Diffuse reduction of myocardial beta-adrenoceptors in hypertrophic cardiomyopathy: a study with positron emission tomography.

OBJECTIVES: This study was conducted to determine the myocardial beta-adrenoceptor density as a marker of sympathetic function in patients with hypertrophic cardiomyopathy and normal control subjects. BACKGROUND: Although some cases of hypertrophic cardiomyopathy are familial with an autosomal dominant pattern of inheritance, there remains a substantial proportion of cases in which neither a family history nor genetic abnormalities can be demonstrated. Additional abnormalities, both genetic and acquired, may be important in the phenotypic expression of this condition. Clinical features of the disease and metabolic studies suggest an increased activity of the sympathetic nervous system. METHODS: Eleven patients with hypertrophic cardiomyopathy, none of whom had previously received beta-blocking drugs, and eight normal control subjects underwent positron emission tomography to evaluate regional left ventricular beta-adrenoceptor density and myocardial blood flow using carbon-11-labeled CGP 12177 and oxygen-15-labeled water as tracers. Plasma catecholamines were also measured. RESULTS: Mean (+/- SD) myocardial beta-adrenoceptor density was significantly less in the hypertrophic cardiomyopathy group than in the control group (7.70 +/- 1.86 vs. 11.50 +/- 2.18 pmol/g tissue, p < 0.001). Myocardial blood flow was similar in both groups (0.91 +/- 0.22 vs. 0.91 +/- 0.21 ml/min per g, p = NS). The distribution of beta-adrenoceptor density was uniform throughout the left ventricle in both groups. In the hypertrophic cardiomyopathy group, there was no correlation between regional wall thickness and myocardial beta-adrenoceptor density. There were no significant differences in either plasma norepinephrine or epinephrine concentrations between the two groups. CONCLUSIONS: There is a diffuse reduction in myocardial beta-adrenoceptor density in patients with hypertrophic cardiomyopathy in the absence of significantly elevated circulating catecholamine concentrations. This most likely reflects downregulation of myocardial beta-adrenoceptors secondary to increased myocardial concentrations of norepinephrine and is consistent with the hypothesis that cardiac sympathetic drive is increased in this condition.

Myocardial infarction in young patients.

Myocardial infarction in persons under the age of 45 years accounts for 6% to 10% of all myocardial infarctions in the United States. In this age group, it is predominantly a disease of men. Important risk factors include a family history of myocardial infarction before age 55 years, hyperlipidemia, smoking, and obesity. Unlike older patients, approximately half of young patients have single-vessel coronary disease, and in up to 20%, the cause is not related to atherosclerosis. Coronary angiography may be warranted in young patients with myocardial infarction to define the anatomy of the disease and to permit optimal management.

Comparison of coronary vasodilator reserve in elite rowing athletes versus hypertrophic cardiomyopathy.

Compared to normal volunteers, coronary vasodilation reserve is reduced in patients with hypertrophic cardiomyopathy but not in rowing athletes with left ventricular hypertrophy. Positron emission tomography can provide complementary information to distinguish between the athlete's heart and hypertrophic cardiomyopathy.

Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy.

Angina, despite angiographically normal coronary arteries, is a common symptom in patients with hypertrophic cardiomyopathy (HC). Verapamil has been shown to ameliorate silent myocardial perfusion defects documented by thallium-201 in patients with HC. The aim of this study was to investigate the effects of verapamil on absolute regional myocardial blood flow and flow reserve, measured by positron emission tomography (PET) in patients with HC. Echocardiography, exercise stress testing, and measurements of myocardial blood flow at rest and after administration of intravenous dipyridamole (0.56 mg/kg) were undertaken in 20 patients with HC at baseline study and 8 +/- 2 weeks after double-blind randomization to either slow-release verapamil 240 mg or placebo once daily. During treatment, resting myocardial blood flow in the interventricular septum was 0.81 +/- 0.23 versus 0.96 +/- 0.42 ml/min/g in the placebo and verapamil group, respectively (p = NS between groups and when compared with respective baseline study); resting myocardial blood flow in the left ventricular free wall was 0.67 +/- 0.17 versus 0.74 +/- 0.45 ml/min/g, respectively (p = NS). After dipyridamole infusion, myocardial blood flow in the interventricular septum was 1.42 +/- 0.52 versus 1.92 +/- 1.23 ml/min/g (p = NS between groups and when compared with respective baseline study); myocardial blood flow in the left ventricular free wall was 1.25 +/- 0.41 versus 1.68 +/- 1.37 ml/min/g, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy.

