Pulmonary atresia with intact ventricular septum associated with congenitally corrected transposition.

We present a rare case of pulmonary atresia with intact septum associated with congenitally corrected transposition. The patient was a nondysmorphic female infant. Despite a right Blalock-Taussig shunt on day 13 of life and a balloon atrial septostomy on day 23, she remained ventilator dependent with poor systemic ventricular function. The patient died at the age of 160 days, and postmortem findings are presented. The literature on this condition is reviewed, and the possibility that the left-sided morphologic right ventricle could not sustain the systemic circulation is discussed.

Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors.

GATA-family transcription factors are critical to the development of diverse tissues. In particular, GATA-4 has been implicated in formation of the vertebrate heart. As the mouse Gata-4 knock-out is early embryonic lethal because of a defect in ventral morphogenesis, the in vivo function of this factor in heart development remains unresolved. To search for a requirement for Gata4 in heart development, we created mice harboring a single amino acid replacement in GATA-4 that impairs its physical interaction with its presumptive cardiac cofactor FOG-2. Gata4(ki/ki) mice die just after embryonic day (E) 12.5 exhibiting features in common with Fog2(-/-) embryos as well as additional semilunar cardiac valve defects and a double-outlet right ventricle. These findings establish an intrinsic requirement for GATA-4 in heart development. We also infer that GATA-4 function is dependent on interaction with FOG-2 and, very likely, an additional FOG protein for distinct aspects of heart formation.

FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium.

We disrupted the FOG-2 gene in mice to define its requirement in vivo. FOG-2(-/-) embryos die at midgestation with a cardiac defect characterized by a thin ventricular myocardium, common atrioventricular canal, and the tetralogy of Fallot malformation. Remarkably, coronary vasculature is absent in FOG-2(-/-) hearts. Despite formation of an intact epicardial layer and expression of epicardium-specific genes, markers of cardiac vessel development (ICAM-2 and FLK-1) are not detected, indicative of failure to activate their expression and/or to initiate the epithelial to mesenchymal transformation of epicardial cells. Transgenic reexpression of FOG-2 in cardiomyocytes rescues the FOG-2(-/-) vascular phenotype, demonstrating that FOG-2 function in myocardium is required and sufficient for coronary vessel development. Our findings provide the molecular inroad into the induction of coronary vasculature by myocardium in the developing heart.

Truncus arteriosus with anomalous pulmonary venous connection.

The anatomic, diagnostic, and management findings of 6 patients with truncus arteriosus and anomalous pulmonary venous connections are described. Additional risk factors indicative of poor prognosis were found in 3 of 4 patients with truncus arteriosus and totally anomalous pulmonary venous connection and in 1 patient with partially anomalous pulmonary venous connection.

Clinicopathologic heterogeneity in hypertrophic cardiomyopathy with regard to age, asymmetric septal hypertrophy, and concentric hypertrophy beyond the pediatric age group.

BACKGROUND: To our knowledge, no histopathologic study of the differences between hypertrophic cardiomyopathy in different age groups or that contrasts the pathologic findings in the asymmetric septal hypertrophy and concentric hypertrophy forms of hypertrophic cardiomyopathy has been published. METHODS: The clinicopathologic findings of younger (< or =60 years) (n = 35) and older (>60 years) (n = 20) patients with hypertrophic cardiomyopathy were assessed. Each group was subdivided into groups of patients with asymmetric septal hypertrophy or concentric hypertrophy. RESULTS: Among the young patients, asymmetric septal hypertrophy was more prevalent than concentric hypertrophy, whereas among the elderly patients, concentric hypertrophy was more common. Sudden death was prevalent only among the young. Most young patients had a mirror-image endocardial fibrous septal plaque, whereas most elderly patients with concentric hypertrophy did not. Ventricular septal myocyte disarray and intramural coronary artery thickening were far more marked among the young with asymmetric septal hypertrophy than the young with concentric hypertrophy and the elderly. CONCLUSIONS: Key differences exist between younger and older patients with hypertrophic cardiomyopathy. Much higher degrees of ventricular disarray and intramural coronary artery disease were noted in younger patients with asymmetric septal hypertrophy compared to the elderly patients and the younger patients with concentric hypertrophy.

Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat.

