Mototsugu Nishii

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.

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.

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.

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.

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.

Biomarker for Cardiomyopathy-B-Type Natriuretic Peptide

Cardiomyopathy is cardiac condition in which the normal muscular function of the myocardium has been altered by a variety of etiologies. Atherosclerotic coronary artery disease is the most common cause of cardiomyopathy in North America and Europe. Idiopathic cardiomyopathy is the second most common cause, although this may partially include undiagnosed etiologies such as viral infection, drug toxicity, and genetic factors. Other causes include endocrine diseases, collagen vascular diseases, metabolic disorders (hemochromatosis, amyloidosis, glycogen storage disease), neuromuscular disorders, and granulomatous diseases (sarcoidosis). The cardiac malfunctions are variable, namely left ventricular (LV) systolic dysfunction, LV diastolic dysfunction, or both in accordance with etiologies and morphological findings (cardiac hypertrophy or dilatation). For example, hypertrophic cardiomyopathy initially has LV diastolic dysfunction, while amyloidosis that shows similar morphological change has LV systolic dysfunction. Ischemic or idiopathic cardiomyopathy with ventricular dilatation is represented by systolic dysfunction. Cardiac malfunctions are also altered on disease course. Initially, patients with cardiomyopathy may have asymptomatic LV systolic or diastolic dysfunction alone. However, adverse disease processes finally lead to both dysfunctions. Imbalance between cardiac malfunctions and compensatory mechanisms worsens an outcome of cardiomyopathy. When abnormal LV filling pressure and volume is unable to be compensated by hemodynamic alterations such as the increases in heart rate and peripheral vascular tone by the accelerated vasoconstrictors including norepinephrine (NE), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone (RAA), this imbalance precipitates decompensated heart failure (HF). Early and simply identifying the decompensatory process is important therapeutic strategy in cardiomyopathy. Clinical utility of B-type natriuretic peptide (BNP) sensitively produced and secreted from heart in response to LV overload has been extended rapidly in patients with HF. At first, BNP emerged as a diagnostic marker for decompensated HF. Furthermore, BNP has been proved to predict a subsequent outcome in patients with HF. Recently, the efficiency of BNP-guided therapy in patients with HF has been demonstrated. In this chapter, we discuss about clinical utility of BNP assessments in patients with cardiomyopathy.

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.