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

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.

The effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis in Japanese patients with dyslipidemia.

AIM: To demonstrate the clinical benefit of inhibiting intestinal cholesterol absorption, we evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis, lipid and glucose metabolism, and markers of obesity and inflammation. METHODS: A total of 120 patients with dyslipidemia (46 men; mean age 66.5 years), who had not achieved the low density lipoprotein cholesterol (LDL-C) goal recommended by the Japan Atherosclerosis Society Guideline despite diet and exercise or any statin therapy, were enrolled and additionally treated with ezetimibe (10 mg/day) for 12 weeks. RESULTS: Compared to the baseline, LDL-C was reduced by 19.2% (p<0.001) after ezetimibe monotherapy and by 24.7% (p<0.001) after co-administration with ezetimibe and any statin. Ezetimibe therapy decreased cholesterol absorption markers and increased a cholesterol synthesis marker. Treatment with ezetimibe reduced the fasting serum insulin level (p<0.05) and HbA1c (p<0.05), increased serum adiponectin (p<0.01), and showed a significant decrease of high-sensitive C-reactive protein (hsCRP, p<0.01). No adverse events occurred during the study. CONCLUSION: Thus, cholesterol absorption inhibition by ezetimibe is an important therapeutic strategy since LDL-C and cholesterol absorption markers had a positive correlation. Ezetimibe not only reduced the serum LDL-C level but also improved glucose metabolism as well as obesity and inflammation markers. These findings support the benefit of ezetimibe as a new option for the treatment of dyslipidemia.

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.

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.

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 >or=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.

Clinical course of myocarditis through the acute, fulminant and fatal chronic stages: an autopsy case.

Most patients with acute myocarditis manifest particular clinical signs and symptoms, including marked cardiac failure and/or a high degree of atrioventricular block on admission. However, a 78-year-old man did not have symptoms and was hospitalized as a result of abnormalities observed on an incidentally obtained electrocardiogram (ECG). Several days later, he developed cardiogenic shock and fulminant myocarditis, which required percutaneous cardiopulmonary support; however, the cardiac failure persisted and he died approximately 4 months later. The ECG showed findings similar to those of acute inferior myocardial infarction, and on left ventriculography, diffuse hypokinesis was observed most prominently in the inferoposterior wall. During autopsy, interstitial fibrosis was marked in the inferoposterior wall, with small, round, cell infiltration prominent at the same site. Clustering of these cells is a characteristic feature of chronic myocarditis.

Relief of left ventricular outflow obstruction by cibenzoline in a patient with Fabry's disease--a case report.

A 46-year-old man was admitted for further evaluation of exertional chest discomfort. One family member had experienced sudden death, and 2 others had died of heart failure, including 1 known to have had Fabry's disease. The patient was also diagnosed with Fabry's disease, based on reduced leukocyte alpha-galactosidase A activity, 2.0 nmol/mg protein/hour, as well as endomyocardial biopsy findings of marked sarcoplasmic vacuolization of cardiac muscle cells by light microscopy and lamellated "zebra bodies'' in the cytoplasm shown by electron microscopy. Echocardiography disclosed marked left ventricular hypertrophy and systolic anterior motion of the mitral leaflets. On cardiac catheterization, a left ventricular peak systolic outflow gradient of 50 mm Hg was noted; this decreased to 10 mm Hg following intravenous administration of 100 mg of cibenzoline. It is imperative to recognize the existence of cases with Fabry's disease associated with left ventricular outflow obstruction.

National survey on status of steroid therapy for cardiac sarcoidosis in Japan.

AIM: This investigation was undertaken to clarify the current status of steroid therapy for cardiac sarcoidosis in Japan. METHODS: A questionnaire survey was conducted throughout Japan concerning cases in which steroid therapy had been administered. Replies describing 52 cases (15 men, 37 women; mean age +/- SD, 59.8 +/- 14.5 years) were analyzed. RESULTS: Of the 49 patients whose New York Heart Association (NYHA) functional classification was reported, 29 (55.8%) were in class I; 13 (25.0%) class II; 4 (7.7%) class III and 3 (5.8%) class IV. The most common initial steroid dose (used in 35 cases, or 67.3%) was 30 mg/day or 60 mg on alternate days. In most cases (85.4%), this dose was continued for 1 month followed by tapering by 5 mg every 2 to 4 weeks until reaching the maintenance dose of 5 to 10 mg/day. Steroid therapy was reported to result in improvement in 54%, no change in 40%, and deterioration in 6%. CONCLUSION: This nationwide questionnaire survey indicated fairly uniform patterns of steroid therapy for cardiac sarcoidosis in Japan, with clinical improvement in over one-half of cases and possible stabilization in most others.