Phenotypic heterogeneity in hypertrophic cardiomyopathy (HC) makes definitive diagnosis difficult, particularly during family screening. We studied the electrocardiogram (ECG) as a potential initial screening test in patients with HC. Using accepted diagnostic criteria, we examined the ECGs and echocardiograms of 159 patients with a confirmed clinical or genetic diagnosis of HC. An abnormal ECG was found in 154 patients (97%) while only 146 (92%) showed an abnormal echocardiogram. Of the former, 9 patients (6%) had normal echocardiograms and had been diagnosed on the basis of identification of a mutation in the beta myosin heavy chain gene (n = 8) or obligate carrier status (n = 1). Only 1 of these 9 patients was under age 20, the time at which hypertrophy is normally expressed on the echocardiogram. The remaining 5 patients (3%) without ECG abnormality consisted of 1 patient with an echocardiogram clearly diagnostic of HC and 4 clinically normal patients (aged 13, 24, 29, and 33 years) with normal echocardiograms who had been diagnosed by mutation identification (n = 3) or obligate carrier status (n = 1). Thus only these latter 4 patients (3%) would not have been diagnosed as having HC based on an abnormal ECG and/or abnormal echocardiogram. Screening relatives for HC by ECG criteria alone detects all those whom an echocardiogram will diagnose. While echocardiography aids in the specificity of HC diagnosis, the ECG, within the context of a family with a proven case of HC, is a more sensitive marker of the disease. It is therefore both a cost-effective and useful tool for screening those to proceed to echocardiography.

Effects of chronic administration of amitriptyline or mianserin on rat cardiac and central adrenoceptors.

Rats were administered either amitriptyline (20 mg kg-1, i.p.) or mianserin (10 mg kg-1, i.p.) for 21 consecutive days and the alpha- and beta-adrenoceptor characteristics of cardiac ventricles, cerebral cortex and hippocampus examined by ligand-binding procedure. Chronic administration of amitriptyline significantly reduced the maximum density of beta-receptors in the cerebral cortex without significantly altering cardiac alpha- or beta-receptors; mianserin treatment had no significant effect on any of the receptors studied.

Myocardial beta adrenoceptors and left ventricular function in hypertrophic cardiomyopathy.

OBJECTIVE: To assess the relation between left ventricular function and myocardial beta adrenoceptor density. METHODS: 17 patients with hypertrophic cardiomyopathy, six with and 11 without heart failure, were studied. Left ventricular function was assessed by echocardiography, and myocardial beta adrenoceptors by positron emission tomography. Patient data were compared with those obtained in normal controls. RESULTS: Myocardial beta adrenoceptor density in the 17 patients was 7.00 (SD 1.90) pmol/g v 11.50 (2.18) pmol/g in normal controls (P < 0.01). beta Adrenoceptor density in the six patients with left ventricular failure was 5.61 (0.88) pmol/g v 7.71 (1.86) pmol/g in the 11 patients with normal ventricular function (P < 0.05), and there was a significant correlation (r = 0.52; P < 0.05) between left ventricular fractional shortening and myocardial beta adrenoceptor density. A positive correlation (r = 0.51; P < 0.05) was also found between myocardial beta adrenoceptor density and the E/A transmitral flow ratio, an index of left ventricular diastolic function. CONCLUSIONS: There is myocardial beta adrenoceptor downregulation in patients with hypertrophic cardiomyopathy with or without signs of heart failure.

An additional marker for familial hypertrophic cardiomyopathy?

BACKGROUND: Family screening for hypertrophic cardiomyopathy using conventional techniques yields some equivocal cases. Although mutations in the beta-cardiac myosin heavy-chain gene (MYH7) have been demonstrated in some patients, additional diagnostic methods are desirable to clarify the equivocal cases until the full genetic spectrum is characterized. Because coronary flow reserve is reduced in patients with typical hypertrophic cardiomyopathy independent of the severity of left ventricular hypertrophy, this measurement may help to identify patients with equivocal features of the disease. METHODS: Coronary flow reserve was measured in two subjects: one with a MYH7 mutation but without typical diagnostic features of hypertrophic cardiomyopathy, and one with borderline left ventricular hypertrophy but no mutation in the MYH7 gene. Both subjects underwent screening for hypertrophic cardiomyopathy because of a family history of the disease. Positron-emission tomography was performed to measure myocardial blood flow (MBF) with oxygen-15 labeled water. MBF was measured at baseline and during coronary vasodilatation obtained by intravenous dipyridamole (0.56 mg/kg body weight infused over 4 minutes). Coronary flow reserve was expressed as the ratio MBF-dipyridamole/MBF-baseline. RESULTS: Coronary flow reserve was 1.69 and 1.12 in the two subjects. Both of these values are 2 SD below that (3.87 +/- 1.08) measured in 17 normal subjects using the same method. CONCLUSIONS: Noninvasive quantification of coronary flow reserve by positron-emission tomography may have a role in identifying patients with equivocal hypertrophic cardiomyopathy and should be further explored.

