Takayuki Inomata

Rat dilated cardiomyopathy after autoimmune giant cell myocarditis.

One of the possible causes of dilated cardiomyopathy is considered to be a sequel to myocarditis. Two mechanisms have been proposed in the process of progression of myocarditis into dilated cardiomyopathy: one is a persistent viral infection, and the other is an autoimmune myocardial injury. To clarify the possible part played by the autoimmune mechanism in the process, using an animal model, we investigated whether autoimmune myocarditis, exclusively not related to viral infection, might develop into dilated cardiomyopathy. Experimental autoimmune myocarditis was elicited in Lewis rats by immunization with cardiac myosin fraction. Rats of the control group were immunized with ovalbumin. The clinical course was observed over 4 months. Six rats from the myosin-immunized group died during the acute phase and the healing phase, and all those rats had severe myocarditis. All rats that survived until the end of the study showed enlarged and discolored hearts. Aneurysmal changes were observed in the right ventricle during thoracotomy. The ratio of heart weight to body weight of the myosin-immunized group was significantly higher than that of the control group (3.36 +/- 0.49 versus 2.69 +/- 0.06 g/kg, respectively; P < .005). The lengths of the anterior interventricular fissure and the posterior interventricular fissure of the hearts of the myosin-immunized group were significantly longer than those of the control group. The external diameter of the left ventricle of the myosin-immunized group was also significantly larger than that of the control group. Diffuse myocardial muscle loss and replacement fibrosis were the prominent histological findings of the rats of the myosin-immunized group.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic Utility of B-Type Natriuretic Peptide Assessment in Stable Low-Risk Outpatients With Nonischemic Cardiomyopathy After Decompensated Heart Failure

OBJECTIVES We investigated the clinical utility of B-type natriuretic peptide (BNP) assay in stable outpatients with nonischemic dilated cardiomyopathy (NICM) after decompensated heart failure (HF). BACKGROUND Patients with NICM admitted for decompensated HF frequently experience sudden death or redecompensation after hospital discharge. The prognostic value of BNP during hospitalization has been demonstrated. However, clinical utility of BNP in stable outpatient setting has been poorly investigated. METHODS Eighty-three NICM outpatients who were clinically stable in New York Heart Association functional class 1 to 2 for 6 months after discharge for decompensated HF were enrolled, and then followed for an additional 18 months. The main end point was first readmission for decompensated HF or death. B-type natriuretic peptide levels were measured at 3-month intervals from discharge to enrollment, and echocardiographic dimensions at discharge and enrollment. RESULTS Mean discharge BNP level was 210 +/- 148 pg/ml. Twenty-eight patients were readmitted for decompensated HF or suddenly died at a median time of 11 months from the time of discharge. Among various variables including BNP measurements, clinical parameters and echocardiographic dimensions, a 6-month post-discharge BNP of >190 pg/ml was most closely associated with combined event in the Cox proportional hazards model (hazard ratio 2.29; 95% confidence interval 1.42 to 3.56; p = 0.0005), and had the best discriminatory power (area under the receiver operating characteristic curve 0.91, sensitivity 96%; specificity 76%). CONCLUSIONS Even in stable low-risk outpatients with NICM at 6 months after hospital discharge for decompensated HF, BNP assessment predicts a long-term risk of redecompensation.

Anti‐αβ T cell receptor antibody prevents the progression of experimental autoimmune myocarditis

We investigated the effects of anti‐αβ T cell receptor antibody in rat experimental autoimmune myocarditis (HAM), using a new animal model of autoimmune myocarditis characterized by the appearance of multinucleated giant cells. KAM was induced by injecting Lewis rats subcutaneously in the footpads with 1.0 mg of human cardiac myosin in an equal volume of Freunds complete adjuvant (FCA) on days 0 and 7. In experiment 1, we evaluated the effect of long‐term anti‐αβ TCR antibody therapy on prevention of progression of EAM. Long‐term administration of anti‐αβ TCR antibody prevented progression of FAM in a dose‐dependent manner. Flow cytometry performed at the time of sacrifice showed that the percentage of αβ T cells in lymph nodes and spleen was similar in the control group and the group in which almost no histologic evidence of myocarditis was found. In experiment 2, we examined the effects of short‐term therapy. Rats were killed at different stages and pathologic specimens were examined. Short‐term therapy delayed the onset of myocarditis. Results of flow cytometry suggested that impairment of antigen recognition or T cell function by occupancy of the TCR rather than depletion of TCR was the mechanism responsible for suppression of EAM.

Baseline cardiac magnetic resonance imaging versus baseline endomyocardial biopsy for the prediction of left ventricular reverse remodeling and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy.