Relationship between basal thinning of the interventricular septum and atrioventricular block in patients with cardiac sarcoidosis.

BACKGROUND: Basal thinning of the interventricular septum (IVS) and atrioventricular block (AVB) are characteristic features of cardiac sarcoidosis. Since the conduction system passes along IVS, it has been considered that a close connection exists between basal thinning of IVS and AVB. However, neither the incidence of cases showing basal thinning of IVS nor the relation between it and AVB has been clarified. We thus investigated to elucidate these two issues. METHODS: Thirty-five patients with cardiac sarcoidosis were selected for this study and underwent echocardiographic examination. The wall thickness of IVS was measured at a site 1 cm below the aortic valve inserted point of IVS. Thickness of this site < or = 5 mm was defined as thinning. Twelve-lead and Holter electrocardiograms were obtained to determine the presence/absence and degree of AVB. RESULTS: Basal thinning of IVS was noted in 7 of the 35 patients (20%). AVB was present in 4 of these 7 (57%), and was first degree in 3 (43%) and third degree in one (14%). AVB was not present in 3 patients. Basal thinning of IVS was not apparent in 28 of the 35 patients (80%). AVB was observed in 14 of the 28 patients, 3 had first degree block, 2 had second degree block, and 9 had third degree block. AVB was not observed in 14 of the 28 patients. CONCLUSIONS: These results clarified that basal thinning of IVS is not as common as previously thought in cardiac sarcoidosis, basal thinning of IVS and the presence/absence and degree of AVB are not necessarily correlated.

An autopsy case of Brugada syndrome with significant lesions in the sinus node.

A 30-year-old man with Brugada syndrome died suddenly. The heart weighed 380 g. The left ventricular wall showed mild thickening, and marked fatty tissue deposition was noted in the right ventricular outflow tract. Neither ventricle was enlarged. Contraction band necrosis was diffuse in both ventricles. In the ventricles no cardiac muscle cell hypertrophy or atrophy, or significant interstitial fibrosis was observed. In the sinus node the number of nodal cells was reduced by half, with fatty tissue and fibrosis prominent. But no lesions were evident in the right bundle branch.

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.

Suppressed expression of GTP cyclohydrolase I mRNA and accelerated expression of inducible nitric oxide synthase mRNA in endomyocardial biopsy specimens from patients with dilated cardiomyopathy.

BACKGROUND: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase, and GTP cyclohydrolase I (GCHI) is a rate-limiting enzyme in the biosynthesis of BH4. The expression of inducible nitric oxide synthase (iNOS) was earlier demonstrated in the ventricles of patients with dilated cardiomyopathy (DCM) although that of GCHI was not clarified. The present study was designed to determine the GCHI mRNA expression as well as to confirm iNOS mRNA expression in endomyocardial biopsy specimens from patients with DCM. METHODS: Clinical details were assessed in 19 patients with DCM and in 9 control subjects. The real-time reverse transcription polymerase chain reaction (PCR) was performed on total RNA extracted from endomyocardial biopsy specimens. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was quantified for use as an internal control. RESULTS: iNOS/GAPDH for the DCM samples was 4.8-fold greater than that for the control ones (P<0.01), whereas the GCHI/GAPDH for the DCM samples was reduced to 31.1% of the control (P<0.05). CONCLUSIONS: The increased expression of iNOS mRNA was confirmed in endomyocardial biopsy specimens from patients with DCM. The GCHI mRNA level was suppressed in these specimens.

Risk factors for patients developing a fulminant course with acute myocarditis.