Ethical challenges in voluntary blood donation in Kerala, India.

The National Blood Policy in India relies heavily on voluntary blood donors, as they are usually assumed to be associated with low levels of transfusion-transmitted infections (TTIs). In India, it is mandatory to test every unit of blood collected for hepatitis B, hepatitis C, HIV/AIDS, syphilis and malaria. Donors come to the blood bank with altruistic intentions. If donors test positive to any of the five infections, their blood is discarded. Although the blood policy advocates disclosure of TTI status, donors are not, in practice, informed about their results. The onus is on the donor to contact the blood bank. Out of approximately 16 000 donations in the past 2 years, 438 tested positive for TTI, including 107 for HIV. Only 20% of the donors contacted the blood bank; none of them were HIV positive. Disclosure by blood banks of TTI status by telephone or mail has resulted in serious consequences for some donors. Health providers face an ethical dilemma, in the absence of proper mechanisms in place for disclosure of test results, regarding notification to donors who may test positive but remain ignorant of their TTI status. Given the high cost of neglecting to notify infected donors, the authors strongly recommend the use of rapid tests before collecting blood, instead of the current practice, which takes 3 h to obtain results, and disclosure of results directly to the donor by a counsellor, to avoid dropouts and to ensure confidentiality.

Two regional (rural-urban) life tables for India.

"This paper proposes to construct, for India, a two-regional life table, considering two regions viz., rural and urban. Such a table provides information on the probabilities of survivorship and migration, as well as life expectancy by age, region and place of birth and in particular information on: (1) The probability that an individual living in a rural area at age x will be living in an urban area at age y. (2) Life expectancy at birth in a rural area, and the number of years on average this individual may live in an urban area. The aim here is to compare and contrast rural to urban and urban to rural migration probabilities by sex and age for the years 1971, 1981 and 1991, and provide the underlying reasons. Region-specific life expectancy is also compared for these years." (SUMMARY IN ITA AND FRE)

A comparative study of the life tables of Assam, Kerala and India, 1980.

The authors construct "life tables for Assam...using the Sample Registration System data of 1980 [and applying] Greville's method of constructing abridged life tables. These tables are compared with those of Kerala and India. Brass' two parameter logit system [when] fitted to survivors shows that risk of mortality of Kerala females, is much lower than that of India and Assam."

Torsades de pointes due to drug interaction between disopyramide and clarithromycin.

Torsades de pointes (TdP) is polymorphic ventricular tachycardia occurring in the setting of a prolonged cardiac repolarization. Drug interactions between macrolide antibiotics such as erythomycin and pharmacologic agents that prolong the QT interval have been known to cause TdP. However, clarithromycin is thought to be less frequently associated with drug induced TdP, because it inactivates hepatic cytochrome P-450 to a lesser extent than erythromycin. We describe a case of TdP caused by a drug interaction in a 76-year-old woman taking long-term disopyramide after she was given clarithromycin concomitantly for chronic bronchitis.

Coronary vasodilator reserve in primary and secondary left ventricular hypertrophy. A study with positron emission tomography.

OBJECTIVES: Coronary vasodilator reserve is reduced in hypertrophic cardiomyopathy and secondary left ventricular hypertrophy despite angiographically normal coronaries. The aim of the present study was to assess whether quantitative differences exist between these conditions. METHODS: Using positron emission tomography with H2(15)O, myocardial blood flow was measured at baseline and following intravenous dipyridamole (0.56 mg.kg-1) in 12 hypertrophic cardiomyopathy patients (age 34 (11) years, mean (SD), all male), 16 secondary left ventricular hypertrophy patients (age 58 (20) years, P < 0.01 vs hypertrophic cardiomyopathy; 10 female) and 40 normal controls (age 54 (20), 13 female). In view of the known decline of post-dipyridamole myocardial blood flow with age, myocardial blood flow was compared between the patient groups and appropriately matched subsets of the total control group. RESULTS: Baseline myocardial blood flow in the hypertrophic cardiomyopathy patients was 0.82 (0.23) ml.min-1.g-1 vs 0.94 (0.14) ml.min-1.g-1 in its matched control group, P = ns. For the secondary left ventricular hypertrophy patient group, baseline myocardial blood flow was 1.17 (0.40) ml.min-1.g-1 vs 1.06 (0.28) ml.min-1.g-1 for the secondary left ventricular hypertrophy matched control group, P = ns. Following dipyridamole, myocardial blood flow was 1.64 (0.44) ml.min-1.g.-1 in hypertrophic cardiomyopathy patients vs 3.50 (0.95) ml.min-1.g-1 for the hypertrophic cardiomyopathy matched control group, P = 0.0001. For the left ventricular hypertrophy patients, post-dipyridamole myocardial blood flow was 2.27 (0.60) ml.min-1.g-1 vs 2.94 (1.29) ml.min-1.g-1 for the left ventricular hypertrophy controls, P = 0.06. Coronary vasodilator reserve (dipyridamole-myocardial blood flow/baseline-myocardial blood flow) was 2.05 (0.61) for hypertrophic cardiomyopathy patients vs 3.81 (0.98) for the hypertrophic cardiomyopathy controls (P = 0.0001, patients vs controls) and 2.06 (0.62) for left ventricular hypertrophy patients vs 2.90 (1.38) for the left ventricular hypertrophy controls, P < 0.03 patients vs controls. After correction of baseline myocardial blood flow for baseline heart rate x systolic pressure product, coronary vasodilator reserve for the hypertrophic cardiomyopathy patients was 2.06 (1.06) vs 4.34 (1.54) for the hypertrophic cardiomyopathy controls. P = 0.0002 and in the secondary left ventricular hypertrophy patients, the values were 2.13 (0.64) vs 2.89 (1.42) in the secondary left ventricular hypertrophy controls, P < 0.05. CONCLUSION: In both hypertrophic cardiomyopathy and secondary left ventricular hypertrophy, the computed coronary vasodilator reserve is impaired, even after correction for baseline cardiac work. However, the extent of the reduction is greater in the hypertrophic cardiomyopathy patients. In the blunting of vasodilator reserve of secondary left ventricular hypertrophy, the patients' greater hyperaemic response is partly offset by the higher baseline myocardial blood flow.

Use of hydrogen peroxide to assess the sperm susceptibility to oxidative stress in subjects presenting a normal semen profile.

Human sperm susceptibility to oxidative stress is vital as it affects various characteristics of sperm function. In the present study, we report a simple, sensitive and quick method of assessing the capacity of the sperms to withstand increased oxidative stress. The basis for the test was derived from the fact that human sperms suspended in Ham's F-10 medium tend to lose the forward progressive motility when co-incubated with H(2)O(2) (600 microm). Replacement of the medium with seminal plasma (1: 1) was able to reduce the loss of sperm motility (40%). Retention of sperm motility in semen (0-30%) following 10 min of H(2)O(2) (600 microm) exposure was taken as the criteria for delineating the quality of sperm as poor, moderate, good and excellent types. The protocol was tested in 87 subjects presenting a normal semen profile. On the basis of this test, 44% of the semen samples were classified as poor and the rest as moderate, good or excellent. Lipid peroxidation was found higher in the sperms from the 'poor' category. Activities of superoxide dismutase and catalase were also significantly elevated in the seminal plasma of these subjects as compared with combined categories of good or excellent. The test described here can be used routinely in laboratory investigations to assess sperm susceptibility to oxidative stress in subjects presenting a normal semen profile.

Myocardial beta adrenoceptor density in primary and secondary left ventricular hypertrophy.

OBJECTIVES: Myocardial beta-adrenoceptor density has been found to be reduced in hypertrophic cardiomyopathy, even when systolic function is preserved. Our purpose in the current study was to investigate whether beta-adrenoceptor down-regulation was unique to hypertrophic cardiomyopathy, or is also present in secondary myocardial hypertrophy. METHODS: Myocardial beta-adrenoceptor density was measured in 11 patients with hypertrophic cardiomyopathy, eight patients with left ventricular hypertrophy secondary to arterial hypertension or aortic valve disease and 18 normal control subjects, using positron emission tomography with 11C-CGP-12177 as the myocardial beta-adrenoceptor ligand. RESULTS: Reflecting the natural incidence of the conditions, the age of the hypertrophic cardiomyopathy patients was 37 (10) [mean (SD), range 20-51] years and that of the secondary hypertrophy patients 64 (18), [range 26-80] years; P < 0.01. The controls' ages were 50 (13), [range 21-65] years; however, since beta-adrenoceptor density is known to be influenced by age, the controls' data was split into groups matched to the hypertrophic cardiomyopathy and secondary hypertrophy patient sets. For the hypertrophic cardiomyopathy patients, mean left ventricular beta-adrenoceptor was 7.70 (1.86) pmol.g-1 compared to 10.17 (2.44) pmol.g-1 for a matched set of 15 controls; P < 0.01. In secondary left ventricular hypertrophy, beta-adrenoceptor was 6.35 (1.70) pmol.g-1 compared to 9.16 (2.00) pmol.g-1 for a matched set of 10 controls; P < 0.01. Plasma noradrenaline was 5.5 (2.2) nmol.l-1 in hypertrophic cardiomyopathy and 2.5 (1.0) nmol.l-1 for the matched controls; P < 0.01. The results for adrenaline were 2.2 (1.1) vs 0.4 (0.3) nmol.l-1 respectively; P < 0.001. For the secondary hypertrophy patients, the corresponding figures were 2.5 (1.2) vs 2.5 (1.0) nmol.l-1 for noradrenaline for patients and controls respectively (P = ns); and for adrenaline 0.2 (0.1) and 0.3 (0.2) nmol.l-1 respectively, P = ns. On multiple regression analysis, no relationships could be demonstrated amongst plasma catecholamines, beta-adrenoceptor, myocardial blood flow and echocardiographic E/A ratio and fractional shortening. CONCLUSION: Myocardial beta-adrenoceptor density appears to be comparably decreased in both primary and secondary left ventricular hypertrophy in the presence of preserved left ventricular systolic function.

Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

OBJECTIVE: To investigate the molecular genetic basis of the cause of disease in a family with hypertrophic cardiomyopathy. BACKGROUND: Mutation within the beta cardiac myosin heavy chain gene has been shown to be the pathogenetic mechanism underlying the disease in several families, though clear evidence of heterogeneity has been reported. PATIENTS: A family with a history of hypertrophic cardiomyopathy. RESULTS AND CONCLUSION: This paper reports a mutation at aminoacid position 908 within exon 23 of the beta cardiac myosin heavy chain gene, resulting in a conversion of a leucine to valine. This base substitution was identified in an individual with a confirmed family history but with equivocal symptoms of the disease. Inheritance of the mutation by his symptom free juvenile offspring demonstrates the application of the technique to presymptomatic diagnosis.

Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment.

Verapamil alleviates symptoms in patients with hypertrophic cardiomyopathy (HCM), but the underlying mechanism of improvement remains speculative. Baseline and dipyridamole myocardial blood flow (MBF) were measured in 15 HCM patients (14 men, 42 +/- 10 years), before and after 4 weeks of verapamil SR 480 mg daily, using 15O labelled water the positron emission tomography (PET). Subendocardial (endo) and subepicardial (epi) MBF was measured in the septum (thickness 25.4 +/- 5.8 mm). Pre-treatment baseline whole heart MBF was 1.02 +/- 0.28 ml/min/g and 1.01 +/- 0.30 ml/min/g on treatment (p = ns). Dipyridamole MBF was 1.39 +/- 0.31 ml/min/g off treatment and 1.23 +/- 0.34 ml/min/g on treatment (p = ns). Coronary flow reserve (dipyridamole/resting MBF) was 1.45 +/- 0.52 and 1.30 +/- 0.51, respectively (p = ns). At baseline, the septal endo/epi MBF ratio was uniform off and on treatment (1.13 +/- 0.18 vs 1.18 +/- 0.21, p = ns). Before treatment, the endo/epi ratio following dipyridamole decreased to 0.93 +/- 0.24 (p < 0.01 vs baseline) and 5/15 (33%) patients had a ratio < 0.8 which would suggest subendocardial underperfusion. During treatment, the endo/epi ratio following dipyridamole was no more different from baseline (1.06 +/- 0.24, p = ns vs baseline) and 2/14 (14%) patients had an endo/epi < 0.8. PET can be successfully used to determine transmural MBF in vivo in patients with hypertrophied ventricles. Despite symptomatic improvement, high dose verapamil therapy does not increase total MBF in patients with HCM but may improve septal transmural MBF distribution during dipyridamole in some patients.