimination half-life 7.3 hours (n = 12). Of 11 responding patients, 10 completed a 2-week outpatient trial. Pirmenol continued to be effective and tolerated in 8 patients, maintaining an overall average outpatient PVC suppression of 80%. The electrocardiographic intervals were mildly prolonged after multiple dosing (PR + 7%, QRS + 12%, QTc + 8%; all p less than 0.01). Blood pressure and heart rate did not change during treatment. The echocardiographic ejection fraction was maintained. Thus, oral pirmenol appears to be effective, conveniently administered and well tolerated as an antiarrhythmic agent for control of ventricular extrasystoles.     

The automatic implantable defibrillator: local ventricular bipolar sensing to detect ventricular tachycardia and fibrillation

The first-generation automatic implantable defibrillator implanted in man sensed arrhythmias by monitoring a transcardiac electrocardiographic signal. This sensing system reliably detected ventricular fibrillation and sinusoidal ventricular tachycardia but failed to sense all nonsinusoidal ventricular tachycardias. To solve this problem, a new ventricular tachycardia detection scheme was developed using a local ventricular bipolar electrogram and electronic circuits using rate averaging and automatic gain control to permit sensing of electrograms down to 0.1 mV. This detection scheme was tested during electrophysiologic studies in 11 patients with ventricular tachycardia and fibrillation. All 22 episodes of induced ventricular tachycardia with a rate above the selected cutoff were detected after an average of 5.1 +/- 1.8 seconds. No episodes below the rate cutoff were detected. The bipolar circuits also reliably detected ventricular fibrillation. Arrhythmia detection and signal quality in 9 patients receiving automatic defibrillators using the new bipolar rate detection circuit were compared with the findings in 5 patients previously receiving units that sensed arrhythmias using the transcardiac electrocardiographic signal. Compared with the transcardiac monitoring units the newer bipolar units had shorter and more uniform sense times (5.5 +/- 1.4 versus 12.2 +/- 7.1 seconds). It is concluded that malignant ventricular tachyarrhythmias can be sensed accurately using bipolar rate detection and that this system has numerous advantages over the previously used transcardiac electrocardiographic signal.     

Influence of sympathetic tone on ventricular fibrillation threshold during experimental coronary occlusion.

The effects of increased and decreased cardiac sympathetic tone and coronary occlusion on ventricular fibrillation were determined in 14 open chest dogs anesthetized with sodium pentobarbital. Heart rate was kept constant by pacing the right atrium at cycle lengths of 500 msec. Ventricular fibrillation threshold was measured by delivering 350 msec trains of constant current stimuli with a frequency of 100 hertz and 2 msec duration. The minimal current of the train that induced fibrillation was taken as the ventricular fibrillation threshold. In seven animals, the effects of stellate stimulation were studied. Ventricular fibrillation threshold was measured during control periods, after 2 minutes of cornoary occlusion, after 2 minutes of stellate stimulation and after 2 minutes of stellate stimulation and coronary occlusion. Coronary occlusion alone decreased ventricular fibrillation threshold an average of 35 percent of control valvues and stellate stimulation alone decreased the threshold an average of 42 percent of control values. The combination of both these interventions decreased ventricular fibrillation threshold an average of 63 percent of control values. The effects of stellate ablation were studied in seven animals. Ventricular fibrillation threshold was measured during control periods, and during coronary occlusion before and after stellate ganglionectomy. Stellectomy increased the threshold an average of 31 percent above control values. After stellectomy, coronary occlusion decreased ventricular fibrillation threshold by only 11 percent of control values, a value 26 percent higher than the threshold during coronary occlusion before stellectomy. These findings may have therapeutic implications for the management of arrhythmias in patients with acute myocardial infarction or some forms of central nervous system disease.     

Action of drugs in patients early after cardiac surgery: I. comparison of isoproterenol and dopamine

Dopamine and isoproterenol were each administered in two different doses to 12 patients with coronary artery disease in the period immediately after open heart surgery. The two doses of dopamine resulted in respective increases in cardiac output of 23 and 43 percent and reductions in systemic vascular resistance of 23 and 32 percent; neither dose significantly altered heart rate. The two doses of isoproterenol caused respective increases of 23 and 37 percent in cardiac output and 18 and 28 percent in heart rate and reductions in systemic vascular resistance of 22 and 29 percent. We conclude that lack of chronotropic effect of dopamine as compared with isoproterenol may make the former the agent of choice in patients requiring inotropic agents for their care in the early period after cardiac surgery.     

