Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Congenital heart disease associated with sporadic Kallmann syndrome.

A 17-year-old boy with Kallmann syndrome had complex congenital heart disease that included double-outlet right ventricle, d-mal-position of the great arteries, right aortic arch, and hypoplastic main pulmonary artery. He had neurosensory hearing loss and mental retardation. The 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with height > or = 2 standard deviations below the mean for age (5/7), lacked a family history of Kallmann syndrome (6/6), and were mentally retarded (4/4). Patients presenting with Kallmann syndrome and congenital heart defects appear to represent a distinct subgroup of patients with Kallmann syndrome. The cause of this association is unclear, but may involve either autosomal recessive inheritance, sporadic dominant mutation, or a shared teratogenic event during the first trimester of gestation.

Doppler echocardiographic assessment of filling and emptying parameters and ambulatory blood pressure measurements in normotensives and hypertensives.

To evaluate the relationship between office and ambulatory BP measurements and filling and emptying parameters, 15 hypertensive and 15 control subjects underwent both 24 hour ambulatory BP monitoring and Doppler echocardiography. No patient received antihypertensive medication for 3-4 weeks, had echocardiographic left ventricular hypertrophy (greater than or equal to 12 mm) or a diastolic BP greater than 100 mm Hg. The time from R wave on the electrocardiogram to onset of ejection was prolonged in hypertensives (P less than 0.05). There were no differences between the hypertensives and normotensives for diastolic filling abnormalities. Finally, neither office nor ambulatory BP correlated with either Doppler filling or emptying parameters.

Family history of myocardial infarction and hemodynamic responses to exercise in young black boys.

The influence of family history of coronary artery disease on children's hemodynamic responses to exercise was examined with 25 black boys aged 7 to 10 years. Blood pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance were evaluated during preexercise, peak exercise, and recovery stages. Children with a family history of CAD exhibited greater systolic blood pressure and total peripheral resistance during preexercise and peak exercise stages than did those without a family history of coronary artery disease. After controlling for preexercise differences, the group with a family history of coronary artery disease exhibited greater increases in systolic blood pressure and less attenuation of total peripheral resistance to peak exercise than the group without a family history of coronary artery disease. Cardiac output indexed by body surface area and stroke volumes were higher at all times in the group without a family history compared with the group with a family history of coronary artery disease. Findings are compared with those of adult studies in terms of influence of family history of coronary artery disease on cardiovascular reactivity to stress.

Racial differences in hemodynamic responses to the cold face stimulus in children and adults.

The prevalence of essential hypertension is higher among blacks than whites. One reason for this difference may be that blacks are more reactive to stressors that produce vasoconstrictive responses. Two studies were conducted to test this hypothesis, one with 10- to 14-year-old males (20 whites, 20 blacks) and one with young adult males (10 whites, 10 blacks). Subjects had blood pressure, heart rate, cardiac output, and total peripheral resistance measured before, during, and after exposure to forehead cold stimulation. In both studies, blacks exhibited greater increases in diastolic blood pressure and total peripheral resistance to the stressor than whites. The findings are discussed in relation to blacks' greater pressor reactivity to stress, which appears to be mediated by changes in total peripheral resistance.

Facial dysmorphologic and skeletal cephalometric findings associated with conotruncal cardiac anomalies. off.

Anomalous conotruncal cardiac morphology and facial dysmorphology have been associated with neural crest-pharyngeal arch abnormalities. To assess these associations, 20 patients 3 to 18 years old with tetralogy of Fallot (TOF) or persistent truncus arteriosus (PTA) were evaluated by cardiologic, facial dysmorphic, and cephalometric criteria. The average number of facial abnormalities of neural crest derivation was two, while pharyngeal arch derivative abnormalities were observed with an average of five defects per subject. The total group had many more facial malformations than normal populations (P less than .00001). The occurrence of defects was not significantly different between TOF and PTA patients. Thirteen TOF patients 8 years, 9 months to 18 years, 10 months old (x = 13 years, 4 months) had lateral cephalograms analyzed for skeletal relationships. The TOF patients exhibited higher than usual distribution of dolichofacial growth patterns (6 of 13), Class II skeletal relationships (6 of 13), mandibular retrusion (7 of 13), and maxillary protrusion (6 of 13). Trends were not absolute, since opposite patterns were individually expressed, and referencing by race tended to show more normal values for respective groups.

Cardiac and peripheral vascular responses to adrenoceptor stimulation and blockade after cardiac transplantation.

