Short- and long-term experience with flecainide acetate in the management of refractory life-threatening ventricular arrhythmias

Thirty-eight patients with organic heart disease and history of sudden cardiac arrest or recurrent sustained ventricular tachycardia were treated with flecainide. Coronary artery disease was present in 33 patients. Previous antiarrhythmic therapy consisted of two to eight drugs (mean four). Fourteen patients were resuscitated from sudden cardiac death and 24 patients had chronic recurrent sustained ventricular tachycardia. Twenty-eight patients had electrophysiologic testing before and during flecainide treatment. Sustained ventricular tachycardia became noninducible in 5 patients, nonsustained in 5 patients and slowed in 13 patients (cycle length increased from 278 +/- 64 to 395 +/- 91 ms; p = 0.002). Three of the 14 patients with sudden cardiac death and 15 of the 24 patients with recurrent sustained ventricular tachycardia remained on long-term flecainide treatment. The mean left ventricular ejection fraction in 16 of these 18 patients was 37%. Nonlimiting side effects occurred in seven patients (18%). Proarrhythmic effects were seen in four patients (10%). At a mean follow-up time of 11 +/- 3 months, 15 patients (39%) had had no recurrence, including 5 who had inducible sustained ventricular tachycardia and 5 who did not on retesting during treatment. In the 18 patients who received long-term therapy, 3 late deaths occurred, 1 of which was of arrhythmic origin. These data suggest that flecainide is effective in about 40% of patients with severe refractory ventricular arrhythmias. Its value as a single drug in the treatment of sudden cardiac death remains to be defined.     

Long-term prognosis after first Q-wave (transmural) or non-Q-wave (nontransmural) myocardial infarction: analysis of 593 patients

Follow-up results in 593 patients less than or equal to 7 years (mean 4.7) after hospital discharge for their first myocardial infarction (MI) are presented. Patients were grouped according to the presence or absence of Q waves on electrocardiograms after the MI and by peak serum glutamic oxalacetic transaminase (SGOT) level during hospitalization. Cardiac mortality varied. Patients with Q-wave infarcts and an SGOT level less than or equal to 240 IU/liter had a cardiac mortality of 3.1% per year, whereas patients with Q-wave MI and an SGOT level greater than 240 IU/liter had an 11% 6-month mortality and a 3.8% per year cardiac mortality thereafter. However, patients with non-Q-wave (nontransmural) MI had a excellent survival rate for 2 years (96.8%) which continued in patients aged less than or equal to 60 years thereafter. However, patients with non-Q-wave infarcts aged greater than 60 years had a 12% per year cardiac mortality in the third post-MI year and an additional 12% died each year thereafter. Early mortality was related to enzyme level, whereas late mortality was a function of type (Q-wave or non-Q-wave) and age.     

Treatment of d-transposition of the great arteries: Management of hypoxemia after balloon atrial septostomy

Between 1975 and 1979, a group of 43 patients with d-transposition of the great arteries were diagnosed and underwent Rashkind balloon atrial septostomy at the time of initial catheterization. Thirty-six (88 percent) survived to the time of intraatrial baffle repair, and 31 (72 percent) are long-term survivors, 2 of them now awaiting repair. Palliative operations were performed in nine patients before definitive surgery; four of these patients are long-term survivors. Prostaglandin E₁ infusion improved oxygenation and relieved acidosis in four patients. It is concluded that most patients with d-transposition of the great arteries will survive to elective intraatrial baffle repair between 6 and 12 months without surgical palliation in spite of significant hypoxemia. Prostaglandin E₁ infusion may be lifesaving and provide sufficient palliation in patients with persistent hypoxemia and acidosis after balloon atrial septostomy.     