Clinical efficacy and electrophysiology of imipramine for ventricular tachycardia

Invasive electrophysiologic studies were performed before and during treatment with imipramine in 18 patients with inducible ventricular tachycardia (VT). All received imipramine, 50 mg twice daily for 3 days, and then 100 mg twice daily for 3 days. Imipramine increased the infranodal conduction times (HV) (from 58 +/- 7.8 to 65 +/- 10 ms) and QRS duration (from 133 +/- 21 to 153 +/- 39 ms) and significantly decreased sinus cycle length (from 875 +/- 145 to 711 +/- 116 ms) and maximal corrected sinus nodal recovery time (from 457 +/- 656 to 380 +/- 603 ms). The Wenckebach cycle length tended to decrease and the QT interval to increase, but these changes were not statistically significant. Atrial and ventricular refractory periods, atrioventricular nodal conduction times and induced VT cycle length did not change significantly. Imipramine prevented induction of VT in 2 patients, and VT was more difficult to induce in 1 patient. These 3 patients received chronic imipramine therapy. The 2 patients in whom no VT could be induced while taking imipramine have had no recurrence of arrhythmia at 6 and 12 months of follow-up. The third patient died suddenly 4 months after discharge from the hospital. One patient had worsening of arrhythmias while taking imipramine and 61% had minor adverse effects. The mean combined plasma imipramine and desmethylimipramine concentration at the time of the repeat electrophysiologic study was 227 +/- 114 ng/ml. Imipramine is effective against VT in some patients; however, like other type I antiarrhythmic drugs, the rate of efficacy is low.     

Sequential studies of left ventricular function and wall motion after coronary arterial bypass surgery

Left ventricular performance and segmental wall motion were studied sequentially in 12 patients during the 1st postoperative year after coronary arterial bypass graft surgery with use of computer-aided fluoroscopic analysis of radiopaque tantalum markers implanted into the left ventricular wall at operation. Measurements were made 1 week, 2 months and 1 year after operation. Ejection fraction decreased significantly early postoperatively (to 42 ± 3 percent [mean ± standard error of the mean]) but recovered to near preoperative values (55 ± 3 percent) at 2 months (49 ± 2 percent) and 1 year (51 ± 3 percent). Stroke volume increased from 51 ± 4 ml 1 week after operation to 70 ± 6 ml at 1 year; heart rate decreased from 91 ± 2 to 69 ± 4 beats/min during this interval. Both circumferential fiber shortening velocity and cardiac output were constant over the year. Total peripheral resistance was reduced in the early postoperative period. The data in the early postoperative period were consistent with those observed with an increase in heart rate alone, with only a small chronotropic augmentation of the myocardial contractile state. Total wall motion increased from 1 week to 2 months after operation primarily because of an increase in the extent of contraction of inferior wall segments, particularly in zones of previous infarction. Five of seven patients who had a preoperative myocardial infarction with hypokinesia of the infarcted region showed increased shortening in the region in the first 2 postoperative months. Four of six patients whose ejection fraction was less than 40 percent 1 week after operation had recurring angina; the six patients with a larger ejection fraction at this time had no recurrence.Because resting left ventricular performance varies significantly during the 1st postoperative year, it is concluded that (1) results of evaluations made at widely differing times after operation should not be pooled in determining operative results; (2) studies made 2 or more months postoperatively are not subject to the rapidly changing values associated with the early postoperative period; (3) frequent sequential studies of left ventricular performance are required to evaluate operative outcome in an individual patient; and (4) wall motion in regions of previous infarction can be improved by coronary bypass graft surgery.     

Atypical ventricular tachycardia as a manifestation of disopyramide toxicity

An unusual ventricular tachyarrhythmia developed in a 57 year old woman with recurrent ventricular tachycardia and toxic disopyramide plasma concentrations. The rhythm was similar to the patient's previous ventricular tachycardia, but the rate was slower and the QRS complex was markedly widened, mimicking the electrocardiographic changes associated with electrolyte abnormalities. Disopyramide, which has electrophysiologic properties similar to those of quinidine, probably caused the arrhythmia and should be added to the list of drugs associated with atypical ventricular tachycardia.     