The role of physiologic estrogen levels (pg) on post-ischemic myocardial function was studied in the isolated working rat heart without (n=28, experiment No. 1) or with (n=15, experiment No. 2) preconditioning. For experiment No. 1, female ovariectomized rats were treated with placebo (n=19) or 17beta-estradiol (E2, n=9; chronic E2), and 14 days later hearts were removed and perfused with modified Krebs-Henseleit buffer in vitro. In nine placebo-treated rats, E2 was administered at 20 min prior to ischemia (acute E2). The hearts were subjected to 15 min of global ischemia and 20 min of reflow. In experiment No. 2, ovariectomized rats were treated with placebo (n=8) or 17beta-E2 (chronic E2, n=7). In this experiment, hearts were first preconditioned and then subjected to 20 min of sustained ischemia followed by 20 min of reflow. Global ischemia was produced by clamping the aorta and restricting left atrial flow so that coronary flow was reduced to zero; hemodynamics were continuously monitored throughout the study. Aortic flow, coronary flow, cardiac output, and dP/dt were assessed at baseline, at the end of the ischemic period, and during reflow. The severity of ischemia was measured by post-ischemic release of lactate, lactate dehydrogenase, and creatine kinase and was similar among all groups in each study. In experiment No. 1, recovery of aortic flow, cardiac output, and dP/dt following reperfusion, was significantly improved in rats treated with chronic E2 (P<0.05); acute E2 had no significant benefit. Post-ischemic recovery of coronary flow was not significantly affected. In experiment No. 2, chronic E2 treatment also significantly improved post-ischemic recovery of cardiac function in preconditioned hearts when compared with controls (P<0. 05). In summary, E2 replacement in ovariectomized rats improves contractile function following global ischemia and reflow; cardioprotection by estrogen was observed over and above that conferred by ischemic preconditioning. Since the cardioprotective effect of E2 was independent of a significant improvement in coronary flow a direct effect of the hormone on the cardiac myocytes is postulated.

Giant cell myocarditis: an entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells.

Giant cell myocarditis (GCM) is a rare, rapidly fatal myocarditis with histologic features that have some similarities to cardiac sarcoidosis (CS). The natures of the inflammatory infiltrates of GCM and CS have not been systematically compared. We retrospectively compared the immunohistochemical and light microscopic findings at autopsy in eight hearts with GCM and seven hearts with CS. The patients with GCM were six women and two men (mean age, 50 +/- 13 yr) who presented with congestive heart failure with a mean duration of 46 days until death (range, 1-180 d). We observed three histologic phases, often within a single heart. The acute phase (seven cases of eight) demonstrated an extensive infiltrate of lymphocytes and eosinophils with plentiful macrophages and macrophage-derived KP-1 positive giant cells (GCs) associated with myocytic necrosis. No granulomas were identified. A healing phase (three cases of eight) showed granulation tissue, moderate macrophagic GCs, and scattered KP-1-negative myogenic GCs. A healed phase (three cases of eight) showed dense scar with no GCs. Macrophagic GCs were present preferentially in areas of myocytic damage and were never present in epicardial fat. The majority of lymphocytes were T cells, with a predominance of CD8 cells. The seven patients with CS were men (mean age, 44 +/- 18 yr). Six patients presented with sudden cardiac death and one with congestive heart failure. The histologic patterns were similar in all seven, with scattered interstitial and epicardial (five cases of seven) granulomas composed of KP-1 positive macrophages and macrophagic GCs and T lymphocytes, which were predominantly CD4 cells. Necrosis, myogenic GCs, and significant numbers of eosinophils were absent. Dense scarring was present in five cases of seven. GCM is characterized by myocytic destruction mediated by cytotoxic T cells, macrophagic GCs, and eosinophils. In contrast, CS is an interstitial granulomatous disease without myocytic necrosis.

Effect of age, race, body surface area, heart weight and atherosclerosis on coronary artery dimensions in young males.

Compensatory arterial enlargement in response to atherosclerosis has been demonstrated for the left main coronary artery. Only limited data is available on the interaction of patient characteristics and atherosclerosis with coronary artery dimensions. The purpose of the present study was to evaluate the influence of age, race, body habitus, heart weight and atherosclerosis on coronary artery dimensions of young males. Hearts from 137 young men (age 32 +/- 8 years; 78 black, 59 white) with unnatural deaths (homicide, suicide, accident, drug overdose) were perfusion-fixed, and histologic sections were obtained from the left main, proximal left anterior descending and left circumflex coronary arteries. Computerized planimetry was performed on Movat stained sections. Multiple regression analysis was used to evaluate the relative contribution of plaque size, age, race, heart weight and body surface area on coronary dimensions and compensatory enlargement in response to atherosclerosis. In the left anterior descending and left main coronary arteries, black race, body surface area and age were independent predictors of increased lumen area. In the left circumflex, age was a predictor of lumen area. Plaque area, black race and body surface area independently predicted increased area enclosed by the internal elastic lamina area. There was compensatory enlargement of internal elastic lamina with increasing plaque size in both races in the three arteries, but the percent luminal stenosis was greater in whites due to smaller artery size. Luminal narrowing did not develop until plaques occupied 30% of internal elastic lamina area. Among a population of young men with non-cardiac deaths, blacks have larger lumen and area enclosed by internal elastic lamina than whites. Age and body surface area are major determinants of lumen areas, and compensatory arterial enlargement was seen in all examined arteries in the present study.

Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium.