Changes in ventricular refractoriness after an extrastimulus: effects of prematurity, cycle length and procainamide

This study was performed to determine the ability of extrastimuli to change ventricular refractoriness. We prospectively evaluated the effects of stimulus prematurity and paced cycle length (PCL) in 30 patients and the effect of procainamide in 8 patients on changes in the ventricular effective refractory period (ERP) after a right ventricular extrastimulus (S2). An S2 was introduced at preselected coupling intervals at a PCL (S1-S1) of 600 and 400 ms. At each S1-S2 interval, a second extrastimulus (S3) was introduced in 5-ms decrements and the ERP of S2 measured. The decrease in the ERP after an S2 was directly related to prematurity and most of the shortening occurred over a narrow range of S1-S2 intervals. At a PCL of 600 ms, the ERP of S2 at S1-S2 intervals less than or equal to 400 ms was significantly shorter than the ERP of S1 (maximal shortening 23%). At a PCL of 400 ms, the ERP of S2 at S1-S2 intervals less than or equal to 350 ms was significantly shorter than the ERP of S1 (maximal shortening 25%). The ERP of S2 at the shortest S1-S2 interval was greater with a PCL of 600 ms than with 400 ms (200 +/- 31 versus 180 +/- 26 ms, p less than 0.001). However, the total shortening in ERP (ERPS1 - ERPS2 at shortest S1-S2 interval) was similar at both PCLs (55 +/- 14 versus 59 +/- 13 ms). Procainamide significantly prolonged the ERP of S2 at each S1-S2 interval.(ABSTRACT TRUNCATED AT 250 WORDS)     

Progressive nature of myocardial injury in selected patients with cardiogenic shock

To determine whether the extensive myocardial injury associated with cardiogenic shock in some patients results from a progressive rather than a discrete massive insult, a study was made of 15 selected patients who had cardiogenic shock within 48 hours of admission, 5 patients with hypovolemic shock without myocardial infarction and 11 patients with myocardial infarction without shock. Peak plasma MB creatine kinase (CK) activity was significantly higher in the seven patients with cardiogenic shock associated with initial infarction (213 international units [IU]/liter) than in patients with shock and previous infarction (98 IU/liter) and in patients with uncomplicated myocardial infarction (125 IU/liter). A prolonged time to peak MB CK activity (averaging 26 hours) and a plateau of elevated MB CK activity were seen in patients with shock associated with initial infarction. Because shock itself did not slow the rate of apparent MB CK disappearance, results obtained suggest that cardiogenic shock associated with initial infarction in selected patients results from progressive myocardial damage underlying continuing release of MB CK into the circulation. The findings are compatible with the concept that, in these patients, cardiogenic shock reflects a vicious cycle of spreading myocardial injury, progressive compromise of cardiac function, exacerbation of ischemia and perpetuation of myocardial damage.     

Initiation of repetitive ventricular depolarizations by relatively late premature complexes in patients with acute myocardial infarction.

To determine whether repetitive ventricular depolarizations are more commonly precipitated by early compared with late premature ventricular complexes, we analyzed continuous electrocardiographic recordings obtained during the first 10 hours in 38 patients with myocardial Infarction without shock with the Argus/H computer system with editor verification of all premature ventricular complexes. Episodes of repetitive ventricular depolarization were defined as two or more consecutive complexes at a rate of 120 beats/min or greater. Premature ventricular complexes occurring with coupling intervals from the preceding normal complex equal to or less than the Q-T interval of the normal complex were defined as early, and those with longer coupling intervals as late. Among all premature ventricular complexes, early premature ventricular complexes accounted for 38 percent. The average coupling interval of premature ventricular complexes from a preceding normal complex did not correlate with heart rate, blood pressure, infarct size estimated enzymatically, the electrocardiographic locus of Infarction or history of previous Infarction. Twenty-nine patients had a total of 337 episodes of repetitive ventricular depolarizations. Somewhat surprisingly, 78 percent of these episodes, and all episodes in 22 patients, were initiated by late premature ventricular complexes. Thus, repetitive ventricular depolarizations in patients with acute myocardial infarction are often precipitated by late rather than early premature ventricular complexes.     

Adult hypophosphatasia with chondrocalcinosis and arthropathy: Variable penetrance of hypophosphatasemia in a large Oklahoma kindred

Three sisters, each with chondrocalcinosis/arthropathy, are described who have the clinical, laboratory and pathologic findings characteristic of the adult form of hypophosphatasia. Premature loss of adult teeth, arthralgias and pain from bilateral femoral pseudofractures were associated with subnormal circulating alkaline phosphatase levels, phosphoethanolaminuria and osteomalacia diagnosed by iliac crest biopsy. Assay of alkaline phosphatase activity in the blood of kindred members revealed hypophosphatasemia in one of two younger brothers. Several subjects in subsequent generations also had suspiciously tow alkaline phosphatase activity, but did not have histories of significant dental, bone or joint disease. Review of the medical records of the sisters' parents, aunts and uncles revealed normal alkaline phosphatase levels in their father and five of his siblings, but consistently low levels in their mother and two of her siblings. Despite hypophosphatasemia, the sisters' mother and her siblings lived to old age without clinical or radiographic evidence of bone disease.Our findings suggest that although adult hypophosphatasia can be transmitted as a dominant trait in some kindreds, there is considerable variation in the clinical expression of the biochemical defect. One person, generation or family may manifest clinical bone disease and arthropathy whereas the biochemical defect may be present but remain asymptomatic in others. Furthermore, in some cases, the adult form of hypophosphatasia may represent a developmental disorder with hypophosphatasemia appearing during adulthood.     

Osteopetrosis,renal tubular acidosis and basal ganglia calcification in three sisters

Three adult sisters with osteopetrosis in infancy had spontaneous resolution of bone modeling defects and osteosclerosis. During adolescence, basal ganglia calcification developed in two. Renal tubular acidosis (type I) was diagnosed in each during early adulthood. The disorder was transmitted apparently as a recessive trait—the same mode of inheritance as for the “malignant” form of osteopetrosis which is usually fatal during childhood. Electron microscopy of bone suggested that osteoclasts failed to form “ruffled membranes” characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations of this new syndrome.     

Gated cardiac blood pool imaging and thallium-201 myocardial scintigraphy for detection of remote myocardial infarction

The primary goal of this study was to assess the frequency of persistent regional wall motion abnormalities and myocardial perfusion defects detectable late after myocardial infarction with radionuclide ventriculography and thallium-201 imaging, respectively. The study was performed prospectively in 32 patients in whom infarct size was estimated enzymatically at the time of the acute episode and in 10 patients without infarction. Thallium-201 imaging and radionuclide ventriculography were performed with the patient at rest an average of 11 months after infarction (range 6 to 20 months) and analyzed independently by two observers who were unaware of results of other clinical and laboratory data. Perfusion defects were detected in 94 percent (30 of 32) by observer I and in 91 percent (29 of 32) by observer II. Wall motion abnormalities were detected in 78 percent (25 of 32) and 75 percent (24 of 32) by observers I and II, respectively, but in 10 of the patients with an infarct size less than 20 creatine kinase-gram-equivalents (CK-g-eq), wall motion abnormalities were found in only 50 and 40 percent, respectively, by these observers (p <0.04). Electrocardiographic changes of infarction (Q waves) were present in only 56 percent (18 of 32) of patients. Sixty-eight percent of patients with an infarct size greater than 20 CK-g-eq had persistent Q waves but these were present in only 30 percent with an infarct size less than 20 CK-g-eq (p <0.04). The sites of perfusion defects and of wall motion abnormalities corresponded closely and were concordant with electrocardiographic localization. Thus, thallium-201 imaging and radionuclide ventriculography are sensitive noninvasive techniques for identifying prior myocardial infarction, and are particularly helpful in patients with conduction abnormalities or equivocal electrocardiographic findings.     

Considerations in the surgical management of infantile coarctation of aorta.

The results of a recent 5 year experience with resection of coarctation of the aorta in infants less than 1 year of age are compared with those of an earlier series from the same institution. The significant improvement in mortality and morbidity statistics is attributed to modifications in operative and postoperative care. Operative mortality has decreased from 38 to 17 percent and the incidence rate of significant restenosis has diminished from 60 to 33 percent. It is suggested that in patients with large associated intracardiac shunt banding of the main pulmonary artery should be performed before resection of the coarctation. Three of five patients have survived procedures performed in this sequence. Microsurgical techniques and careful approximation of the aortic lumen with interrupted sutures are the major factors responsible for the reduced incidence of recoarctation. Prolonged ventilatory support postoperatively with the occasional addition of controlled positive airway pressure and continued aggressive medical therapy for heart failure are recommended.     

Improved detection of myocardial infarction with technetium-99m stannous pyrophosphate and serum MB creatine phosphokinase.

The relative sensitivity and combined value of myocardial technetium-99m stannous pyrophosphate imaging and determinations of serum MB creatine phosphokinase (the "myocardial" CPK isoenzyme) in detecting acute myocardial infarction were evaluated in 41 patients with suspected infarction and 23 patients recovering from cardiac surgery. In the patients with suspected infarction, myocardial infarction was confirmed in 25 and was consistently associated with increased serum MB CPK. Abnormal radionuclide images were obtained in 23 of 25 patients (92 percent) with definite myocardial infarction and in 2 of 16 patients without confirmed infarction. Although the localization of infarction by imaging correlated well with the localization by electrocardiogram, infarct size estimated by imaging did not correlate well with estimates based on peak total serum CPK activity or serial changes in CPK activity. Serum MB CPK activity increased after cardiac surgery in 6 patients undergoing valve replacement and in 17 patients undergoing coronary arterial bypass surgery. However, no patient with valve replacement and only 1 of the 17 with bypass surgery had an abnormal radionuclide image. These results suggest that (1) abnormal radionuclide images in patients without infarction can be distinguished from abnormal images indicative of ischemic necrosis by consideration of MB CPK activity and (2) interpretation of elevated MB CPK activity, particularly in particularly in patients undergoing cardiac surgery, is facilitated by evaluation with imaging.     

Axial osteomalacia: Clinical,laboratory and genetic investigation of an affected mother and son

Axial osteomalacia—a rare osteosclerotic bone disorder characterized by axial skeleton pain, coarsening of the trabecular bone pattern on radiographs of the axial but not appendicular skeleton, and osteomalacia on biopsy of a rib or iliac crest—has been reported in 10 apparently sporadic cases, all of which were in middle-aged or elderly Caucasian men. The etiology is unknown but has been postulated to be a bone cell defect. We describe the clinical, laboratory, pathologic and family study of a black mother and son with axial osteomalacia associated with polycystic liver and kidney disease. Investigation of the son suggested that radiographic osteosclerosis can be detected in early adulthood. Limited skeletal survey of his three children revealed no abnormalities. Examination of undecalcified iliac crest bone after in vivo tetracycline labeling revealed severe osteomalacia in the son despite normal circulating calcium, inorganic phosphate and vitamin D metabolite levels and persistently elevated alkaline phosphatase activity. Although osteoblasts appeared flat and inactive, histochemical studies showed intense alkaline phosphatase activity in the osteoblasts along most trabecular bone surfaces. Electron microscopy revealed intact matrix vesicles within unmineralized osteoid. The presence also of unexplained myopathy in the son—characterized by proximal muscle weakness, persistently elevated circulating creatine phosphokinase levels and pathologic changes of myopathy on biopsy of quadriceps muscle—together with impaired bone mineralization, suggests that a disorder of vitamin D action may be involved in the pathogenesis of this unusual condition. Axial osteomalacia affects blacks as well as Caucasians, women as well as men, may be familial, and may perhaps be a developmental abnormality inherited in association with polycystic kidney and liver disease.     