A denervated heart coupled to a periphery previously exposed to high catecholamine levels provides a unique model to study adrenoceptor physiology. Six orthotopic transplant patients (1.3 +/- 0.8 years postoperative) were age matched with six atropine-treated normal subjects. Simultaneous two-dimensionally targeted left ventricular echo-cardiograms and calibrated carotid pulse tracings were recorded. Left ventricular contractility was assessed with use of heart rate- and load-independent end-systolic indexes. Studies were performed at baseline and during dobutamine infusion with and without beta-adrenergic blockade with use of propranolol; effects were assessed during afterload changes generated by the alpha 1 agonist methoxamine. There were no differences in baseline contractility or reserve between transplant patients and normal subjects. The heart rate response to dobutamine was greater for transplant patients (p less than 0.001). In both groups, the positive inotropic and chronotropic effects of dobutamine were ablated by propranolol. Dobutamine plus propranolol (unopposed alpha 1 effect) did not change mean systemic pressure in transplant patients while markedly raising mean systemic pressures in normal subjects (36 +/- 18 mm Hg; p less than 0.001). In addition, during initial challenge with methoxamine, the transplant patients required 60% more alpha 1 agonist than did the normal subjects (p less than 0.001) to obtain a pressor effect. In summary, transplant patients who were previously in severe heart failure have normal left ventricular inotropic response to beta 1 activation and blockade, exaggerated chronotropic response to dobutamine and reduced sensitivity to stimulation with alpha 1-adrenoceptor agonists. These findings are consistent with a differential response of adrenoceptors to long-term stimulation after cardiac transplantation.

Exercise-induced differences in cardiac output, blood pressure, and systemic vascular resistance in a healthy biracial population of 10-year-old boys.

Previous studies have documented systolic blood pressure differences in response to dynamic exercise when blacks were compared with whites. This study was performed to validate these data and to determine if the cardiac output and systemic vascular resistance responses to exercise are different in a biracial population of 10-year-old boys. Nineteen blacks and 31 whites underwent maximum supine graded exercise tests with Doppler determination of cardiac output and measurement of systolic and diastolic blood pressure and systemic vascular resistance. The blacks had a body surface area that was marginally larger than that of the whites, but no differences were noted in height or weight. Working capacities, when indexed by weight, were virtually identical between the two groups. No differences were noted in either systolic or diastolic blood pressure during preexercise, maximum exercise, or early and late recovery. White males had significantly higher cardiac indexes during preexercise, maximum exercise, and early and late recovery. Black males had greater systemic vascular resistance during preexercise, maximum exercise, and early and late recovery. Thus, the black children's blood pressure responses to exercise were comparable with those of the white children but they had a greater systemic vascular resistance and lower cardiac index. These racial differences may serve as potential markers for the prehypertensive state.

Left ventricular filling in sickle cell anemia.

M-mode echocardiography was performed on 11 normal black subjects and 38 patients with sickle cell anemia while they were at rest to evaluate their left ventricular (LV) systolic and diastolic function. The patients with sickle cell anemia were also evaluated by radionuclide exercise tests and, based on their ejection fraction (EF) response, were separated into 2 groups: a group with a normal EF response to exercise (73 +/- 9%, mean +/- standard deviation) and a group with an abnormal EF response to exercise (53 +/- 9%). Computer-assisted analysis of the M-mode echocardiograms identified abnormalities of diastolic function (impaired left ventricular filling) in patients with sickle cell anemia compared with the normal subjects. The abnormal EF response group had significantly more impaired diastolic function and did less exercise than the normal EF response group. Both groups of patients had a decrease in left ventricular end-diastolic volume during exercise. The patients with sickle cell anemia had abnormalities of systolic and diastolic function on echocardiographic and radionuclide testing. The abnormalities in diastolic and systolic function assumed greater significance at the increased heart rates associated with exercise, accounting for the decrease in left ventricular end-diastolic volume and the abnormal EF response, and contributed to exercise intolerance in patients with sickle cell anemia.

Computer assisted echocardiographic assessment of left ventricular function before and after anatomical correction of transposition of the great arteries.

Left ventricular function before and after anatomical correction of transposition of the great arteries was assessed by computer assisted analysis of 78 echocardiographs from 27 patients obtained one year before to five years after operation. Sixteen patients had simple transposition, and 11 had complex transposition with additional large ventricular septal defect. Immediately after correction mean shortening fraction fell from 46(9)% to 33(8)%. There was a corresponding drop in normalised peak shortening rate from 5.4(3.7) to 3.3(1.1) s-1 and normal septal motion was usually absent. Systolic shortening fraction increased with time after correction and left ventricular end diastolic diameter increased appropriately for age. The preoperative rate of free wall thickening was significantly higher in simple (5.6(2.8) s-1) and complex transposition (4.5(1.8) s-1) than in controls (2.9(0.8) s-1). After operation these values remained high in both the short and long term. Thus, computer assisted analysis of left ventricular dimensions and their rates of change before and after anatomical correction showed only slight postoperative changes which tended to become normal with time. Septal motion was commonly absent after operation. This was associated with an increase in the rate of posterior wall thickening that suggested normal ventricular function associated with an altered contraction pattern. Computer assisted echocardiographic analysis may be helpful in the long term assessment of ventricular function after operation for various heart abnormalities.

