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Biomedical subjects

T Kamada

Publications and source records attributed to T Kamada.

At least 199 records · Page 11Linked to original sources
PubMed1995

Clinical characteristics and antibody profiles of chronic hepatitis C patients: relation to hepatitis C virus genotypes.

Genotyping of 179 consecutive Japanese chronic hepatitis C patients was carried out based on the variation in the hepatitis C virus (HCV) core gene. The results were correlated with clinical features and antibody responses toward specific HCV proteins deduced from the nucleotide sequence of genotype I/1a. Genotypes II/1b, III/2a, and IV/2b were identified in 138 (77%), 24 (13%), and 12 (7%) patients, respectively. Five patients had double infections. Genotype dependence was observed only for antibody response toward the NS4 (5-1-1) protein, which was infrequent in genotype III/2a patients (33%) compared with genotype II/1b (81%; P < 0.01) and genotype IV/2b (75%; P < 0.05). Following interferon-alpha therapy, sustained amniotransferase normalisation was achieved by 89% (eight of nine) patients without antibody to the 5-1-1 protein and 33% (17 of 51) with it (P < 0.01). These findings indicate that absence of antibody response to the 5-1-1 protein is frequent in genotype III/2a HCV carriers and may serve to predict responses to interferon therapy.

Adult↗
PubMed1995

Serial density analysis of hepatitis C virus particle populations in chronic hepatitis C patients treated with interferon-alpha.

In interferon treatment of chronic hepatitis C patients, the biochemical and virological responses mostly parallel each other. However, some patients who show persistent ALT normalization display continued viremia after cessation of therapy. High-density hepatitis C virus (HCV) particles, which are immune complex forms, are reported to be less infectious both in vitro and in vivo. To assess whether high-density HCV contributes to the response discrepancies and to clarify the association with patient outcome, sera were examined from chronic hepatitis C patients who were treated with interferon-alpha. This study included 10 sustained responders with viremia (SR + ve), 5 SR without viremia, 3 transient responders (TR), and 3 nonresponders (NR). The SR + ve patients were defined as those with continued ALT normalization and serum HCV-RNA positivity at 24 weeks after therapy completion. Serum samples obtained before and 24 weeks after therapy were ultracentrifuged on 35% sucrose. The ratio between high-density and low-density HCV was determined by quantification of HCV-RNA titers in the bottom and top fractions by competitive reverse transcription and by the polymerase chain reaction, and expressed as the bottom/top (B/T) ratio. The B/T ratios before therapy were 1:1 in all groups of patients, and 1:1 after therapy in TR and NR groups. Five out of 6 SR + ve patients who showed 1:1 ratio after therapy relapsed within 1 year. In contrast, all SR + ve patients whose ratios were 10-100:1 continued to show ALT normalization. These findings demonstrate that patients who have high-density HCV dominance after therapy show persistent ALT normalization despite viremia, which can be explained by predominance of the neutralized immune complex.

Adult↗
PubMed1995

Tumor necrosis factor-alpha and interferon-gamma inhibit synergistically viral replication in hepatitis B virus-replicating cells.

The effects of tumor necrosis factor-alpha and/or interferon-gamma on the replication of hepatitis B virus were examined using HB611 cells. These cells were derived from human hepatoblastoma cells, Huh6, by integrating hepatitis B virus DNA, and produce hepatitis B virus continuously. Each of the cytokines inhibited hepatitis B virus replication in the cells assessed as the amount of episomal hepatitis B virus DNA, without a decrease in cell viability. When the two cytokines were administered together, the inhibitory effect became greater. Incubation of the cells with 1,000 U/ml tumor necrosis factor-alpha decreased HBV DNA replicative intermediates by 55%, and that with 1,000 U/ml interferon-gamma decreased these by 51%. Furthermore, incubation with 1,000 U/ml tumor necrosis factor-alpha and 1,000 U/ml interferon-gamma in combination decreased HBV DNA replicative intermediates by 71%. In contrast, the amount of hepatitis B virus RNA and secretion of hepatitis B e antigen were not apparently reduced by the cytokines, and 2',5'-oligoadenylate synthetase activity was not detected in the supernatant. These results suggest that tumor necrosis factor-alpha and interferon-gamma inhibit hepatitis B virus replication by blocking some step in reverse transcription and that the 2',5'-oligoadenylate synthetase is not involved in the mechanism underlying the inhibition by these two cytokines.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

Pharmacological effects of concomitant administration of beta-adrenoceptor blocker and agonist in normal subjects: characterization by heart rate response to exercise. Effects of beta-blocker combined with beta-agonist.

The effects of a combination regimen of metoprolol and beta 1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion. During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats.min-1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats.min-1, respectively. Peak oxygen uptake was also significantly decreased by both regimens. We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective beta-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for beta-adrenoceptor blocker therapy in patients with chronic heart failure.

Adrenergic beta-Agonists↗
PubMed1995

Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery.

Atherosclerotic changes have not been demonstrated directly in asymptomatic hyperglycaemic non-diabetic subjects, although high mortality due to coronary heart disease has been reported. We measured arterial wall thickness non-invasively, in order to directly demonstrate atherosclerosis of the carotid arteries of hyperglycaemic non-diabetic subjects and to evaluate its risk factors. The thicknesses of the intimal plus medial complex (IMT) of the carotid arteries of 112 asymptomatic hyperglycaemic non-diabetic subjects (aged 22-81, 95 males and 17 females) were compared with those of 55 healthy male subjects and 211 non-insulin-dependent NIDDM male diabetic patients. The subjects were subgrouped into impaired glucose-tolerant (IGT) subjects who had a 2-h glycaemic level of more than 7.8 mmol/l, and non-IGT subjects whose 2-h glycaemic levels were within 6.7-7.7 mmol/l. Non-IGT and IGT subjects showed significantly greater IMTs than age-matched healthy males and showed no significant differences compared to age-matched NIDDM patients. Multivariate analysis demonstrated that the risk factors for IMT of non-IGT and IGT subjects were age and systolic blood pressure. According to data on the accumulation of atherogenic risks (hypertension, dyslipidaemia, and smoking), IMT increased linearly in non-IGT and IGT subjects. However, non-IGT and IGT subjects without hyperlipidaemia, hypertension, or smoking risk still had significantly greater IMT than age-matched normal males (1.019 +/- 0.063 vs 0.770 +/- 0.111 mm, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Roles of hepatocyte growth factor and its receptor in gastric mucosa. A cell biological and molecular biological study.

Hepatocyte growth factor (HGF) stimulates the growth of hepatocytes and other epithelial cells. A gene for the HGF receptor, c-met, is detected in the intestinal tract and the liver, as well as in gastric carcinoma cells. However, the role of HGF in the regeneration of the normal gastric mucosa is not known. The purpose of the present study was to elucidate the effects of HGF on the morphogenesis of cultured gastric mucosal cells and to evaluate the role of HGF and c-met in the healing process in rat gastric mucosa. The cultured gastric mucosal cells developed a branching morphology in a collagen matrix supplemented with HGF or fetal calf serum. They did not form this morphology on a plastic dish or in the collagen without HGF or the serum. In an in vivo study, total RNA was extracted from rat gastric mucosa 6, 24, 48, and 96 hr after the exposure to a solution of 0.6 M HCl. HGF messenger RNA was not detected, but c-met was expressed in the mucosa. The increased expression of c-met was followed by healing of the mucosal injury. These results indicate that HGF plays important roles in the morphogenesis of gastric mucosal cells and that the HGF receptor gene participates in the healing process of gastric mucosa.

Animals↗
PubMed1995

Colonic mucosal hemodynamics and tissue oxygenation in patients with ulcerative colitis: investigation by organ reflectance spectrophotometry.