Endomyocardial biopsy (EMB) and late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging performed at baseline are both used to evaluate the extent of myocardial fibrosis. However, no study has directly compared the effectiveness of these diagnostic tools in the prediction of left ventricular reverse remodeling (LVRR) and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Seventy-five patients with newly diagnosed IDCM who were undergoing optimal therapy were assessed at baseline using LGE-CMR imaging and EMB; the former measured LGE area and the latter measured collagen volume fraction (CVF) as possible predictive indices of LVRR and cardiac event-free survival. Among all the baseline primary candidate factors with P < 0.2 as per univariate analysis, multivariate analysis indicated that only LGE area was an independent predictor of subsequent LVRR (β = 0.44; 95 % confidence interval (CI) 0.87–2.53; P < 0.001), as indicated by decreasing left ventricular end-systolic volume index over the 1-year follow-up. Kaplan–Meier curves indicated significantly lower cardiac event-free survival rates in patients with LGE at baseline than in patients without (P < 0.01). By contrast, there was no significant difference in prognosis between patients with CVF values above (severe fibrosis) and below (mild fibrosis) the median of 4.9 %. Cox proportional hazard analysis showed that LGE area was an independent predictor of subsequent cardiac events (hazard ratio 1.06; 95 % CI 1.02–1.10; P ≤ 0.01). The degree of myocardial fibrosis estimated by baseline LGE-CMR imaging, but not that estimated by baseline EMB, can predict LVRR and cardiac event-free survival in response to therapy in patients with newly diagnosed IDCM.

FK506 therapy of experimental autoimmune myocarditis after onset of the disease

Preventive effects of FK506 on autoimmune myocarditis have been demonstrated, but the therapeutic efficacy of the agent in established myocarditis yet remains to be assessed. In this study, effects of FK506 on experimental autoimmune myocarditis were investigated by the use of the agent after the onset of the disease. Lewis rats were immunized with either cardiac myosin or bovine serum albumin (BSA) in complete Freunds adjuvant. The onset of the disease was ascertained by examining randomly chosen cardiac myosin-immunized rats. Animals were divided into four groups: the BSA-immunized saline-treated group (group A, n = 6); the BSA-immunized FK506-treated group (group B, n = 6); the myosin-immunized saline-treated group (group C, n = 6); and the myosin-immunized FK506-treated group (group D, n = 11). Saline or 1.0 mg/kg/day of FK506 were intramuscularly injected from day 16 to day 27. All the rats were put to death on day 28. Rats of group C became severely ill by the third week, while in contrast, rats of group D remained active, as did rats of groups A and B. The heart weight/body weight ratio was significantly lower in group D than in group C rats. Group mean values were 3.48 +/- 0.10 gm/kg for group A, 3.48 +/- 0.16 gm/kg for group B, 4.94 +/- 0.66 gm/kg for group C, and 3.88 +/- 0.43 gm/kg for group D. Rats of group C showed severe myocarditis with mononuclear cell infiltration, myocardial necrosis, and interstitial edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of heart rate during acute decompensated heart failure to predict left ventricular reverse remodeling and prognosis in response to therapies in nonischemic dilated cardiomyopathy

Although an increased heart rate (HR) is a strong predictor of poor prognosis in cases of chronic heart failure (HF), the clinical value of HR as a predictor in acute decompensated HF (ADHF) is unclear. Seventy-eight patients with nonischemic dilated cardiomyopathy (NIDCM) with sinus rhythm who were first hospitalized for ADHF from 2002 to 2010 were retrospectively investigated after exclusion of patients with tachycardia-induced cardiomyopathy. The patients were divided into two groups stratified by HR on admission with a median value of 113 beats/min (Group H with HR ≥ 113 beats/min; Group L with HR < 113 beats/min). Despite similar backgrounds, including pharmacotherapy for HF, HR changes responding to titration of β-blocker (BB) therapy and myocardial interstitial fibrosis, left ventricular (LV) ejection fractions improved more significantly 1 year later in Group H than in Group L (57 % ± 11 % vs. 46 % ± 12 %, P < 0.001). Cardiac event-free survival rates were also significantly improved in Group H (P = 0.038). Multiple regression analysis revealed that only the peak HR on admission was an independent predictor of LV reverse remodeling (LVRR) 1 year later (β = 0.396, P = 0.005). High HR on first admission for ADHF is a strong predictor of LVRR, with a better prognosis in the event of NIDCM in response to optimal pharmacotherapy, independent of pre-existing myocardial damage and subsequent HR reduction by BB therapy.

Effects of 15-Deoxyspergualin on Experimental Autoimmune Giant Cell Myocarditis of the Rat

BACKGROUND The benefits of immunosuppressive therapy for human myocarditis are controversial. The effects of a new immunosuppressant agent, 15-deoxyspergualin (DSG), on rats with experimental autoimmune myocarditis (EAM), an animal model of human giant cell myocarditis, were examined. METHODS AND RESULTS Lewis rats were immunized with cardiac myosin in Freunds complete adjuvant on day 0. In the first experiment, the effective doses of DSG required to prevent EAM were investigated. Rats were placed into one of five groups: the control group (A) was administered saline from days 1 to 10; group B, 0.3 mg/kg per day of DSG; group C, 1.0 mg/kg per day of DSG; group D, 3.0 mg/kg per day of DSG, and group E, 10.0 mg/kg per day of DSG. Rats were killed on day 28. The heart weight/body weight ratios of the rats of groups D and E were significantly lower than that of the control group. Macroscopic and microscopic scores for myocarditis decreased in groups D and E. In the next experiment, the effects of delayed administration of DSG in preventing autoimmune myocarditis were studied. Two groups of rats received 3.0 and 10.0 mg/kg per day of DSG from days 6 to 15, respectively. Two other groups of rats received the same doses of DSG from days 11 to 20. No preventive effect of delayed DSG treatment was observed. The effects of long-term, delayed initiation therapy then were evaluated. Rats were administered 10.0 mg/kg per day of DSG from days 6 to 25. The heart weight/body weight ratio and macroscopic and microscopic scores of the rats so treated significantly decreased compared with the controls. CONCLUSIONS It was demonstrated that DSG can prevent the development of cardiac myosin-induced autoimmune myocarditis.