Factors presaging early recurrent myocardial infarction (“Extension”)

A prospective study of 200 consecutive patients with acute myocardial infarction was undertaken to characterize the frequency and severity of early recurrent infarction (extension), manifested by secondary plasma MB creatine kinase (CK) and myoglobin peaks, and to identify patients at particularly high risk. Serial MB CK and myoglobin determinations and continuous electrocardiographic recordings were obtained in all patients for 14 days, and serial radioventriculograms were obtained in selected patients. Chest pain and S-T segment changes occurred often, in 57 and 43 percent, respectively, of the entire group of patients. However, a secondary rise in plasma MB CK levels indicative of recurrent infarction, occurring an average of 10 ± 4 days after the initial infarct, was evident in only 17 percent of patients. Forty-three percent (25 of 58) of patients with initial subendocardial infarction exhibited recurrent infarction compared with only 8 percent of those with initial transmural infarction. The mortality rate was 7 percent in patients with subendocardial infarction without early recurrence compared with 16 percent among those with recurrence. Logistic regression analysis indicated that obese women with initial subendocardial infarction and repeated episodes of prolonged chest pain had a high probability rate (60 percent) of recurrence in contrast to the low probability (2 percent) in patients without these features. Thus, early recurrent infarction is frequent after subendocardial infarction and is associated with a marked increase in mortality. These results suggest that patients with subendocardial infarction are at particularly high risk for recurrent infarction and that patients with this type of infarction require vigorous monitoring and prolonged surveillance.     

Coupling interval and types of ventricular ectopic activity associated with ventricular runs

Repetitive 10-hour ECG recordings of 289 patients obtained within a year after myocardial infarction were analyzed for the presence of ventricular runs, and their association with various types of ventricular ectopic activity (VEA), average rate of premature ventricular complexes (PVCs), and coupling interval of PVCs initiating the runs. Tapes which contained complex VEA (bigeminy, multiform PVCs, couplets, or runs), early PVCs (coupling interval less than 400 msec), or late PVCs (coupling interval greater than 600 msec) had a substantially higher average PVC rate than those without them. The occurrence of ventricular runs was significantly more likely in tapes having other complex VEA or late PVCs than in those without them, and when tapes were stratified by PVC rates the presence of these dysrhythmias appeared to have an independent predictive value for the occurrence of runs. In contrast, the influence of early PVCs on the occurrence of runs was rather minimal, and this seemed to be related to their common association with the PVC rate. Furthermore, a larger percentage of isolated PVCs had coupling intervals between 400 msec and 600 msec, and most couplets (77%) and runs (67.8%) were initiated by PVCs with coupling intervals in this range. However, the proportion of either short (less than 400 msec) or long (greater than 600 msec) coupling interval PVCs initiating couplets or runs was significantly higher than those with intermediate coupling intervals (between 400 and 600 msec).     

Detection of cardiomyopathic changes induced by doxorubicin based on quantitative analysis of ultrasonic backscatter

Ultrasonic measurements are valuable in characterizing cardiac dimensions and structure. Recently, analysis of ultrasonic properties of tissue has proved useful in detecting morphologic changes such as those accompanying myocardial infarction. This study was undertaken to determine whether acoustic properties of tissue can be utilized to detect cardiomyopathic changes as well. Cardiomyopathy was induced by prolonged administration of doxorublcin (Adriamycin) (1.2 mg/kg twice weekly) in 25 rabbits and results were compared with those in normal control rabbits, housed identically. The 15 surviving treated animals were killed at selected intervals 10 to 18 weeks after initiation of drug administration and the hearts were analyzed for collagen content based on hydroxyproline. Regional ultrasonic backscatter was assessed with a frequency-averaging procedure to minimize effects of phase cancellation and with an independent method employing spectral display over the frequency range of 1 to 11 megahertz from which an index of backscatter at a single frequency (2.25 megahertz) could be calculated. In hearts from treated animals, collagen content was significantly increased (p <0.05). Integrated ultrasonic backscatter was markedly increased (by more than 500 percent, that is, equivalent to 7 decibels) in fibrotic regions and significantly, although less markedly, in myopathic regions without marked collagen deposition. Thus, increased backscatter correlated with collagen deposition. Backscatter at 2.25 megahertz was significantly increased (by more than 500 percent, that is, equivalent to 7 decibels) in fibrotic regions.These results indicate that alterations in acoustic properties occur in cardiomyopathic tissue and that such alterations can be detected with the use of reflected ultrasound. Accordingly, assessment of integrated backscatter offers a promising approach for early clinical detection and characterization of evolution of cardiomyopathy induced by doxorubicin or of other causes.     

