Hitoshi Takehana

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.

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.

β2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis Potential Role of β2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis

Background— The therapeutic potential of β2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure–induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. Methods and Results— Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the β2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-γ mRNA levels. Propranolol, a nonselective β-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a β1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin–primed lymph node cells from drug-treated rats. In vitro addition of β2-selective AR agonists inhibited the activation of cardiac myosin fragment–specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a β2-selective AR antagonist. Furthermore, treatment with 2 different β2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. Conclusions— β2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin–specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. β2-AR–stimulating agents may represent important immunomodulators of the cardiac myosin–induced autoimmune process and have potential as a new therapy for myocarditis.

A Peptide Fragment of β Cardiac Myosin Heavy Chain (β-CMHC) Can Provoke Autoimmune Myocarditis as well as the Corresponding a Cardiac Myosin Heavy Chain (α-CMHC) Fragment

The validity of the general belief that a cardiac myosin heavy chain (α-CMHC) is primarily responsible for causing experimental autoimmune myocarditis because of the more profound tolerance induction to β-CMHC due to its expression during the embryonic stage has been examined. In order to completely avoid cross-contamination among components of the two myosin heavy chains, recombinant myosin fragments were synthesized in Escherichia coli using cDNA fragments of rat a- and (J-CMHC cloned by reverse transcription polymerase chain reaction (RT-PCR). Two fragments corresponding to amino acid residues 1107-1164 derived from a-and β-heavy chains were equally capable of provoking severe myocarditis in Lewis rats when immunized in complete Freunďs adjuvant. No significant differences in the severity, as judged from histological scoring, were observed between the diseases induced by the two different peptide fragments, indicating conclusively that β-CMHC is as pathogenic as α-CMHC.

Myosin Autoreactive T Cells And Autoimmune Myocarditis. Lessons from the Disease Caused by Cardiac Myosin Peptide CM2

We have proposed a unique animal model of experimental autoimmune myocarditis (EAM). This rat myocarditis is systematically provoked by immunization with cardiac myosin, and evolves toward dilated cardiomyopathy through repetitive immunizations. In this process, myosin epitopes, dendritic cells and myosin autoreactive T cells are the three major elements initiating and promoting this disease. Despite many attempts, we have failed, thus far, to identify myosin autoreactive and myocarditogenic T cells in vitro. However, recently, T cell lines specifically reactive to the cardiac myosin peptide, CM 2 (AA: 1539-1555), and showing myocarditogenecity have been identified. Line characterization of harvested T cells from EAM rats rendered ill by whole cardiac myosin was repetitively and systematically tested. Thus, T cell lines autoreactive to CM 2 and inducing transfer myocarditis were isolated out of many candidates. Acute myocarditis transferred by means of these T cell lines became more severe, and disease transfer with these cell lines caused chronic myocarditis in syngenic Lewis rat. Importantly, the myosin autoreactive and myocarditogenic T cells were also able to transfer the myocarditis into SCID mice beyond the MHC restriction.

Fulminant Myocarditis—From Lethal Disease to Survival

Fulminant myocarditis is a representative lethal heart disease, in which patients have only been urgently rescued with the help of mechanical cardiopulmonary supports. Nevertheless, the therapeutic outcomes of fulminant myocarditis treated with PCPS has not been elucidated. Recently, a national survey was conducted to undertake these tasks by considering the current situation of patients in Japan and to propose a therapeutic guidelines for fulminant myocarditis using PCPS. Thirty (57.7%) out of 52 patients could be rescued in the survey. Important factors concerning the prognosis were the severity and improvement grade of cardiac and renal dysfunction. Based on the data, management guidelines using PCPS to improve the survival rate of fulminant myocarditis patients were published. Of the individual prognosis of patients treated with PCPS, limiting factors have not been identified even in the present survey.