Colonic mucosal hemodynamics were investigated at the rectosigmoidal region of the colon in 46 patients with ulcerative colitis and in 18 normal subjects by organ reflectance spectrophotometry under colonoscopy. The value for the index of mucosal hemoglobin concentration (IHb) was significantly higher, and value for the index of mucosal hemoglobin oxygen saturation (ISO2) was significantly lower in patients with active ulcerative colitis than values in the normal controls or in patients with inactive ulcerative colitis. The results indicate mucosal congestion and hypoxemia in patients with active ulcerative colitis. The changes in IHb and ISO2 correlated well with the severity of ulcerative colitis scored by endoscopic findings and with the number of infiltrating inflammatory cells in the mucosa analyzed histologically in biopsy samples. In conclusion, the colonic mucosal microcirculation in patients with active ulcerative colitis was disturbed and showed congestion and hypoxemia. The analysis of hemodynamic changes may be helpful for assessing the activity of ulcerative colitis.

Adult↗
PubMed1995

Intraventricular dispersion of early diastolic filling: a new marker of left ventricular diastolic dysfunction.

Mitral flow velocity patterns are frequently "normalized" by the alteration in the loading condition even in the presence of left ventricular (LV) diastolic dysfunction. In addition, a simple index, the ratio of mitral peak early diastolic flow velocity to mitral peak flow velocity at atrial contraction, is not obtainable in patients with atrial fibrillation (Af). Thus these limitations hamper the value of analyzing the mitral flow velocity pattern in the assessment of abnormal LV diastolic characteristics. This study was designed to elucidate the hypothesis that peak early diastolic flow velocity decreases progressively from the base to the apex in patients with LV diastolic dysfunction. Regional diastolic flow velocity patterns at 1, 2, or 3 cm from the mitral tip toward the apex were simultaneously recorded with the mitral flow velocity pattern by using multigate pulsed Doppler echocardiography in 42 subjects with normal LV function (31 normal volunteers and 11 patients with Af only), 17 patients with hypertensive heart disease, and 22 patients with dilated cardiomyopathy. In the normal subjects early diastolic flow velocity at the mitral tip was maintained at the positions 1 to 3 cm away from the tip into the LV cavity. In contrast, regional peak early diastolic flow velocity progressively decreased toward the apex in patients with hypertensive heart disease and dilated cardiomyopathy. These findings were observed even in patients with a normalized mitral flow velocity pattern or those with Af. Thus the assessment of the intraventricular decrease in peak early diastolic flow velocity may be useful in detecting LV diastolic dysfunction, particularly in patients with Af or a "normalized" mitral flow velocity pattern.

Adult↗
PubMed1995

Doppler echocardiographic pulmonary venous flow-velocity pattern for assessment of the hemodynamic profile in acute congestive heart failure.

The hemodynamic profile of congestive heart failure (CHF) is best described in terms of its two primary sets of hemodynamic parameters, that is, left atrial pressure and cardiac output, each of which has a specific and independently variable hemodynamic cause. To assess whether analysis of the mitral and/or pulmonary venous flow-velocity patterns provides valuable information in the noninvasive assessment of the hemodynamic profile of CHF, these patterns were obtained by using the transthoracic approach in 18 patients with acute CHF with simultaneous measurements of catheter-derived mean pulmonary capillary wedge pressure and thermodilution cardiac index. Measurements were repeated on two occasions in each case: at the acute stage of CHF and 1 to 5 days after treatment. Peak diastolic pulmonary venous forward flow velocity was higher, the ratio of pulmonary venous systolic to diastolic peak forward flow velocity was lower, and the ratio of mitral early diastolic to late diastolic flow velocity was greater in patients with higher mean pulmonary capillary wedge pressure (r = 0.80, n = 36, p < 0.01; r = -0.69, n = 36, p < 0.01; r = 0.71, n = 36, p < 0.01). Peak systolic pulmonary venous forward flow velocity and time-velocity integral of the systolic pulmonary venous flow wave were greater in patients with larger cardiac index (r = 0.80, n = 36, p < 0.01; r = 0.62, n = 36, p < 0.01). In conclusion, two primary sets of hemodynamic parameters, that is, left atrial pressure and cardiac output, can be estimated with Doppler pulmonary venous flow parameters in patients with acute CHF.

Acute Disease↗
PubMed1995

Hepatitis C viral complexity detected by single-strand conformation polymorphism and response to interferon therapy.

BACKGROUND/AIMS: Hepatitis C virus (HCV) genome heterogeneity by sequence analysis in association with interferon (IFN) inefficacy has been reported. This study was performed to establish a convenient method for detecting the HCV quasispecies complexity and to determine the correlation between the complexity and the responsiveness to IFN therapy in patients with chronic hepatitis C. METHODS: The quasispecies complexity of HCV hypervariable region 1 in patients treated with IFN-alpha was analyzed by polymerase chain reaction-mediated single-strand conformation polymorphism (SSCP). RESULTS: Seven of 25 patients (28%) with low complexity (SSCP band number of < or = 2) were HCV RNA negative after treatment, whereas in 24 patients with high complexity (SSCP band number of > or = 3), the response to IFN was almost insignificant because only 1 patient (4.5%) remained HCV RNA negative after treatment (P < 0.05). Among type 1b patients, IFN therapy was only effective for patients with low amounts of HCV RNA (< or = 10(7.5) copies/mL serum) and low complexity. In contrast, most type 2a patients tended to respond to the therapy with exceptions being those with high amounts of HCV RNA and high complexity. CONCLUSIONS: The complexity of the hypervariable region 1 quasispecies may be a factor for predicting IFN inefficacy in patients with chronic hepatitis C.

Amino Acid Sequence↗
PubMed1995

Therapeutic effect of bifemelane on unilateral cerebral ischemia in gerbils.

To examine the therapeutic effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane) on neuronal ischemia-reperfusion injury, we evaluated the neurological score in gerbils subjected to unilateral common carotid occlusion. Using the neurological score method, we selected animals which showed stroke symptoms without seizures, because seizure activity can modify the neurological outcome. Just after the clip removal following 30 min of ischemia, 0.2 ml of either vehicle (0.9% saline, n = 10) or bifemelane (25 mg/kg, n = 10) was administered intraperitoneally. Then, the neurological score and the maximum inclination at which the gerbil could maintain its equilibrium were recorded at 5, 10, and 30 min, and 1, 2, 3, 6, and 24 hr after the insult. Animals were then decapitated and their brains were processed for immunohistochemical investigation. Treatment with bifemelane after reperfusion significantly improved the neurological score and motor function. Immunohistochemistry using an antibody for microtubule-associated protein 2 clearly demonstrated preservation of staining especially in the caudate-putamen in the animals treated with bifemelane. The present findings suggest a beneficial effect of bifemelane on neuronal ischemia-reperfusion injury, which may be common after cerebral ischemia.

Animals↗
PubMed1995

Influence of oral sulfonylurea agents on hepatic glucose uptake.

Although the metabolic derangement in the subjects with well-established NIDDM is characterized by both insulin resistance and diminished insulin secretion, the impaired sensitivity to insulin in the target tissues is assumed to represent the primary defect in most NIDDM individuals. Therefore, the therapeutic modality that can augment insulin-mediated glucose metabolism in the target tissues seems rational in the treatment of NIDDM. Glimepiride (HOE490), a newly developed sulfonylurea, has been reported to have a more potent hypoglycemic action than glibenclamide while its ability to stimulate insulin secretion is much weaker. Thus, part of the potent hypoglycemic action of HOE490 has been speculated as being due to an extrapancreatic effect. First we examined the effect of strict glycemic control on insulin resistance seen in NIDDM using euglycemic hyperinsulinemic clamp combined with oral glucose loading (Clamp-OGL) to 9 subjects with NIDDM. After 3 to 4 weeks of intensified insulin therapy, insulin-mediated glucose uptake by the liver significantly increased while peripheral glucose disposal did not change. Secondly we applied Clamp-OGL to 5 subjects with IDDM to study the acute metabolic effect of HOE490 on glucose handlings by the target tissues. Intravenous administration of HOE490 at a rate of 6.0 micrograms/min did not affect hepatic glucose uptake in these subjects. Thus we studied subacute metabolic effect of HOE490 on glucose handlings by the target tissues in 7 normal dogs using euglycemic clamp combined with hepatic venous catheterization technique.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Insulin resistance in essential hypertensive patients with impaired glucose tolerance.