Detection of ischemic myocardium in vivo through the chest wall by quantitative ultrasonic tissue characterization

Quantitative analysis of ultrasound offers a potentially valuable method for noninvasive differentiation of specific types of cardiac disease and for assessment of their severity. Clinical application necessitates quantitative measurement of the ultrasonic properties of myocardium through the chest wall. This study was designed to determine whether such measurements could be made noninvasively with the aid of conventional M mode echocardiographic guidance and to characterize the quantitative effects of intervening tissue (chest wall) on the ultrasonic signals backscattered by ischemic and normal myocardium. Frequency-dependent ultrasonic backscatter (2 to 7 MHz) from normal myocardium was measured in dogs in vivo through the closed chest with the use of M mode guidance and with the chest open, directly from the myocardium. Closed-chest and open-chest measurements were repeated after ligation of the left anterior descending coronary artery in the same animals. Closed-chest data were compensated by correcting for the average value for the slope of the attenuation-frequency function of chest wall, which was determined from measurements obtained by analysis on excised tissue. Compensated closed-chest measurements correlated with measurements obtained from the epicardial surface of the heart. The differentiation of normal from ischemic myocardium with both the closed- and open-chest measurements was consistent (p < 0.005). The successful differentiation of normal from ischemic myocardium by determination of quantitative backscatter through the intervening chest wall supports the concept that tissue characterization by quantitative analysis of backscattered ultrasound is a potentially useful, clinically applicable approach to noninvasive detection and differentiation of intrinsic properties of normal and diseased myocardium.     

Abnormal technetium-99m pyrophosphate images in unstable angina: Ischemia versus infarction?

There is controversy concerning the specificity of myocardial infarct imaging with technetium-99m pyrophosphate due to the high frequency of false positive images, especially in patients with unstable angina. In this study technetium-99m pyrophosphate images were compared with frequent determinations of plasma creatine kinase, MB isoenzyme (MB CK) activity in 116 patients admitted with the diagnosis of unstable angina. It was hypothesized that frequent measurement of MB CK activity, a sensitive and specific marker for myocardial necrosis, using sensitive assay techniques would detect small amounts of myocardial necrosis which might have been unrecognized by conventional clinical methods. The scintigraphic results and isoenzyme determinations agreed in 88 percent of patients; both tests were normal in 69 percent and both were abnormal, indicating acute myocardial infarcation, in 19 percent of patients. In the remaining 14 patients (12 percent), the scans were abnormal, but MB CK activity was normal. In five of these patients (4 percent), abnormal scintigrams presumably reflected persistent scan positivity after previous myocardial infarction. Only the remaining nine patients (8 percent) could be classified as having unexplained false positive scans, a frequency substantially less than that reported by other investigators who based the diagnosis of myocardial infarction on conventional clinical criteria. These results suggest that abnormal technetium-99m pyrophosphate images in patients with unstable angina generally indicate myocardial necrosis.     

Nifedipine blockade of ergonovine-lnduced coronary arterial spasm: Angiographic documentations

To determine whether calcium-flux blockade with nifedipine blunts coronary vasospasm, four patients with angiographically demonstrable coronary arterial spasm in the absence of Significant fixed coronary arterial stenosis were evaluated with coronary arteriography before and after treatment with nifedipine. After initial coronary arteriography, ergonovine was administered in successive doses of 0.05, 0.1 and (when necessary) 0.2 mg intravenously at 3 minute intervals. Three patients had symptomatic high grade focal coronary arterial spasm with electrocardiographic changes, and the fourth exhibited asymptomatic 60 percent constriction of the left anterior descending coronary artery. A maximal ergonovine challenge was repeated 30 minutes later after each patient had been pretreated with a 20 mg sublingual dose of nifedipine. Under these conditions, no patient had chest pain or electrocardiographic changes. Furthermore, neither focal nor diffuse coronary arterial spasm was demonstrable angiographically after the second challenge. Thus, in each case, a single dose of nifedipine precluded the angiographie expression of ergonovine-provoked coronary arterial spasm.