Electrophysiologic studies in the denervated transplanted human heart: II. Response to norepinephrine, isoproterenol and propranolol

Five patients who had received a transplanted human heart 1 to 3 years previously were studied to determine the effects of norepinephrine, isoproterenol and propranolol on the atrioventricular (A-V) conduction system. Using the His bundle technique, atrial, His bundle and ventricular electrograms were recorded, and central aortic pressure was monitored during the administration of these drugs. Norepinephrine was given by continuous infusion to four patients in doses ranging from 4 to 8 μg/min, with the systolic arterial pressure increasing by an average of 72 mm Hg. Concomitantly, there was an average increase in the rate of the donor atrium of 32 beats/min, and a reflex slowing of the recipient atrium of 23 beats/min. The A-H interval shortened by an average of 27 msec. Isoproterenol dose-response curves were performed in three patients, with the maximal dose being 5.2 μg by intravenous bolus infusion. The rate of the donor atrium increased by an average of 40 beats/min, and that of the recipient atrium by 18 beats/ min. The A-H time shortened by an average of 25 msec, with a drop in systolic blood pressure averaging 23 mm Hg. Propranolol (7 mg intravenously) was given to three patients and the peak doses of norepinephrine and isoproterenol were again infused. Beta adrenergic blockade was achieved at this dose of propranolol since there was only a minimal increase in the donor atrial rate after infusion of the drug. The A-H interval was not altered by catecholamine infusion after achievement of beta blockade. However, the levels of systolic hypertension noted after infusion of norepinephrine were not altered by propranolol. The denervated transplanted human heart appears to respond normally to norepinephrine and isoproterenol, and the electrophysiologic effects of these agents are blocked by propranolol.

Extensive investigative work in the denervated canine model has demonstrated the presence of the alpha and beta cardiovascular receptors. Although the autonomic nervous system is important in cardiac performance, this work is the first validation in man that (1) the functional integrity of the beta receptor is maintained even when the autonomic nerves are absent, and (2) the intrinsic properties of the sinus and atrioventricular nodes are the keystone in stabilizing cardiac electrophysiology after denervation.     

Techniques for right and left ventricular endomyocardial biopsy

Right ventricular endomyocardial biopsy using percutaneous right internal jugular approach proved a safe and easily performed technique in more than 1,300 procedures. Adequate tissue was obtained in more than 98 percent of patients and morbidity rate was remarkably low. Other approaches to the right ventricle may be used, but retrograde left ventricular endomyocardial biopsy appears to be the safest and most reliable alternative to transjugular right ventricular biopsy. The safety and success of the techniques for right and left heart biopsy described depend on meticulous attention to methodologic detail.     

Effects of digitalis on normal and abnormal left ventricular segmental dynamics.

To study the effects of digoxin on regional left ventricular performance, continuous ventricular dynamics were assessed in nine patients with stable coronary disease. Computer-assisted analysis of the fluoroscopic motion of surgically implanted mid wall myocardial markers was used. The markers define six minor ventricular radii and outline the left ventricle. One and one-half hours after administration of 1 mg of intravenous digoxin, mean velocity of circumferential fiber shortening for all segments increased 19 percent, from 0.67 +/- 0.06 to 0.78 +/- 0.06 circumference/sec (P less than 0.01) and ejection fraction increased 4.5 percent, from 0.50 +/- 0.03 to 0.53 +/- 0.03 (P less than 0.05). Segmental velocity of circumferential fiber shortening, total segmental shortening and early segmental systolic shrtening increased in 83 percent to 91 percent of normal segments, depending on which index was used. Only 45 to 55 percent of initially abnormal segments benefited from digoxin. In general, segmental dyssynergy increased even when net ventricular function was enhanced. These results suggest that in pateints with chronic left ventricular contraction abnormalities due to coronary disease, deterioration of performance in abnormal regions after administration of digoxin may result from increased stress imposed by increased afterload and by improved segmental dynamics in more normal areas.     

Do calcium-dependent ionic currents mediate ischemic ventricular fibrillation?