This study evaluated insulin secretion and insulin sensitivity in 17 non-obese hypertensive patients (aged 45.6 +/- 2.2 years, body mass index 24.0 +/- 0.5 kg/m2, mean +/- S.E.M.) with (n = 8) and without glucose intolerance (n = 9) and compared the results with those of 16 age-matched non-obese normotensive subjects with (n = 7) and without glucose intolerance (n = 9). The hypertensive patients without glucose intolerance showed a significantly lower insulin-mediated glucose disposal and a compensating increase in second-phase insulin secretion compared with normotensives without glucose intolerance. In hypertensives with glucose intolerance, insulin-mediated glucose disposal was significantly lower and second-phase insulin secretion was comparable to that in normotensives without glucose intolerance. After 3 months of angiotensin-converting enzyme (ACE) inhibition with oral administration of delapril, blood pressure was significantly reduced in the hypertensives with glucose intolerance (n = 9). The insulin-mediated glucose disposal significantly (P < 0.01) recovered from 6.0 +/- 0.81 to 8.0 +/- 0.71 mg/kg per min. The second-phase insulin secretion tended to be lower (but not significantly) but insulin clearance increased from 15.4 +/- 0.85 to 19.1 +/- 1.42 ml/min (P < 0.05). These data show that in hypertensive patients without glucose intolerance insulin resistance might compensatorily augment second-phase insulin secretion and lead to hyperinsulinemia. In hypertensives with glucose intolerance, insulin resistance might induce postprandial hyperglycemia, which leads to hyperinsulinemia because of second phase insulin secretion at a level similar to that of normotensives.

Administration, Oral↗
PubMed1995

Density analysis of hepatitis C virus particle population in the circulation of infected hosts: implications for virus neutralization or persistence.

Hepatitis C virus has a low buoyant density in sucrose, but high-density particles are often observed in hepatitis C virus infection. To investigate the characteristics of circulating hepatitis C virus particles and their association with liver disease progression, we examined sera from two histologically normal hepatitis C virus carriers, 20 chronic hepatitis patients and five acute hepatitis C patients. The supernatants obtained after immunoprecipitation with anti-immunoglobulins antibody were subjected to sucrose equilibrium centrifugation. HCV-RNA positive fractions separated after the treatments were further examined for immunoprecipitation with anti-core hepatitis C virus antibody. We separated hepatitis C virus particle populations according to the density difference on 35% sucrose with centrifugation. The proportions of high and low density particles in hepatitis C virus populations were determined by means of competitive reverse transcription and polymerase chain reaction. Circulating hepatitis C virus particles in chronically infected patients could be separated into two populations: those immunoglobulin-bound with high densities and -unbound with low densities. Patients with severe liver inflammation had high-density hepatitis C virus that did not precipitate with anti-immunoglobulins but with anti-core hepatitis C virus antibodies. Thus, hepatitis C virus particle populations consist of low-density virions and high-density immune complexes and/or nucleocapsids. Among the chronic hepatitis patients, the dominant population shifted from low-density to high-density particles with the progression of liver disease. In acute hepatitis patients, this density shift was observed with alanine aminotransferase normalizations. Therefore, the major hepatitis C virus populations change from virion to immune complex and/or nucleocapsid with the progression of liver disease or inflammation.

Acute Disease↗
PubMed1995

Pretreatment viral load and response to prolonged interferon-alpha course for chronic hepatitis C.

