Left ventricular function in cyanotic congenital heart disease

Left ventricular function was studied with quantitative biplane cinean-giocardiography in 39 preoperative and 23 postoperative patients wlth cyanotic congenital heart disease. Diagnoses included pulmonary atresia or critical pulmonary stenosis with intact ventricular septum (group 1), tricuspld atresia (group 2) and pulmonary atresia with ventricular septal defect (group 3). Preoperative patients ranged in age from 1 day to 7 years and postoperative patients from 7 weeks to 23 years. Left ventricular end-diastolic volume was increased in preoperative patients in groups 1 and 2 (132 and 136 percent of normal, respectively) but was normal in patients in group 3. Left ventricular ejection fraction was decreased to a similar extent in preoperative groups 1 to 3: 0.54, 0.55 and 0.56, respectively. After a shunt procedure left ventricular end-diastolic volume increased to 228 and 266 percent of normal in groups 1 and 2, respectively, but remained within normal limits in group 3. Left ventricular ejection fraction was normal in postoperative group 1 patients, whose ages averaged 1.8 years, but remained decreased in group 2 and 3 patients, whose ages averaged 8.1 and 5.6 years, respectively. Duration of cyanosis and degree of left ventricular dilatation appear to be important variables in regard to pump function in patients with cyanotic congenital heart disease.     

Variant angina pectoris: Investigation of indexes of sympathetic nervous system function

One thousand forty-five spontaneous episodes of S-T segment elevation were observed in three patients over a total of 72 days of continuous electrocardiographic monitoring. Eighty-nine percent of episodes were asymptomatic; chest pain tended to occur with episodes longer than 3 minutes, and ventricular ectopy occurred almost exclusively with symptomatic episodes. Nitroglycerin regularly relieved angina or S-T elevation, or both.

Plasma and urinary catecholamines and their metabolites were normal. Episodes of variant angina were not associated with a generalized increase in sympathetic outflow because serum catecholamine levels at the onset and termination of the S-T abnormalities were not elevated. Controlled trials of propranolol showed no significant beneficial effect. Propranolol significantly increased the length of episodes of S-T elevation in one patient, increasing ventricular irritability. The overall course of variant angina was quite variable, with spontaneous and long-lasting remissions, necessitating cautious interpretation of clinical trials.     

Arterial and coronary sinus catecholamines in the course of spontaneous coronary artery spasm

We studied plasma catecholamine levels in 10 patients with frequent spontaneous episodes of coronary artery spasm to evaluate the role of the sympathetic nervous system. Peripheral venous norepinephrine in supine and upright postures, urinary excretion of catecholamines, and functional testing of the sympathetic nervous system did not differ from the same measurements in control subjects. Arterial and coronary sinus levels of norepinephrine and epinephrine drawn early in ischemia were not elevated over baseline; coronary sinus norepinephrine levels were higher than those in arterial samples and rose from 315 ± 32 (pg/ml ± SE) at the onset of ST elevation to 490 ± 49 pg/ml late in ischemia (p < 0.05). Plasma epinephrine levels, higher in arterial than coronary sinus samples, also rose significantly only late in ischemia, from 44 ± 14 pg/ml to 148 ± 35 pg/ml (p < 0.05) in arterial blood and from 33 ± 10 pg/ml to 108 ± 29 pg/ml in coronary sinus samples (p < 0.05). Generalized sympathetic nervous system activation is not likely to be the sole cause of coronary artery spasm.     

Accuracy of radionuclide ventriculography for estimation of left ventricular volume changes and end-systolic pressure-volume relations

Estimation of left ventricular end-systolic pressure-volume relations depends on the accurate measurement of small changes in ventricular volume. To study the accuracy of radionuclide ventriculography, paired radionuclide and contrast ventriculograms were obtained in seven dogs during a control period and when blood pressure was increased in increments of 30 mm Hg by phenylephrine infusion. The heart rate was held constant by atropine infusion. The correlation between radionuclide and contrast ventriculography was excellent. In the individual animals, the average r value for left ventricular volume was 0.96 +/- 0.03 (+/- SD) (p = 0.001, n = 7) and the mean r value for end-systolic volume changes was 0.90 +/- 0.08 (n = 7, range 0.76 to 0.99). For the entire series, there were 33 end-systolic volume changes, and there was an equally strong radionuclide-contrast correlation (r = 0.89, p less than 0.001, n = 33), even though the volume changes averaged only 11.9 +/- 8.2 ml (range 0.3 to 38.1). The systolic pressure-volume relations were linear for both radionuclide and contrast ventriculography (r = 0.98 and 0.97, respectively, n = 7). The mean slope for radionuclide ventriculography (2.9 +/- 1.4) was lower than the mean slope for contrast ventriculography (4.8 +/- 1.7) (p = 0.004); however, the slopes correlated well (r = 0.81, n = 7, p = 0.026). The radionuclide-contrast volume relation was compared using background subtraction, attenuation correction, neither of these or both. By each method, radionuclide ventriculography was valid for measuring small changes in left ventricular volume and for defining end-systolic pressure-volume relations.     

Evaluation of left ventricular performance using digital subtraction angiography

Cardiac applications for digital subtraction angiography appear promising, but few correlative studies with contrast ventriculography have been done. Left ventricular volume, ejection fraction, and regional wall motion by digital subtraction angiography were evaluated after intravenous injection of 40 ml of iodinated contrast medium and after left ventricular injection of 5 to 10 ml of contrast medium. A film-based system of the authors' own design was used. Results were compared with those after direct left ventricular injection of 40 ml of contrast medium. The ventriculograms after intravenous injection were of diagnostic quality in 9 of 12 studies, and there were close correlations between intravenous and direct-injection studies for left ventricular ejection fraction (r = 0.89, n = 9, and p = 0.001) and for left ventricular volume (r = 0.91, n = 18, and p less than 0.001). Regional wall motion scores showed close correspondence in 83% of sectors. After small-volume left ventricular injections, the ventricular image was enhanced considerably by digital subtraction. Correlations between small- and large-volume ventriculograms were close for left ventricular ejection fraction (r = 0.91, n = 8, and p = 0.002) and for left ventricular volume (r = 0.96, n = 16, and p less than 0.001). There was close correspondence of wall motion scores in 87% of sectors. Thus, digital subtraction angiography improves the visibility of the left ventricle after either intravenous or small-volume direct left ventricular injection. Digital images produce excellent estimates of left ventricular volume and should have considerable usefulness for the study of cardiac performance and anatomy.     

Radionuclide evaluation of right and left ventricular function in children: Validation of methodology

Validation of an equilibrium radionuclide technique for assessing right and left ventricular function has not been reported in children with heart disease. Resting equilibrium radionuclide ventriculograms were performed in 71 children with diverse types of heart disease (age range 1 to 19 years, mean 10.2) with exercise studies in 52 of the children. Cardiac catheterization was performed in 39 of the 71 children within 2 weeks of radionuclide study. Resting left and right ventricular ejection fractions from radionuclide study and catheterization were compared by linear regression analysis: right ventricular ejection fraction, r = 0.83; left ventricular ejection fraction, r = 0.90. Interobserver correlations for right and left ventricular ejection fractions were 0.93 and 0.94, respectively. With exercise, the interobserver correlations for right and left ventricle were 0.97 and 0.92, respectively. Thus, right and left ventricular ejection fractions showed good correlations with cineangiographic ejection fractions. Furthermore, it was possible to perform this study in exercising children with no deterioration in interobserver correlations. This technique can provide important information on ventricular function in children and aid in long-term evaluation of current methods of treatment for several congenital heart defects.     

Increased vascular beta2-adrenoceptor responsiveness in autonomic dysfunction

Responsiveness to the vasopressor, vasodepressor and chronotropic effects of several sympathomimetic amines was assessed in 12 patients with severe autonomic dysfunction and in 8 age-matched control subjects. The patients with autonomic dysfunction showed a profound increase in responsiveness to both isoproterenol and phenylephrine as compared with control subjects. The mean bolus dose of isoproterenol required to increase heart rate by 25 beats/min was 0.9 + 0.2 microgram in the patients and 5.4 + 2.1 micrograms in the control subjects. The dose of isoproterenol required to reduce mean blood pressure by 25 mm Hg was 0.3 + 0.2 and 5.2 + 1.8 micrograms, respectively. Thus, although there is a 6-fold increase in responsiveness to the chronotropic effect of isoproterenol in autonomic dysfunction, the responsiveness to the drug's depressor effect is increased 17-fold. This enhanced depressor sensitivity is quite marked, even with oral beta-adrenoceptor agonists. Beta-adrenoceptor agonists must be used with caution in conditions associated with autonomic dysfunction if dangerous hypotension is to be avoided.     

Myocardial injury in infants with congenital heart disease: Evaluation by creatine kinase MB isoenzyme analysis