Experimental autoimmune myocarditis and its pathomechanism.

The pathomechanisms of autoimmune myocarditis are quite different from viral infection. In this type of myocarditis, cardiac myosin fragments, proper dentritic cells and autoreactive T cells are the 3 major elements in initiating and promoting the inflammation. The causative epitope is locating on the S2 rod portion of the myosin heavy chain (MHC). Through our recombinant study, the peptide was found to be located on the latter half of MHC residues 1070 to 1165. Activity of antigenicity was not different between α and β chain. The cardiac dentritic cell presents a unique structure with large mononuclear and interdigitating process. This antigen presenter is quickly activated and suppressed by the antigen. The autoreactive T cell is closely linked with cytokine production. In the initial stage of myocarditis, IL-2 and IL-12 are increased. According to the progression of inflammatory changes, a great amount of IL-1b, INF-γ and TNF-α is released around the diseased tissue. At the same time, NO is massively produced from infiltrating macrophages. Cytokines secreted from inflammatory cells accelerate T cell induction from Th0 to Th1. In the convalescent stage, production of TGF-β1 and IL-10 become dominant. They contribute to cell induction from Th0 to Th2.ZusammenfassungDie Pathomechanismen einer Autoimmunmyokarditis unterscheiden sich von denen einer viralen Entzündung. Bei einer autoimmunen Myokarditis kommt kardialen Myosinfragmenten, dendritischen Zellen und autoreaktiven T-Zellen eine entscheidende Bedeutung für die Auslösung und das Fortestehen der Entzündung zu. Das auslösende Epitop befindet sich auf dem S2-Teil der schweren Kette von Myosin (MHC). Unsere rekombinanten Studien haben gezeigt, dass sich das Epitop auf der zweiten Hälfte der MHC-Aminosäuren 1070 bis 1165 befindet. Das Ausmaß der Antigenität der α- und β-Ketten war nicht verschieden. Die kardialen dendritischen Zellen haben eine charakteristische Morphologie mit großen mononukleären ineinander greifenden Fortsätzen. Diese Antigen präsentierende Zelle wird schnell durch das Antigen aktiviert und später supprimiert. Die autoreaktive T-Zelle ist entscheidend an der Zytokinproduktion beteiligt. Im initialen Stadium der Myokarditis sind die IL-2- und IL-12-Spiegel erhöht. Beim Fortbestehen der Entzündung werden große Mengen von IL-1b, INF-γ und TNF-α in der Randzone des entzündeten Gewebes und gleichzeitig NO durch infiltrierende Makrophagen freigesetzt. Die durch Entzündungsquellen freigesetzten Zytokine beschleunigen den T-Zell-Übergang von Th0 nach Th1. Im Ausheilungsstadium überwiegt die Produktion von TGF-β1 und IL-10 und führt zum Übergang von Th0- zu Th2-Lymphozyten.

No accumulation of globotriaosylceramide in the heart of a patient with the E66Q mutation in the α-galactosidase A gene

BACKGROUND Fabry disease is an X-linked lysosomal disorder resulting from mutations in the α-galactosidase A (GLA) gene. Recent reports described that the E66Q mutation of GLA is not a disease-causing mutation. However, no pathological study was reported. We carried out pathological studies using a cardiac biopsy specimen from a patient with the E66Q mutation. MATERIALS AND METHODS The case was a 34 year old male patient with end-stage renal failure and cardiomegaly. He was diagnosed with gout at 15 years of age and hemodialysis was started for gouty nephropathy from 31 years of age. He was suspected of having Fabry disease as the result of a screening study for Fabry disease in patients with end-stage renal failure and was referred to our hospital for mutation analysis of the GLA gene. We carried out enzymatic and genetic analysis for GLA and pathological studies of a cardiac biopsy specimen. RESULTS The patient had the E66Q mutation in the GLA gene. GLA activity in leukocytes was 36.2% of the average of normal controls. The pathological study of the cardiac biopsy sample showed no characteristic findings of Fabry disease. The immunohistochemistry for GL3 of the cardiac biopsy sample showed no positive cells. CONCLUSION Although the E66Q mutation reduced enzyme activity, the characteristic pathological findings of Fabry disease and the abnormal accumulation of GL3 were not detected in cardiac tissues. The E66Q mutation of the GLA gene is thought to be a functional polymorphism based on enzymatic and pathological studies.

Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study).

The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged ≥ 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as ≥ 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients.