Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article we review the techniques of molecular biology as they apply to the elucidation of the genetic basis of hypertrophic cardiomyopathy. We review the evidence for linkage to chromosome 14 and the specific mutations described to date. The evidence for genetic heterogeneity is presented. We speculate on the pathophysiology of the disease from the perspective of the known molecular defects and review the clinical implications the evolving information may have.
J Mol Cell Cardiol 1992 Dec
PMID:The genetic basis of hypertrophic cardiomyopathy. 129 18

The activity of phospholipid base exchange enzymes has been evaluated in cardiac sarcolemmal membranes from Syrian Golden hamsters and from a hamster strain (UM-X7.1) characterized by a genetic form of hypertrophic cardiomyopathy. No choline base exchange activity and only a little serine base exchange activity were detected, whereas the ethanolamine base exchange enzyme was found highly active in membranes from both strains. For this reason, the present study is focussed on the ethanolamine base exchange enzyme. The apparent Km for ethanolamine of ethanolamine base exchange enzyme from Syrian Golden membranes and from UM-X7.1 strain membranes are 18 and 32 microM, respectively. The specific activity of the sarcolemmal ethanolamine base exchange enzyme is lower in the UM-X7.1 strain than in Syrian Golden hamsters. The calcium-dependence of the enzyme appears different when the membranes from the two strains are compared. Indeed, after removal of the membrane-bound divalent cations, comparable activities are found in both membrane preparations, whereas, upon addition of Ca2+ to the incubation mixtures, the activity of the enzyme is enhanced in the membranes from Syrian Golden strain more than in those from UM-X7.1 strain. The cholesterol content of sarcolemmal membranes is higher in the cardiomyopathic strain than in the Syrian Golden hamsters. A possible relation between changes of the membrane lipid composition and of the ethanolamine base exchange activity is discussed.
Mol Cell Biochem 1992 Mar 04
PMID:Phospholipid base exchange enzyme activity in sarcolemmal membranes from the heart of cardiomyopathic hamsters. 157 31

There are marked differences between human cardiomyopathies, especially of the hypertrophic variety, and animal models. There is no simple way in which a hyperadrenergic state can explain the contractile abnormalities, although additional effects of calcium overload or marked hypertrophy come somewhat closer to linking animal and human diseases. One of the best links between excess catecholamine stimulation and myocardial damage lies in the enhanced sarcolemmal permeability which is mediated by beta-adrenergic stimulation and calcium ions in an isolated rat heart model. The therapeutic success of beta-adrenergic blockade and especially calcium antagonists in no way provide firm evidence for a hyperadrenergic state nor for intracellular calcium overload. In human hypertrophic cardiomyopathy, these agents may be acting merely by enlarging cavity size. In dilated cardiomyopathy, the use of beta-adrenergic blockers is still highly controversial and calcium antagonists are not well tested. It is the lack of appropriate models for both hypertrophic cardiomyopathy and dilated cardiomyopathy which is holding up research in this important area.
J Mol Cell Cardiol 1985 Jul
PMID:Calcium and catecholamines: relevance to cardiomyopathies and significance in therapeutic strategies. 286 85

The various etiologic suggestions for hypertrophic cardiomyopathy in man have been reviewed and experimental studies for endogenous pathways have been investigated experimentally. Intramuscular administration of triac to adult rats resulted in severe myocardial hypertrophy but no disarray. When studying the effect of triac on the myocardium of developing rats profound changes of disarray as well as hypertrophy were produced, mimicking the ultrastructural changes of hypertrophic cardiomyopathy in man. By using a variety of compounds with beta-adrenergic blocking action or predominantly membrane stabilizing properties or agonist action together with triac, the site where triac exerts its effect has been shown to be the cell membranes. A mechanism for production of cellular disarray has been delineated. Extrapolating to man, these experiments lend support to the suggestion that an endogenous hormonal mechanism may be operative in some patients with hypertrophic cardiomyopathy.
J Mol Cell Cardiol 1985 Jul
PMID:An endocrine experimental model for myofibrillar disarray as found in hypertrophic cardiomyopathy. 286 86

The three main clinical types of cardiomyopathy are: hypertrophic cardiomyopathy; dilated cardiomyopathy; and restrictive cardiomyopathy. In each case the basic cellular mechanisms still remain to be defined.
J Mol Cell Cardiol 1985 Jul
PMID:Mechanisms in cardiomyopathies. 286 88

In patients with hypertrophic cardiomyopathy, clinical symptoms such as exertional dyspnea, angina and collapse are considered to be rather the consequence of diastolic than of systolic dysfunction of the left ventricle. Beta-blocker therapy is aimed at reducing systolic overcontraction while calcium blockers predominantly therapy is aimed at reducing systolic overcontraction while calcium blockers predominantly improve diastolic filling characteristics. Therefore 61 consecutive patients with well defined hypertrophic cardiomyopathy were treated with calcium channel blockers: 60 patients with verapamil at average dose 530 mg (320 to 720 mg/d) and one patient received 30 mg nifedipine. All patients had clinical, noninvasive and cardiac catheterization evaluation at the time of entry into the study. Therapy was continued for an average of 54 months (10 to 96). Follow-up studies were performed at 6-month intervals. Subjective improvement was achieved in 47 of 55 symptomatic patients (85%). Heart size, judged as heart volume from tele-chest X-ray in supine position, showed a reduction in 36/61, no change in 15/61 and increase in 10/61. On average in all 61 patients, a significant reduction from 947 to 833 ml/1.73 m2 was seen. Twenty-six patients who had been followed for an average of 24 months prior to verapamil therapy on beta blockers or no treatment had heart volume increases averaging 12% in the pre-verapamil period. Electrocardiography (ECG) showed a significant reduction in QRS amplitude and a tendency towards normalization of ST/T segments. Serial echocardiography study showed small but significant reduction in left atrial diameter. Repeat catheterization was performed in 19 patients and a significant reduction in intraventricular pressure gradient, left ventricular muscle mass and coronary artery diameter was demonstrated. Three patients died during the study (256 patient-treatment-years) for an annual mortality rate of 1.3%. This mortality is considerably lower than reported for patients receiving no treatment, beta-blockade, or surgery. Of all 61 patients only one had surgery related to the hypertrophic cardiomyopathy. One patient had the dose of verapamil reduced because of the occurrence of heart block. No patient discontinued the drug because of side-effects. Utilizing serial noninvasive and invasive studies, we conclude that verapamil therapy in hypertrophic cardiomyopathy results in objective and subjective improvement, a low death rate and little need for operation as compared to standard therapy.
J Mol Cell Cardiol 1985 Jul
PMID:Treatment of hypertrophic cardiomyopathy: relation to pathological mechanisms. 404 Sep 78

