Akihisa Uemura

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.

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

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.

Role of myocardial interstitial edema in conduction disturbances in acute myocarditis

The presence of myocardial interstitial edema in acute myocarditis (AM) leads to thickening of the ventricular wall, and conduction disturbances, such as complete atrioventricular block (CAV), also frequently develop. This study was undertaken in order to clarify the relationship between conduction disturbances and myocardial interstitial edema in AM. The subjects comprised 50 patients with acute lymphocytic myocarditis. Based on the results of echocardiographic examinations during the acute stage, the patients were divided into a hypertrophy group (n = 29) in which the sum of the thickness of the interventricular septum and left ventricular (LV) posterior wall was ≥24 mm, and a non-hypertrophy group (n = 21) in which the sum of these parameters was <24 mm. Right ventricular endomyocardial biopsies were performed in the acute stage and the degree of interstitial edema was scored histologically. Left ventricular wall thickness and QRS duration in the acute stage were 27.7 ± 3.6 mm and 124.1 ± 29.6 ms, respectively, in the hypertrophy group, and 19.9 ± 2.4 mm (P < 0.001) and 98.6 ± 21.7 ms (P < 0.01) in the non-hypertrophy group. Complete atrioventricular block was found in 13 of 29 cases (45%) in the hypertrophy group and two of 21 cases (10%) in the non-hypertrophy group (P < 0.01). Myocardial interstitial edema was scored at 1.3 ± 0.8 points in the hypertrophy group and 0.8 ± 0.6 points in the non-hypertrophy group (P < 0.05). Left ventricular wall thickness and QRS duration in the convalescent stage decreased to 21.1 ± 2.6 mm (P < 0.0001) and 97.1 ± 17.4 ms (P < 0.01) in the hypertrophy group, respectively. Only one case (4%) in the hypertrophy group continued to show CAV during the convalescent stage (P < 0.05). The results of this study suggest that myocardial interstitial edema is implicated in the conduction disturbances that occur in AM.

Feasibility of diagnosing chronic myocarditis by endomyocardial biopsy

SummaryIn studies of all the layers of autopsied hearts from patients with chronic myocarditis, local clusters of lymphocytes are frequently noted, in contrast with hearts obtained from patients with acute myocarditis. Myocardial biopsy specimens, however are no larger than about 2mm×3mm. With this in mind, the present study was undertaken to determine whether chronic myocarditis can be diagnosed by endomyocardial biopsy. Specimens were obtained from seven patients in whom chronic myocarditis was confirmed by the clinical course and by autopsy findings. In H&E stained specimens, sites corresponding to the biopsy sites in both ventricles (right ventricular free wall, right ventricular side of the ventricular septum, left ventricular lateral wall) were selected at random (five sites each from the right and left ventricles in each patient) and examined under a light microscope. A mean of 5 or more lymphocytes per visual field (by light microscopy at 400-fold magnification), a proposed quantitative diagnostic criterion of myocarditis, was noted in the right ventricle in three patients (5 lymphocytes in two patients and 6 in one patient) and in the left ventricle in one patient (5 lymphocytes). Also, when the presence of lymphocyte clusters, considered to be a characteristic feature of chronic myocarditis, was determined, clusters of 20 or more lymphocytes per visual field were found in the same patients as those mentioned above, namely, in three patients (42.8%) in the right ventricle, as mentioned above, and in one patient (14.3%) in the left venricle. At the sites of these lymphocyte clusters, findings such as degenerative changes of the myocardial cells and interstitial fibrosis were also associated, making possible a diagnosis of myocarditis. Therefore, in chronic myocarditis, even if five specimens are obtained by right ventricular biopsy, in approximately one half of patients the diagnosis of chronic myocarditis will be missed because of sampling errors.

Successful high-dose intravenous immunoglobulin therapy for a patient with fulminant myocarditis.

A 45-year-old man developed fulminant myocarditis for which ventricular assist devices (intra-aortic balloon pumping and percutaneous cardiopulmonary support) were required for hemodynamic support. Echocardiography showed left ventricular akinesis and, since no improvement was noted on the following day, immunoglobulin (70 g/day for 2 days) was added to the therapy. The left ventricular ejection fraction increased to 25% and 40% at 12 and 36 h, respectively, representing a marked improvement in wall motion within a very short period. An endomyocardial biopsy specimen revealed focal lymphomononuclear infiltrate with adjacent myocytolysis, and acute lymphocytic myocarditis was diagnosed. Two days after administration of immunoglobulin, the serum level of interleukin-6 decreased rapidly from 180 to 5.9 pg/ml. In this patient, cardiac function improved immediately after immunoglobulin administration, suggesting the usefulness of this therapy. Three years after the diagnosis the patient is in good health, with steady normal left ventricular ejection fraction. We conclude that there are cases of acute myocarditis in which high-dose intravenous immunoglobulin therapy is effective.