Calcium ions mediate the adverse effects of myocardial ischemia and have been implicated in the genesis of arrhythmias. Calcium influx blocking drugs protect against early ventricular arrhythmias during experimental coronary occlusion, and recent studies suggest that this effect is at least partly due to inhibition of myocardial cell calcium influx. Most of the pharmacologic maneuvers used to simulate acute ischemic arrhythmias in vivo also produce intracellular calcium overload. Production of calcium overload in small myocardial cell clusters causes fibrillatory electrical and mechanical activity similar to that recorded from fibrillating hearts. Fibrillation in these cell clusters is mediated not by reentrant conduction, but by the same subcellular processes that give rise to depolarizing afterpotentials and abnormal automaticity. Agents favoring calcium influx, such as beta adrenergic agonists, accentuate these processes, while agents that depress calcium influx inhibit them. Although the relation of these experimental models to clinical ischemic arrhythmias has not been fully delineated, calcium influx blocking drugs may prove useful in reducing the incidence of sudden cardiac death.     

Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold

Recent clinical studies suggest that certain betaadrenergic blocking drugs, such as timolol, may reduce sudden death in patients with ischemic heart disease, but the mechanism has not been established. To assess and compare antifibrillatory effects of beta-blocking drugs as a potential mechanism of sudden death prevention, the ventricular fibrillation (VF) threshold was measured in anesthetized, open-chest dogs before and after 3 minutes of coronary ischemia during intravenous administration of saline solution or 3-fold serial increments (0.003 to 1.0 mg/kg) of 5 beta-blocking drugs with various accessory properties. Ventricular fibrillation occurred in control studies after delivery of a current train of 11.7 ± 7.6 mA in the nonischemic state and 7.0 ± 7.4 mA during ischemia (n = 46). All 5 betablocking drugs but not saline solution caused substantial (average 6-fold) increases (p < 0.001) in the VF threshold under both nonischemic (to 67 ± 30 mA) and ischemic conditions (to 42 ± 31 mA). The maximal VF thresholds attained were similar for individual drugs: timolol, 71, 39 mA (nonischemic, ischemic conditions, n = 10): pindolol, 81, 46 mA (n = 7); propranolol, 58,36 mA (n = 7); metoprolol, 60, 40 mA (n = 7); and labetolol, 67,52 mA (n = 6). The effective doses (mg/kg) at which maximal effects first occurred, however, varied widely: timolol, 0.01 mg/kg; pindolol, 0.1 mg/kg; propranolol, 0.3 mg/kg; metoprolol, 1.0 mg/kg; and labetolol, 1.0 mg/kg. The antifibrillatory potency (mg/kg) generally paralleled known ratios of beta-blocking efficacy, except for timolol's apparently greater potency. Interruption of stellate ganglionic impulses accounted for part of the augmentation in VF threshold. Thus, a substantial antifibrillatory effect accompanies experimental blockade of beta-adrenergics timuli. An increase in VF threshold is suggested as a possible protective mechanism by which beta-blocking drugs reduce sudden death.     

Detection of ventricular arrhythmias in real-time with a portable analog computer

Recent studies on the occurrence of sudden death emphasize that many patients have ventricular premature contractions as prodromes of lethal arrhyhmlas. A portable, 6 ounce analog computer has been developed to detect tachycardias (heart rate 150 to 190 beats/min), bradycardias (heart rate less than 50 beats/min) and ventricular premature contractions. When preset limits are exceeded, acoustic warnings are sounded, and the patient may transmit his electrocardiogram by telephone, without additional equipment, to a receiving device that graphically reproduces the electrocardiogram in real-time. Hospital studies in 26 ambulatory patients with a variety of arrhythmias have been completed. Tachycardias and bradycardias were detected in every instance during 30 observation periods in six patients. Reproducible warnings were triggered in 19 of the 20 patients with ventricular premature contractions of various configurations during each of 5 observation periods (100 observations). In one patient, the electrical vector of the ventricular premature contraction closely resembled the normal QRS vector and was not detected. Appropriate electrode placement is essential to avoid initial Q waves and to maximize the difference between the vector of ventricular premature contraction and that of the normal QRS complex. No false positive acoustic alarms were sounded. Our results demonstrate that it is possible to detect ventricular premature contractions readily and reproducibly in ambulatory patients. Use of this detector may permit large scale monitoring of patients with a high risk of sudden death.