Total creatine kinase (CK) and the myocardial isoenzyme CK MB activity were prospectively determined in 282 children hospitalized for cardiac catheterization and evaluation for suspected congenital cardiac abnormalities and compared with a hospitalized control group of children without such abnormalities. The percent CK MB and CK MB activity were abnormally elevated in symptomatic children with a large left to right shunt due either to a large ventricular septal defect (n = 22; p < 0.001) or to complete atrioventricular canal (n = 10; p < 0.001). Serum CK MB activity and percent CK MB were significantly related to the size of the shunt and the age of presentation with clinical symptoms of congestive heart failure in infants with a ventricular septal defect. CK MB activity was abnormally elevated in infants with symptomatic coarctation of the aorta, either with or without a ventricular septal defect (n = 15; p < 0.001), and in infants with symptomatic aortic stenosis (n = 4; p < 0.02). In contrast, CK MB activity was normal in asymptomatic children with coarctation of the aorta (n = 14) or aortic stenosis (n = 8) despite comparable systolic pressure gradients. CK MB activity and percent CK MB were abnormally elevated in those children with the cyanotic congenital cardiac abnormalities of either transposition of the great arteries (n = 32; p < 0.001) or right ventricular outflow tract obstruction (n = 31; p < 0.001). These results suggest that children with congenital cardiac abnormalities may have significant myocardial cell injury and release of CK MB that may be detected by the determination of serum CK MB activity. Cell injury may be secondary to arterial desaturation or acute pressure-volume overload, or both, as manifested by clinical symptoms of heart failure and measured hemodynamic variables.     

Comparative right and left ventricular volumes and pump function in the newborn lamb

A quantitative cineangiographic method is presented for studying neonatal lamb ventricular volumes and pump function without thoracotomy or surgical instrumentation of the heart. When this method was employed in lambs with a mean age of 24.4 hours it was found that the right and left ventricular end-diastolic volumes, ejection fractions and systolic outputs did not differ significantly at this early postnatal time. Restudy of these lambs at a mean age of 15.6 days showed that right and left ventricular end-diastolic volumes, normalized for body weight, and ejection fractions had not changed significantly. Although systolic outputs decreased, the difference was not significant. Thus there is early postnatal equalization of left and right heart volumes, and deviations from this relation should suggest abnormal hemodynamic function.     

Postprandial alterations in cardiovascular hemodynamics in autonomic dysfunctional states

The effect of food ingestion on supine blood pressure was assessed during 25 studies in 10 subjects with autonomic dysfunction. Profound decreases in both systolic and diastolic pressure occurred. The mean (± standard error of the mean) maximal reduction in systolic blood pressure for the entire group was 49 ± 6 mm Hg (range 22 to 98). The response also occurred in a hypertensive subject after surgical sympathectomy and during alpha adrenergic blockade and hence appears to be a general phenomenon when sympathetic vasoconstrictor function is impaired. The depressor effect of food ingestion was enhanced by propranolol, attenuated by indomethacin and unaffected by diphenhydramine and cimetidine. The phenomenon is thus not explained by histamine release, and can only partly be accounted for by release of arachidonic acid metabolites. Evidence that insulin may play a role in the phenomenon is discussed. Manipulation of diet may prove to be an important adjunct in the management of patients with autonomic dysfunction.     

Left ventricular mass and volume/mass ratio determined by two-dimensional echocardiography in normal adults

This study prospectively defined the range of left ventricular mass and volume/mass ratio determined by two-dimensional echocardiography in 84 normal adults. A modified Simpson's rule algorithm was used to calculate ventricular volumes from orthogonal two and four chamber apical views. An algorithm based on a model of the left ventricle as a truncated ellipsoid was used to calculate ventricular mass. Like left ventricular volumes, left ventricular mass values were larger in normal men than in women (mean 148 versus 108 g, p less than 0.001) and remained larger after correction for body surface area. Volume/mass ratios, however, were constant at end-diastole (0.80) and end-systole (0.26). The influence of age and heart rate on all variables in this normal group was minimal, and no correction for these variables was necessary. The definition of normal mass, volume and volume/mass ratios by two-dimensional echocardiography will facilitate the noninvasive, quantitative diagnosis of left ventricular hypertrophy and help clarify the relation between hypertrophy and systolic wall stress.     

Ventricular performance in adults after operation for congenital heart disease

Symptomatic ventricular dysfunction in adults who have had reparative operations for the more common congenital heart defects is uncommon. However, both invasive and noninvasive laboratory assessments of ventricular function have revealed abnormalities in some subsets of patients after repair of atrial septal defect, ventricular septal defect, aortic or pulmonary stenosis, tetralogy of Fallot, transposition of the great arteries and tricuspid atresia. Possible causative factors of late ventricular dysfunction after repair include the duration and severity of volume or pressure overload; the duration and severity of cyanosis; intermittent episodes of imbalance between myocardial oxygen supply and demand; residuae, sequelae and complications of treatment; and acquired disease. Further long-term follow-up studies are needed to assess the effect of current methods of therapy as well as timing of operative intervention on ventricular function in adults.     

Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide

Flecainide acetate is a new antiarrhythmic agent whose pharmacokinetics have suggested that effective therapy could be achieved with twice daily dosing. The antiarrhythmic and electrocardiographic effects of flecainide were evaluated in 11 patients with chronic ventricular ectopic beats. Nine patients had been resistant or intolerant to at least three antiarrhythmic agents and eight had recurrent nonsustained ventricular tachycardia. The antiarrhythmic efficacy of increasing doses of flecainide was determined by comparison with results during administration of a placebo 2 days before and 3 days after increasing doses of flecainide. All 11 patients had an antiarrhythmic response with a mean 97 percent (range 88 to 100) rate of suppression of ventricular ectopic beats and mean 100 percent rate of suppression of ventricular tachycardia with a mean daily dose of 410 mg (range 200 to 600) of flecainide. Effective therapy was accompanied by lengthening of the P-R (+ 29 percent), QRS (+ 27 percent) and Q-Tc (+ 11 percent) intervals. These changes were not associated with a deterioration in exercise tolerance or a reduction in ejection fraction (0.52 ± 0.08 with placebo, 0.53 ± 0.12 with flecainide) as assessed with two dimensional echocardiography. Increasing doses of flecainide were associated with progressive prolongation of the ventricular ectopic coupling interval before suppression of ventricular ectopic beats. During the placebo washout period after multiple oral doses, the terminal (postabsorptive) phase plasma half-life of flecainide was found to range from 13 to 27 hours (mean 20.3). The minimal effective plasma levels of flecainide (resulting in greater than 90 percent suppression of ventricular etopic beats) ranged from 245 to 980 ng/ml (mean 631). Adverse effects during the inpatient evaluation were limited to blurring of vision in three patients, which resolved with smaller but still effective doses.

Suppression of ventricular ectopic beats at a mean rate of 95 percent continued during outpatient therapy. During a mean of 12 months of outpatient follow-up in nine patients, regularly scheduled evaluation of ambulatory arrhythmia frequency continued to document suppression of arrhythmia. Outpatient follow-up occurred monthly for the first 6 months and every 2nd month thereafter. In three patients it was necessary to administer flecainide every 8 hours because blurring of vision occurred at the time of peak plasma levels when the drug was administered every 12 hours. Flecainide was highly effective in suppressing ventricular arrhythmias when administered twice daily.     

Clinical pharmacology of propafenone: pharmacokinetics, metabolism and concentration-response relations

Propafenone is a promising new antiarrhythmic agent marketed in Europe for the past 7 years. The drug is remarkable for great interindividual variability in its pharmacokinetic and pharmacodynamic properties. Propafenone undergoes extensive presystemic clearance that appears to be saturable, with bioavailability increasing as dosage increases. The drug is highly protein bound. Elimination half-life is 5 to 8 hours in most patients, although a range of 2 to 32 hours has been reported. Propafenone slows intracardiac conduction in a concentration-dependent manner. It is a weak beta-adrenergic blocker, but this property is of uncertain clinical significance. The major metabolic pathway for propafenone begins with aromatic ring hydroxylation, a pathway that may be determined by genetic factors.     

Small vessel disease of the heart resulting in myocardial necrosis and death despite angiographically normal coronary arteries.

A 46 year old man who had undergone cardiac transplantation 1 year previously had progressive congestive heart failure without evidence of cardiac rejection. Cardiac catheterization and angiography revealed a reduced ejection fraction and cardiac output caused by diffuse left ventricular hypokinesia, but the epicardial coronary arteries were widely patent. The transit time of injected contrast material across the coronary arterial tree was greatly slowed. Within a few days cardiogenic shock and death occurred. The large epicardial coronary vessels were grossly patent at autopsy, although nonstenosing arteriosclerotic plaques were identifiable histologically. However, intramyocardial vessels showed severe arteriosclerotic narrowing, resulting in multiple, diffuse microinfarcts.     

Flecainide dose-response relations in stable ventricular arrhythmias

Flecainide acetate was evaluated in a placebo-controlled, dose-ranging study performed in patients with stable, high-frequency ventricular arrhythmias. Three centers studied 35 patients in a 3-stage protocol. After a placebo baseline, increasing oral dosages from 100 to 300 mg twice daily were evaluated. Placebo was then reinstituted and after arrhythmia had recurred, the patients were discharged on the effective dosage to return to the clinic for evaluation 7 and 14 days later. Thirty of 35 patients had more than 80% suppression (mean 96%) of ventricular premature complexes (VPCs) and more than 95% reduction in complex VPCs. Arrhythmia suppression was seen at dosages of 100 to 200 mg twice daily in 73% of the patients. Twenty-three percent of patients required 500 to 600 mg/day. Mild side effects were seen in 46% of patients. These resolved or became tolerable at lower dosages in most patients. Effective therapy continued for 2 years in 24 of 29 patients, without any evidence of chronic toxicity. Pharmacokinetic studies indicate that many patients require 5 to 7 days of constant dosing before reaching steady state. Flecainide acetate is an effective antiarrhythmic with a narrow range of effective dosages.