Kyo Adachi

Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy

Genetic impairment was revealed in idiopathic cardiomyopathy and the responsible DNA locus was estimated. Mitochondrial DNA were amplified from autopsied cardiac specimens from three patients who died from hypertrophic or dilated cardiomyopathy by using polymerase chain reaction (PCR). By using two novel methods for PCR gene amplification, the pleioplasmic existence of multiple populations of differently deleted mitochondrial DNA in all specimens from the patients was confirmed. Mitochondrial DNA with a 7,436 bp deletion which commonly existed among the specimens was sequenced and the direct repeat at each edge of deletion was identified as (CATCAACAACCG) which was located in ATPase 6 gene and in the D-loop region. From our results mitochondrial DNA mutations could also be an important contributory factor to cardiomyopathy.

A Myosin Missense Mutation, Not A Null Allele, Causes Familial Hypertrophic Cardiomyopathy

BACKGROUND Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac beta-myosin-heavy-chain (beta-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac beta-MHC gene, ie, an alpha/beta hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood. METHODS AND RESULTS We analyzed the structure of the cardiac beta-MHC gene from patients with HCM by using polymerase chain reaction-DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families. CONCLUSIONS The Arg870His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac beta-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac beta-MHC gene.

Cyclic flow variations in a conscious dog model of coronary artery stenoses and endothelial injury correlate with acute ischemic heart disease syndromes in humans

OBJECTIVES The purpose of this study was to test the hypothesis that episodes of cyclic flow variations (CFVs) in conscious dogs with coronary stenoses and endothelial injury correlate with acute ischemic heart disease syndromes in humans. BACKGROUND Although the canine model with CFVs has proved to be a useful model of coronary thrombosis, whether CFVs progress to these syndromes has not been clearly described. METHODS Cyclic flow variations were produced by an external constrictor placed at the site of the left anterior descending coronary artery with injured endothelium. Blood flow in this artery and 24-h Holter electrocardiogram (ECG) were recorded during the 1st 5 postoperative days. RESULTS Of 41 dogs that underwent the initial operative procedure successfully, 29 developed an episode of CFVs. In five dogs in which CFVs persisted throughout the monitoring period, the left anterior descending coronary artery flow decreased until day 3 and thereafter increased through day 5. Transient coronary occlusion during CFVs induced ST segment changes that returned to baseline after reflow. In 12 dogs, CFVs progressed to persistent coronary occlusion, and histologic examination revealed thrombus formation at the stenotic site and evidence of myocardial infarction. Four of these 12 dogs died suddenly of ventricular arrhythmias during persistent coronary occlusion; another 5 dogs died of reperfusion arrhythmias during CFVs with no evidence of myocardial infarction. CONCLUSIONS Conscious dogs with CFVs closely correlated with clinical acute ischemic heart disease syndromes, suggesting them to be a useful model for investigating the complex mechanisms of cellular interactions in the pathogenesis of these syndromes.

Vitamin E deficiency has a pathological role in myocytolysis in cardiomyopathic Syrian hamster (BIO14.6).

This study revealed the occurrence of vitamin E deficiency in the myocardium of 60-day-old Syrian cardiomyopathic hamsters (BIO14.6), and that this deficiency might be related to the increase in lipid peroxide. Vitamin E administration for ten days effectively restored creatininekinase activity and decreased the lipid peroxide content in the myocardium, returning these to normal control levels (F1b). These results indicate that vitamin E deficiency, possibly combined with oxidative stress in the early cardiomyopathic stage plays an important role in initiating the pathogenesis of myocardial lesions.

Aneurysm of the ductus arteriosus.

A 59-year-old man with an aneurysm of the ductus arteriosus is described. Macroscopically and histologically it was ascertained that the aneurysm had originated from the ductus arteriosus itself. We suggest the following pathogenesis: after obliteration of the pulmonary end, the aneurysm was formed, and as a result of a gradual increase in pressure in the lumen, the obliterated pulmonary end, the aneurysm was formed, and as a result of a gradual increase in pressure in the lumen, the obliterated pulmonary end recanalized.

Cardiac hypertrophy accelerated by left cervical sympathectomy in spontaneously hypertensive rats

Cardiac hypertrophy in spontaneously hypertensive rats was accelerated by denervation of the left cervical sympathetic ganglia. Supersensitivity due to denervation may also exist in cardiac muscles.

Cardiac hypertrophy in surgically denervated dogs with aortic stenosis

Left ventricular cell hypertrophy in dogs with aortic stenosis was accelerated by surgical denervation of the left ventricle. We conclude that there are neural mechanisms which, when present, inhibit cardiac cell hypertrophy.

Noonan Syndrome with Hypertrophic Obstructive Cardiomyopathy

A case of a 20 years old female who had Noonan syndrome associated with obstructive cardiomyopathy was presented. It is well known that Noonan syndrome is frequently complicated with cardiac anomaly, and although no autopsies were performed two cases have been diagnosed clinically as Noonan syndrome accompanied with idiopathic cardiomyopathy in our country. The present case would be the first autopsied case in Japan of Noonan syndrome associated with idiopathic obstructive cardiomyopathy.

Permeability into Aortic Intima and Atherosclerotic Plaque

For the purpose of examining the interrelation between the permeability of the plasma constituents and the site of the atherosclerosis. We have perfused the solution of a dye into human aorta and observed permeability into aortic intima with aging and into atherosclerotic plaque. In addition, the deposition of bilirubin and fibrin into atherosclerotic plaque was also investigated. When the extent of the permeability was expressed as the ratio of the depth of permeability/thickness of intima, it was found that the ratio for the thoracic aorta decreased with advancing age. Permeability of the abdominal aorta occurred to show that the value of the ratio was up to 3.0 in the subject with age from 0 to 19 years and then the ratio slightly decreased with advancing age, followed by a further one step down in the seventies. Permeability into the atheromatous plaque showed diffuse pattern in the young adult but the permeability became shallower with advancing age. Regional difference of permeability around the plaque was studied. The greatest permeability was seen on the lower side of the plaque. Bilirubin and fibrin deposition into plaque was also similar to its permeability pattern.