BACKGROUND/AIMS: We investigated the clinical benefit of long-term interferon therapy in chronic hepatitis C in relation to the pretreatment viral load and genotypes. METHODS: Chronic hepatitis C patients were randomly assigned to receive 28-week (n = 45) or 52-week (n = 43) courses of interferon-alpha. The responses were correlated with pretreatment viremic levels assessed by a branched DNA assay and genotypes. RESULTS: After the 28-week interferon-alpha course, sustained aminotransferase normalization showed correlation with a lower initial viral load. The normalization was achieved by 78% (7/9) of the low viremic (branched DNA-negative) patients, but only 22% (8/36) of the highly viremic (branched DNA-positive) patients (p < 0.01). Treatment with the 52-week interferon-alpha course increased the incidence of a sustained response in highly viremic patients and led to a decrease in relapse after therapy withdrawal (p < 0.05). Thus, 75% (6/8) of the low viremic patients and 49% (17/35) of the highly viremic patients showed a sustained response. The data further showed that frequent sustained responses in patients with genotypes III and IV were associated with a low initial viral load. CONCLUSIONS: These findings suggest that although the pretreatment viral load is an important virological factor for predicting responses to interferon in chronic hepatitis C, relapse in highly viremic patients may be prevented by long-term therapy.

Adult↗
PubMed1995

Improvement of liver fibrosis in chronic hepatitis C patients treated with natural interferon alpha.

To investigate the histological change (change of liver fibrosis) produced by the anti-viral effect of interferon on hepatitis C virus, 40 patients with chronic hepatitis C treated with natural interferon alpha were divided according to the existence of viremia at the end of treatment and 6 months after the end of treatment. The condition of liver fibrosis was scored numerically with a new "hepatic fibrosis score" which is sensitive to more subtle changes than Knodell's fibrosis score. Each portal zone was evaluated separately. End-of-treatment biopsy for the HCV RNA-negative group (negative for HCV RNA at the end of treatment) showed a significant improvement of the "hepatic fibrosis score" as well as the alleviation of necrosis and inflammation. At the end of treatment and 6 months after that, serum procollagen type III peptide levels and serum type IV collagen-7s levels had also decreased significantly in the HCV RNA-negative group. The present study showed that treatment with interferon alpha could alleviate fibrosis in addition to necrosis and inflammation.

Adult↗
PubMed1995

High prevalence of atrial fibrosis in patients with dilated cardiomyopathy.

OBJECTIVES: We examined the extent of fibrotic changes in the left atrium of cardiomyopathic human hearts and investigated the relation of mechanical overload caused by left ventricular dysfunction to fibrosis of the left atrium. BACKGROUND: Left atrial dysfunction in dilated cardiomyopathy may contribute to progression of heart failure. In contrast to fibrosis of the left ventricle, atrial fibrosis has not been extensively studied in cardiomyopathic hearts. METHODS: The extent of fibrosis in the left atrium and left ventricle was determined by an automatic image analyzer in 38 autopsied hearts obtained from 9 patients who died of noncardiac illness (control group), 16 patients with dilated cardiomyopathy, 6 patients with hypertrophic cardiomyopathy with features mimicking dilated cardiomyopathy and 7 patients with a previous myocardial infarction. Transverse sections were obtained at the upper margins of the foramen ovale and left auricle in the left atrium and the median level of the left ventricle. RESULTS: There were no significant differences in extent of left atrial dilation, left ventricular dysfunction or duration of illness among the three groups with cardiac disease. Percent area of left atrial fibrosis (mean +/- SD) was significantly greater in the specimens from patients with dilated cardiomyopathy (13.1 +/- 6.1%, p < 0.01) and hypertrophic cardiomyopathy mimicking dilated cardiomyopathy (26.5 +/- 9.5%, p < 0.01) than in those from patients with an old myocardial infarction (3.8 +/- 1.1%). Percent area of left ventricular fibrosis in hearts from patients with dilated cardiomyopathy (12.9 +/- 8.6%) was significantly smaller than that in hearts from patients with hypertrophic cardiomyopathy mimicking dilated cardiomyopathy (35.8 +/- 11.9%, p < 0.01) and a previous myocardial infarction (38.4 +/- 8.0%, p < 0.01). Percent area of atrial fibrosis was significantly correlated with left ventricular ejection fraction in the group with a previous myocardial infarction but not in the other groups. CONCLUSIONS: There was a high degree of fibrotic change in the left atrium in the groups with dilated cardiomyopathy and hypertrophic cardiomyopathy mimicking dilated cardiomyopathy. Our findings suggest that atrial fibrosis in these patients may not have been related to mechanical overload of the left atrium but to some other, still unknown mechanisms.

Adult↗