Assessment of coronary and aortic anastomoses after anatomic correction of transposition of the great arteries.

Anatomic correction of transposition of the great arteries always entails circumferential anastomoses of the aorta and coronary arteries. Long-term success of this procedure is predicted on adequate growth of these anastomotic sites. To assess the size of these arteries, we performed one or two cardiac catheterization on 25 children from 1 to 53 months (mean 18.8 months) following anatomic correction. Early studies (mean 12 months) were performed in 23 patients and late studies (mean 30 months) in 13 patients. Age at repair ranged from 2 to 168 months (mean 25.5 months) and 15 patients were less than a year of age. Fifteen patients had undergone previous pulmonary artery banding in preparation for anatomic repair. Postoperative catheterizations showed no area of narrowing at the aortic or coronary anastomoses and no kinking of the proximal coronary arteries. Almost all normalized diameters of the aortic root were larger than normal. There were no differences between early and late measurements after anatomic correction. No patient had a pressure gradient across the aortic anastomosis. It is, therefore, concluded that the coronary and aortic anastomoses allow for satisfactory growth even when there has been previous pulmonary artery banding.

Left ventricular contractility and contractile reserve in humans after cardiac transplantation.

Limited data are available concerning left ventricular contractility and contractile reserve in the chronically denervated, transplanted human heart. This is primarily because of the inability of traditional tests of left ventricular performance to distinguish changes in contractility from alterations in ventricular loading conditions. In this study, load-independent end-systolic indexes of left ventricular contractility were measured by echocardiography and calibrated carotid pulse tracings in 10 patients who had undergone orthotopic cardiac transplant (age 48 +/- 4 years; interval from operation to study 1.2 +/- 0.8 years) and in 10 normal control subjects (age 25 +/- 4 years) matched for donor heart age (25 +/- 6 years). None of the transplant patients had evidence of rejection as determined by endomyocardial biopsy. Baseline left ventricular contractility was assessed over a wide range of afterload generated by infusion of methoxamine. Contractile reserve was measured as the response to an infusion of dobutamine plus methoxamine. Before afterload challenge, baseline left ventricular percent fractional shortening was higher for the transplant patients than for the control subjects (36.5 +/- 5.7% vs 32.1 +/- 2.1%; p less than .05). These differences occurred at a time that end-systolic wall stress (a measure of afterload) was significantly lower for the transplant patients (38 +/- 16 vs 50 +/- 9 g/cm2; p less than .05). When the left ventricular end-systolic pressure-dimension and stress-shortening relationships were determined for the transplant and control subjects, no differences in contractility or contractile reserve were noted. Thus the chronically denervated, transplanted, nonrejecting human left ventricle demonstrates normal contractile characteristics and reserve.

Electrocardiographic abnormalities in pediatric neuromuscular disease: a review.

Cardiac abnormalities, often heralded by electrocardiographic alterations, at times may become a serious problem in patients with neuromuscular disorders and occasionally lead to death. Electrocardiographic monitoring can identify patients whose conduction defects will benefit from the use of demand pacemakers.

Influence of two-stage anatomic correction on size and distensibility of the anatomic pulmonary/functional aortic root in patients with simple transposition of the great arteries.

To evaluate the results of the two-stage anatomic correction of simple transposition of the great arteries the size, distensibility, and histologic characteristics of the anatomic pulmonary root, which arises from the anatomic left ventricle and which we termed the functional aortic root after anatomic correction, were determined in seven patients before and twice after anatomic correction (mean 43 and 671 days) and the results were compared with those in normal control subjects. The diameter of the systolic sinus of the anatomic pulmonary root increased after banding on the average to 140% of normal, whereas the diameter of the diastolic sinus of the functional aortic root increased after anatomic correction on the average to 150% of normal. Diameters of both the systolic and diastolic sinuses of the functional aortic root remained 30% to 55% larger than normal after anatomic correction. Growth potential of the functional aortic root after anatomic correction was normal, whereas its distensibility, as assessed by determination of the percent change in radius and pressure-strain elastic modulus (stiffness index), was decreased after anatomic correction. This pressure-strain elastic modulus was directly related to the corresponding body surface area and age at banding. In four of five specimens of the anatomic pulmonary arterial wall that were obtained at the time of anatomic correction, fragmentation and shortening of elastic fibers were observed. The histologic characteristics of the pulmonary root in the patient with the smallest body surface area at banding and normal distensibility of the anatomic pulmonary/functional aortic root before and after anatomic correction revealed normal aortic configuration of the elastic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)