A prolongation of the ventricular effective refractory period in response to cholinergic agonists or vagal stimulation has been demonstrated in a number of in vivo animal models. However, exposure of isolated myocardial tissues obtained from these hearts to as much as 10(-4) M acetylcholine has been shown to produce essentially no change in action potential duration or effective refractory period. The discrepancy between the in vivo and in vitro findings generally has been explained on the basis of accentuated antagonism, whereby parasympathetic agonists exert their influence through antagonism of the effects of beta-adrenergic tone in vivo. The fact that acetylcholine exerts little if any direct effect on the electrical activity of ventricular myocardium, although well accepted, is based exclusively on studies performed using endocardial preparations. Our recent demonstration of major electrophysiological differences between canine ventricular endocardium and epicardium prompted us to examine the effects of acetylcholine and the role of accentuated antagonism in these two tissue types. Using standard microelectrode techniques, we show that acetylcholine (10(-7)-10(-5) M) has little if any effect in canine ventricular endocardium but a pronounced effect to either prolong or markedly abbreviate action potential duration and effective refractory period in epicardium. These effects of acetylcholine on epicardium are attended by an accentuation of the spike and dome morphology of the action potential, are readily reversed with atropine, fail to appear when epicardium is pretreated with the transient outward current blocker 4-aminopyridine, are accentuated in the presence of isoproterenol (10(-7) to 5 x 10(-6) M), and persist in the presence of propranolol. Isoproterenol-induced abbreviation of action potential duration and effective refractory period is also shown to be more pronounced in epicardium than in endocardium; equimolar concentrations of acetylcholine completely antagonize the effects of isoproterenol in endocardium and epicardium. We conclude that acetylcholine exerts important direct effects on the electrical response of canine ventricular myocardium, which are accentuated in the presence of beta-adrenergic agonists. Our findings suggest the differential response of epicardium and endocardium to acetylcholine is due to the presence of a transient outward current-mediated spike and dome morphology in the epicardial action potential. Finally, the data suggest that acetylcholine may exert antiarrhythmic as well as arrhythmogenic effects through its actions to alter conduction and refractoriness.

Rate dependence of action potential duration and refractoriness in canine ventricular endocardium differs from that of epicardium: role of the transient outward current.

Previous studies have provided evidence for an important contribution of the transient outward current to the electrical activity of canine ventricular epicardium, but not endocardium. The present study examines the characteristics of action potential duration and refractoriness in these two tissue types. The time and rate dependence of changes in action potential duration and refractoriness observed in epicardium were significantly more accentuated than in endocardium. The restitution of action potential duration in epicardium paralleled the restitution of phase 1 amplitude of the action potential in this tissue. The correlation between phase 1 amplitude and action potential duration recorded from a large number of epicardial and endocardial preparations was significant under both steady state and restitution conditions. 4-Aminopyridine, a transient outward current blocker, decreased the time dependence of phase 1 amplitude and concomitantly decreased the time dependence of action potential duration in epicardium. 4-Aminopyridine abbreviated the action potential duration of epicardium at slow stimulation rates but had little effect or prolonged it at fast rates or after premature stimulation. (The availability of a transient outward current is relatively small after premature stimulation.) The data support the hypothesis that the prominent presence of a transient outward current in epicardium, but not endocardium, contributes to the differences in the time and rate dependence of action potential duration and refractoriness in the two tissue types. The results also demonstrate the effect of an outward current to prolong the action potential and the effect of an outward current blocker to abbreviate the action potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Transient outward current prominent in canine ventricular epicardium but not endocardium.

Previous studies have denied the presence of a transient outward current (Ito) in ventricular myocardium of dog, sheep, and calf. Using conventional microelectrode techniques, we provide evidence for a significant contribution of Ito to epicardial, but not endocardial, activity of canine ventricular myocardium. The epicardial action potential when compared with that of endocardium shows a smaller phase 0 amplitude, a much more prominent phase 1, and a phase 2 amplitude that is greater than that of phase 0. Epicardial action potentials, unlike those of endocardium, display a "spike and dome" morphology that becomes progressively more accentuated at slower stimulation rates. Using the restitution of phase 1 amplitude as a marker for the process responsible for the spike and dome phenomenon, we were able to delineate two exponential components: 1) a slow component that recovers with a time constant of 350-570 msec and 2) a fast component with a time constant of 41-85 msec. The slow component was largely abolished by 1-5 mM 4-aminopyridine, an Ito blocker. The fast component was diminished by 4-aminopyridine, but it was also inhibited by ryanodine and by Sr2+ replacement of Ca2+, which are interventions known to inhibit the Ca2+-activated component of Ito. Following 4-aminopyridine and Sr2+ or ryanodine treatment, the epicardial responses more closely resembled those of endocardium. In summary, the data demonstrate a marked heterogeneity of active membrane properties in canine ventricular muscle. These observations may aid in understanding the basis for rate-dependent changes in the T wave of the ECG, supernormal conduction in ventricular muscle, the greater sensitivity of epicardium to ischemia, and the rate dependence of some cardiac arrhythmias.