In human hypertrophic cardiomyopathy and hypertension associated ventricular hypertrophy, chronic use of calcium channel blockers results in a significant regression of hypertrophy. The main objective of this study was to test the hypothesis that modulation of calcium influx through the voltage-sensitive L-type Ca2+ channel directly affects myocardial hypertrophy. Agents that modified calcium influx through the L channel, reduced or enhanced mechanical activity, or uncoupled excitation-contraction coupling were evaluated in cell culture models of myocardial hypertrophy. The calcium channel blocker, verapamil, significantly reduced serum-stimulated cardiomyocyte hypertrophy in a stereoselective manner. The 1,4-dihydropyridine (DHP) calcium channel blocker, nifedipine, also significantly inhibited cardiomyocyte hypertrophy while the DHP calcium channel activator, Bay K 8644, promoted a significant increase in serum-stimulated hypertrophy. Norepinephrine (NE) and, to a lesser degree, isoproterenol (ISO) modulated serum-stimulated hypertrophy. KCl, verapamil, and nifedipine at concentrations that completely arrested beating produced comparable reductions in serum-stimulated hypertrophy. The excitation-contraction uncoupler, 2,3-butanedione monoxime (BDM), KCl and verapamil reduced hypertrophy in high density spontaneously contracting serum-free cardiomyocytes. Addition of NE or serum to BDM treated cells partially offset this reduced hypertrophy. In conclusion, agents that altered calcium influx through the L-type Ca2+ channel or inhibited mechanical activity affected cardiomyocyte hypertrophy. The negative inotropic or chronotropic effects of calcium channel blockers on the heart may contribute to their efficacy in the treatment of myocardial hypertrophy.
J Mol Cell Cardiol 1995 Mar
PMID:The effects of modulation of calcium influx through the voltage-sensitive calcium channel on cardiomyocyte hypertrophy. 760 9

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopril-treated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5-75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.
Mol Cell Biochem 1993 Dec 22
PMID:Beneficial effect of ACE inhibitor in congestive heart failure. 817 36

Abnormal long-chain fatty acid metabolism has been suggested as having a role in the genesis of certain cardiac diseases, and depressed myocardial long-chain fatty acid uptake has been clinically demonstrated in some patients with hypertrophic cardiomyopathy. However, the site where long-chain fatty acid metabolism is affected in cardiomyopathy remains unclear. Although cardiac hypertrophy is reported to be induced in rats by a fat-free diet, little is known of the consequences of depressed myocardial long-chain fatty acid uptake. Sulfo-N-succinimidyl derivatives of long-chain fatty acids have been shown to irreversibly inhibit long-chain fatty acid transport. To investigate the possible linkage of abnormal long-chain fatty acid uptake with cardiac hypertrophy, myocardial long-chain fatty acid uptake was blocked in rats using a sulfo-N-succinimidyl derivative of palmitate (SSP). SSP was intraperitoneally administered to rats for 12 weeks, and its effects on physiological parameters, and cardiac morphology were studied, SSP treatment (20 mg/kg) caused a 12% increase in heart weight (663.7 +/- 33.6 mg in controls v 741.2 +/- 26.5 mg after SSP treatment) and an 11% increase in the heart weight to body weight ratio (2.46 +/- 0.10 in controls v 2.72 +/- 0.17 after SSP) without any significant change of body weight. No significant differences were observed in blood pressure, heart rate, and serum hormones (insulin and triiodothyronine) between the control and SSP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Aug
PMID:Effect of sulfo-N-succinimidyl palmitate on the rat heart: myocardial long-chain fatty acid uptake and cardiac hypertrophy. 852 23

We have searched for mutations in alpha-tropomyosin gene in 50 Japanese patients with hypertrophic cardiomyopathy (HCM) by means of polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. Two missense mutations of the alpha-tropomyosin gene were detected in Japanese patients with familial HCM. Sequencing analysis revealed a C to T transition at codon 63 leading to a replacement of Ala with Val residue, and a G to A transition with replacement of Asp by Asn at codon 175. These missense mutations were found at residues which were markedly conserved across the species, and have been reported to interact with troponin T. This is the first report on a mutant alpha-tropomyosin gene in a Japanese population. Familial HCM is a genetically heterogeneous disease in Japanese patients, similar to that reported in Caucasian kindreds.
J Mol Cell Cardiol 1995 Sep
PMID:Novel missense mutation in alpha-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. 852 64


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