BACKGROUND: A fulminant course can be difficult to predict at the onset of acute myocarditis, so the aim of the present study was to identify the predictive clinical symptoms/signs or laboratory findings. METHODS AND RESULTS: Thirty-nine patients with acute lymphocytic myocarditis, excluding 8 who manifested shock at admission, were studied. The fulminant group was defined as 12 patients who developed shock after admission, requiring intraaortic balloon pumping or percutaneous cardiopulmonary support, and the non-fulminant group comprised the 27 patients without shock. Various parameters at admission were compared between the 2 groups, together with multiple logistic regression analysis, excluding 6 patients with partially missing values. In the fulminant group, C-reactive protein (7.0 +/- 7.0 vs 2.3 +/- 2.2 mg/dl, p<0.01) and creatine kinase (1,147 +/- 876 vs 594 +/- 568 IU/L, p<0.05) concentrations were higher, intraventricular conduction disturbances were more frequent (9/12 vs 7/27 patients, p<0.01) and the left ventricular ejection fraction was lower (40.7 +/- 13.9 vs 50.1 +/- 10.6%, p<0.05) than in the non-fulminant group. In the multiple logistic regression analysis model with the presence/absence of a fulminant course considered as the independent variable, and C-reactive protein, creatine kinase, intraventricular conduction disturbances, and left ventricular ejection fraction as dependent variables, a high-risk group (expected proportion of fulminant course > or = 0.5) and a low-risk group (<0.5) could be differentiated. A fulminant course occurred in 9/13 (69%) patients in the high-risk group, but in only 2/20 (10%) patients in the low risk group (p<0.001). CONCLUSIONS: The risk of a fulminant course of acute myocarditis was high in patients with elevated C-reactive protein, and creatine kinase concentrations, decreased left ventricular ejection fraction, and intraventricular conduction disturbances at the time of admission.

Right ventricular endomyocardial biopsy findings in 25 patients with sick sinus syndrome.

A variety of myocardial lesions have been demonstrated in atrial muscle in patients with sick sinus syndrome (SSS), but the right ventricular myocardium has not been studied in detail in a large series. Therefore, we performed right ventricular endomyocardial biopsies in 25 patients with SSS (SSS group), and the presence or absence of ventricular myocardial lesions was determined histologically. As a control, biopsies of corresponding sites in 12 normal autopsied hearts were obtained (N group). The mean cardiac myocyte transverse diameter was 14.2 +/- 3.6 microm in the SSS group and 11.7 +/- 3.1 microm in the N group (P < 0.01). In the SSS group, cardiac myocyte hypertrophy was observed in 20 of 25 subjects (80%), and myocyte size variation was more frequent. Although the difference was not significant, myocyte disorganization, myocytolysis, nuclear deformity, interstitial large mononuclear cell proliferation, and endocardial lesions, which were not seen in the N group, were observed in the SSS group. A variety of myocardial lesions, including cardiac myocyte hypertrophy, are present not only in atrial, but also in ventricular muscle in SSS.

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/mm(3) in four patients, >500/mm(3) but <1,000/mm(3) in three patients, and > or =1,000/mm(3) in one patient. In three of the four patients with an initial eosinophil count of <500/mm(3), an increase to > or =500/mm(3) 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.

Cardiac muscle cell disorganization in apical hypertrophic cardiomyopathy: a cardiac biopsy study.

Apical hypertrophic cardiomyopathy has been divided into two entities: apical asymmetric septal hypertrophy (apical ASH) and apical symmetric hypertrophy (AH). The latter differs clinically from hypertrophic cardiomyopathy (HCM) with ASH, and it is unclear whether AH represents a distinct subtype of HCM. In the present study, the presence or absence and the extent of cardiac muscle cell disorganization, a histologic characteristic of HCM, were compared in patients with AH (n = 10) and ASH (n = 29) in whom cardiac biopsy specimens were obtained from the left ventricular apex and interventricular septum. Disorganization was graded as (1+) in only 1 patient in the AH group and (-) in the remaining 9. In contrast, in the ASH group disorganization was graded as (1+) in 15 patients, (2+) in 7, (3+) in 3, and (-) in only 4 (P < 0.0001). Thus, it was observed that in AH disorganization is virtually absent or at most limited to a very narrow area. It is concluded from a histological stand point as well that the type of apical hypertrophic cardiomyopathy showing apical symmetric hypertrophy differs from usual HCM.

Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block.

BACKGROUND: The usefulness of corticosteroid therapy for cardiac sarcoidosis has not yet been fully clarified. METHODS: Of 40 patients diagnosed with cardiac sarcoidosis, twenty patients complicated by atrioventricular block but normal cardiac function (left ventricular ejection fraction > or = 50%) were divided retrospectively into one group (n = 7) receiving corticosteroids and another (n = 13) not receiving these agents. Over a mean observation period of 79.4 +/- 39.9 months, long-term outcome and laboratory findings were compared between the two groups and side effects also were noted. RESULTS: There were no deaths in the corticosteroid-treated group. In the untreated group, 2 patients died (15.4%). Atrioventricular block resolved in 4 of the 7 patients in the treated group (57.1%), but did not resolve or improve in any of the untreated patients (p < 0.05). Left ventricular ejection fraction did not differ significantly between the treated and untreated groups at the time of initial evaluation (66.7 +/- 6.5% vs. 60.5 +/- 6.4%). In the follow-up period, a marked decline in the ejection fraction had occurred in the untreated group (37.6 +/- 17.3%), but not in the treated group (62.1 +/- 4.4%; p < 0.005). Ventricular tachycardia was not present at the initial assessment in any patient in either group. In the follow-up period, ventricular tachycardia occurred in only 1 of 7 treated patients (14.3%), but was present in 8 of 13 untreated patients (61.5%; p < 0.05). However, side effects of corticosteroid therapy were noted in 6 of the 7 treated patients (85.7%). CONCLUSION: Our findings suggest that corticosteroids are useful in the treatment of cardiac sarcoidosis complicated by atrioventricular block but with normal cardiac function. However, these agents must be used with caution, with the maintenance dose kept as low as possible.

Narrowing of the left ventricular cavity associated with transient ventricular wall thickening reduces stroke volume in patients with acute myocarditis.

It has been reported that some patients with acute myocarditis have transient ventricular thickening associated with narrowing of the left ventricular cavity caused by interstitial edema. The present study investigated this phenomenon in 20 patients with acute myocarditis. Based on the sum of the interventricular septal wall thickness and left ventricular posterior wall thickness (IVST + PWT), measured by M-mode echocardiography, patients were divided into group A (IVST + PWT >/=25 mm, n=12) and group B (IVST + PWT <25 mm, n=8). The IVST + PWT was 31.8 +/-3.5 mm in group A and 21.9+/-2.7 mm in group B (p<0.0001). The left ventricular end-diastolic dimension (LVDd) was 42.3+/-6.0 mm in group A and 49.4+/-6.7 mm in group B (p<0.05). The stroke volume (SV) was 41.1+/-20.5 ml and 73.0+/-32.3 ml in groups A and B, respectively (p<0.05). The left ventricular ejection fraction (LVEF) was similar in group A (47.9+/-13.0%) and group B (56.9+/-9.0%). The SV correlated inversely with IVST + PWT (r=-0.62, p<0.01), and directly with both the LVDd (r=0.95, p<0.0001) and LVEF (r=0.64, p<0.01). The LVDd correlated inversely with IVST + PWT (r=-0.62, p<0.01). In conclusion, the reduction in SV that occurs during the acute phase of myocarditis is not only the result of systolic dysfunction, but also of the concentric left ventricular wall thickening associated with myocardial interstitial edema, which results in narrowing of the left ventricular cavity at end diastole.

[Cardiac sarcoidosis].

Cardiac sarcoidosis induces heart failure death or sudden death in many cases and is thus often associated with a poor prognosis. In Japan 47-78% of sarcoidosis patients die of cardiac lesions. Early diagnosis is important in such cases, and a comprehensive judgment based on the endomyocardial biopsy, echocardiography and nuclear medicine examination findings should be made according to the 'Handbook of the Diagnosis of Cardiac Sarcoidosis'. Once a diagnosis is made the introduction of steroid therapy should be considered. Steroid administration should be conducted referring to the 'Guidelines to the Treatment of Cardiac Sarcoidosis'.