Contribution of cardiac muscle cell disorganization to the clinical features of hypertrophic cardiomyopathy

Abstract Heart failure rarely develops in the setting of hypertrophic cardiomyopathy (HCM). Because of this, cardiac muscle cell disorganization (CD), which is a histologic characteristic of HCM, is not believed to be responsible for the development of systolic dysfunction. The aim of the present study was to clarify whether CD can cause systolic dysfunction and ventricular dilation in patients with HCM. Sixteen hearts from patients with HCM obtained at autopsy were divided into two groups: group A (n = 11), without biventricular dilation, and group B (n = 5), with dilation. Specimens consisting of transverse and longitudinal tissue sections of the ventricles were prepared, and the extent of CD and interstitial fibrosis was quantified, using light microscopy. None of the patients in group A had had chronic congestive heart failure, while all of the patients in group B had died of congestive heart failure. In group B, CD was not limited to the interventricular septum. Rather, diffuse CD was observed in both ventricular free walls. The extent of CD was significantly greater in group B than in group A, while the degree of interstitial fibrosis was similar in the two groups (13.6% in group A vs 14.6% in group B). These results suggest that CD may be responsible for systolic dysfunction and ventricular dilation.

Lesions in side branches of arteries having undergone percutaneous transluminal coronary angioplasty: A histopathologic study

Percutaneous transluminal coronary angioplasty (PTCA) may cause occlusion in side branches. No histologic studies, however, have been made on side branches of the arteries in which PTCA has been performed. A histologic study was therefore made to explain the effect of PTCA on side branches. Histologic specimens were prepared by serial step sectioning from 15 side branches of 10 autopsied cases that had undergone PTCA. The results of examination by light microscope were as follows: (1) Stenoses due to PTCA were seen in seven branches (46.7%). (2) The stenoses were classified into three types: (a) stenosis due to blocking of the orifice of a side branch by the disrupted portion of the intima of the main artery (one branch); (b) stenosis due to medial dissection of the main artery or further dissection occurring even in the side branches (three branches); and (c) stenosis due to fragmentation of the internal elastic lamina of the main artery accompanied by proliferation of smooth muscle cells even in the side branch (three branches). It is now clear that stenosis is caused in side branches long after PTCA. Extra care is required when major side branches exist in the portion where this procedure is to be performed.

Significance of transient left ventricular wall thickening in acute lymphocytic myocarditis

Transient left ventricular (LV) wall thickening is observed in patients with acute lymphocytic myocarditis. The present study was undertaken to clarify the significance of transient LV wall thickening in patients with this disease. The subjects comprised 25 patients with acute lymphocytic myocarditis. Echocardiography was used to measure the thickness of the interventricular septum (IVS) and the LV posterior wall (PW) at four time points after myocarditis onset – namely, on days 1–3, 6–8, 13–15, and 28–30 – to clarify the timing and frequency of wall thickening. The 25 patients were divided into a fulminant myocarditis group (n = 14) and a nonfulminant myocarditis group (n = 11), and the relationship between LV wall thickening and myocarditis severity was investigated. Left ventricular wall thickening was greatest on days 1–3 after myocarditis onset (IVS: 13.3 ± 3.2 mm; PW: 12.1 ± 2.6 mm), with this finding being noted in 14 of the 25 cases (56%). By days 6–8, the thickness of IVS had virtually normalized to 10.6 ± 1.6 mm (P < 0.0001) and that of PW to 10.2 ± 1.4 mm (P = 0.0006). The thickness of the IVS and PW on days 1–3 after myocarditis onset were 14.6 ± 3.7 and 13.0 ± 2.9 mm, respectively, in the fulminant group (P = 0.014), and 11.5 ± 0.9 and 10.9 ± 1.4 mm, respectively, in the nonfulminant group (P = 0.039). In lymphocytic myocarditis, LV wall thickening is greatest on days 1–3 after myocarditis onset and improves to near normal by days 6–8. Such transient LV wall thickening occurs in approximately 50% of cases. Left ventricular wall thickening was more marked in the fulminant compared with the nonfulminant group.

Febuxostat (Feburic tablet) in the management of hyperuricemia in a general practice cohort of Japanese patients with a high prevalence of cardiovascular problems

Abstract Hyperuricemia is increasing in prevalence and this is paralleled by an increased incidence of acute gout. In addition, there is growing evidence of an association between high serum levels of uric acid (sUA) and cardiovascular disease (CVD). In this preliminary report, we present 12–16 week results from a multicenter, general practice study in which we evaluated the usefulness of febuxostat in a cohort of untreated patients with hyperuricemia with a high prevalence of CVD. Febuxostat titrated from 10 mg/day up to 40 mg/day resulted in statistically significant and clinically relevant reductions in sUA after 12–16 weeks. A “responder” level of 6.0 mg/dL or lower was achieved in 95 of 100 (95%) patients. Significant reductions in sUA were achieved regardless of the presence/absence of coexisting diseases (e.g. CVD, renal insufficiency, diabetes and obesity) or the class of antihypertensive agent being used by the patient. No serious adverse reactions were noted with febuxostat. Although allopurinol has been used generally for hyperuricemia/gout, it is excreted fully via the kidneys, restricting its use in patients with reduced renal function, and its three-times-daily administration leads to poor adherence. Based on the results of this study, febuxostat may provide an easier option than allopurinol for clinicians specializing in CVDs.