Shin-ichiro Morimoto

Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone

Cardiac involvement is an important prognostic factor in sarcoidosis, but reliable indicators of mortality risk in cardiac sarcoidosis are unstudied in a large number of patients. To determine the significant predictors of mortality and to assess the efficacy of corticosteroids, we analyzed clinical findings, treatment, and prognosis in 95 Japanese patients with cardiac sarcoidosis. Twenty of these 95 patients had cardiac sarcoidosis proven by autopsy; none of these patients had received corticosteroids. We assessed 12 clinical variables as possible predictors of mortality by Cox proportional hazards model in 75 steroid-treated patients. During the mean follow-up of 68 months, 29 patients (73%) died of congestive heart failure and 11 (27%) experienced sudden death. Kaplan-Meier survival curves showed 5-year survival rates of 75% in the steroid-treated patients and of 89% in patients with a left ventricular ejection fraction > or = 50%, whereas there was only 10% 5-year survival rate in autopsy subjects. There was no significant difference in survival curves of patients treated with a high initial dose (> 30 mg) and a low initial dose (> or = 30 mg) of prednisone. Multivariate analysis identified New York Heart Association functional class (hazard ratio 7.72 per class I increase, p = 0.0008), left ventricular end-diastolic diameter (hazard ratio 2.60/10 mm increase, p = 0.02), and sustained ventricular tachycardia (hazard ratio 7.20, p = 0.03) as independent predictors of mortality. In conclusion, the severity of heart failure was one of the most significant independent predictors of mortality for cardiac sarcoidosis. Starting corticosteroids before the occurrence of systolic dysfunction resulted in an excellent clinical outcome. A high initial dose of prednisone may not be essential for treatment of cardiac sarcoidosis.

Histologic diagnostic rate of cardiac sarcoidosis: Evaluation of endomyocardial biopsies

BACKGROUND An early diagnosis of cardiac sarcoidosis is important, particularly when considering the need for administering corticosteroid therapy. However, no reports are available on the success rate of diagnosis on the basis of biopsy findings in patients with cardiac sarcoidosis. This study investigated the diagnostic success rate of histologic evaluation of endomyocardial biopsy specimens in patients with this disease. METHODS AND RESULTS Right ventricular endomyocardial biopsy was performed in 26 patients in whom cardiac sarcoidosis was strongly suspected according to the Diagnostic Criteria of Sarcoidosis, plus abnormalities on the electrocardiogram, cardiac radionuclide images, or in left ventricular wall motion. A mean of 4.0 sites were sampled per patient. In each case we determined whether a definitive diagnosis of cardiac sarcoidosis could be made histologically. Noncaseating granulomas were found in only 5 (19.2%) of the 26 cases, thus permitting a histologic diagnosis of cardiac sarcoidosis. A histologic diagnosis was made in 4 (36.4%) of 11 patients who exhibited a dilated cardiomyopathy-like clinical picture, in contrast to only 1 (6.7%) of 15 patients in whom conduction disturbances were the major clinical feature and whose left ventricular ejection fraction was within normal limits. CONCLUSIONS The diagnostic rate achieved with biopsy in cardiac sarcoidosis is low; the patients with sarcoidosis and evidence of significant cardiac involvement should be treated for cardiac sarcoidosis despite negative myocardial biopsies for this disease.

Comparison of clinical features and prognosis of cardiac sarcoidosis and idiopathic dilated cardiomyopathy

In the present study, clinical findings of 15 patients with cardiac sarcoidosis presenting as dilated cardiomyopathy were compared with those of 30 consecutive patients with idiopathic dilated cardiomyopathy. The sarcoidosis patients had different clinical features, including female predominance, a high incidence of grave conduction disturbance and abnormal wall thickness, uneven wall motion abnormalities, and perfusion defects preferentially affecting the anteroseptal and apical regions, and poor prognosis compared with those with idiopathic dilated cardiomyopathy.

Use of percutaneous cardiopulmonary support of patients with fulminant myocarditis and cardiogenic shock for improving prognosis.

Percutaneous cardiopulmonary support was used in 9 patients with fulminant myocarditis and cardiogenic shock. Although 2 of the patients died, 7 improved and were able to resume social activities. Percutaneous cardiopulmonary support should be administered routinely to patients with fulminant myocarditis developing into cardiogenic shock.

Diagnostic utility of tenascin‐C for evaluation of the activity of human acute myocarditis

Tenascin‐C (TN‐C) is an extracellular matrix protein that is expressed transiently in close association with tissue remodelling in various body sites. In the heart, TN‐C is only present during early stages of development, is not expressed in the normal adult, but reappears in pathological states. The purpose of this study was to analyse the expression of TN‐C in myocardial tissue from myocarditis patients, and to evaluate the diagnostic value of immunostaining for TN‐C in the assessment of inflammatory activity in biopsy specimens. A total of 113 biopsy specimens obtained from 32 patients with a clinical diagnosis of acute myocarditis were examined by immunohistochemistry and in situ hybridization for TN‐C. The immunostaining was semi‐quantified and compared with histological diagnosis according to the Dallas criteria. Furthermore, serial biopsies from 22 patients were taken during convalescence, and sequential changes in TN‐C levels were analysed. Expression of TN‐C was specifically detected in endomyocardial biopsy specimens from patients with active‐stage inflammation, and disappeared in healed stages. The degree of expression of TN‐C correlated with the severity of histological lesions. These data suggest that TN‐C reflects disease activity in cases of human myocarditis. Immunostaining for TN‐C could enhance the sensitivity and accuracy of diagnosis using biopsy specimens. Copyright

Can β-blocker therapy be withdrawn from patients with dilated cardiomyopathy? ☆ ☆☆ ★

Abstract Background It has yet to be determined whether withdrawing β-blocker therapy from patients with dilated cardiomyopathy (DCM) is safe. Methods The influence of tapering and then stopping metoprolol was clarified in 13 patients with DCM who had been receiving this agent for ≥30 months. Results Seven of the 13 patients deteriorated, including 4 who died suddenly or of congestive heart failure during the 4-month period after metoprolol cessation. Conclusion In patients with DCM in whom β-blocker therapy is effective, withdrawal of these agents may lead to death. We conclude that β-blockers should not be stopped in this patient group. (Am Heart J 1999;137:456-9.)

Histopathologic and ultrastructural observations of acute and convalescent myocarditis: A serial endomyocardial biopsy study

SummarySerial endomyocardial biopsy findings were analyzed in ten cases with acute myocarditis of possible viral origin. The histopathologic findings were analyzed at the acute (0–10 days after the onset), subacute (11–21 days), and convalescent stages (22–167 days). The incidence and severity of various cardiac myocyte and interstitial changes were compared at each stage of the disease.The time-course changes of the histopathologic findings in acute myocarditis were as follows. At the acute stage, we observed: (1) interstitial cell infiltration composed of fibroblasts, macrophages, and lymphocytes, (2) fragmentation of the muscle bundles, (3) myocytolytic changes, (4) swelling and scarcity of the cytoplasm and swelling of nuclei, (5) variation in size of the myocytes, (6) disarrangement of the muscle bundles, (7) interstitial edema, (8) increased glycogen deposition in the myocytes, (9) abnormal branching of the myocytes, and (10) interstitial fibrosis. At the convalescent stage, most of the above findings could still be seen except for myocytolytic changes, swelling of myocytes, and interstitial edema. At the subacute and convalescent stages, an increase in abnormal branching and in double nuclei in the myocytes and nuclear degeneration became observable. A further control study comparing the changes at the convalescent stage of myocarditis and the myocardial changes in cases with chronic right ventricular overload in 58 cases revealed that in the former fragmentation of the muscle bundles, abnormal branching, size variation, glycogen deposition, and large mononuclear cell infiltrations were significantly more frequent.Ultrastructural observation of the myocytes revealed that they have a great potentiality for regeneration; myocytes showing severe myocytolytic changes may recover to regain an architecture of almost normal appearance.

Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles.

PURPOSE Sarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles. METHODS In our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects. RESULTS In the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis. CONCLUSIONS Our studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.

Changes in the peripheral eosinophil count in patients with acute eosinophilic myocarditis

In many cases, the diagnosis of eosinophilic myocarditis is suggested by an elevated peripheral blood eosinophil count. However, no detailed studies have been performed on the sequential changes in the initial peripheral blood eosinophil count over the course of the disease. We measured the peripheral blood eosinophil count at the time of presentation in eight patients with eosinophilic myocarditis proven by endomyocardial biopsy and intermittently thereafter. The eosinophil count at the time of onset was ≪500/mm3 in four patients, ≫500/mm3 but ≪1 000/mm3 in three patients, and ≧1 000/mm3 in one patient. In three of the four patients with an initial eosinophil count of ≪500/mm3, an increase to ≧500/mm3 occurred 7–12 days after the onset. The remaining patient did not develop peripheral eosinophilia. In conclusion, in the early stage of eosinophilic myocarditis, peripheral hypereosinophilia is not present initially in some patients, and may not develop during the course of the illness in a subset of these patients.

Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure

It has been reported that angiotensin converting enzyme (ACE) 2, a homologue of ACE, has direct effects on cardiac function. However, the role of ACE2 in the development of human heart failure is not fully understood. We evaluated the expression of the ACE2 gene by means of real-time RT-PCR in myocardium from 14 patients with end-stage heart failure. The amount of ACE2 mRNA positively correlated with left ventricular (LV) end-diastolic diameter (r(2)=0.56, p<0.01) but did not significantly correlate with LV ejection fraction or plasma brain natriuretic peptide levels. In conclusion, our data show that the up-regulation of the ACE2 gene in the LV myocardium of patients with severe heart failure was associated with the degree of LV dilatation and may thereby constitute an important adaptive mechanism to retard the progression of adverse LV remodeling.