Identification of autoantibodies with the corresponding antigen for repetitive coxsackievirus infection-induced cardiomyopathy.

BACKGROUND: The hypothesis that viral myocarditis causes an autoimmune response and subsequent dilated cardiomyopathy is controversial. To further investigate the autoimmune mechanism of cardiac dilatation and dysfunction after repeated episodes of viral myocarditis, the cardiac autoantigens induced by repetitive coxsackievirus B3 (CVB3) infection were examined. METHODS AND RESULTS: Male inbred A/J mice were inoculated intraperitoneally with CVB3 at 3 and 40 weeks of age. At 8 weeks after the second inoculation, the mortality of the repetitive CVB3 group was significantly increased compared with that of the control group, and was associated with a significant reduction in fractional shortening and marked left ventricular dilatation without inflammatory cell infiltration. The cardiac antigens in the repetitive CVB3 infection were identified by 2-dimensional electrophoresis and subsequent liquid chromatography/tandem mass spectrometry (LC-MS/MS) using the serum at 2 weeks after the second inoculation. LC-MS/MS and immunohistochemistry demonstrated alpha-cardiac actin and heat shock protein 60 (HSP60) as cardiac near-surface antigens induced by the repetitive CVB3 infection. Immunoelectron microscopy disclosed the selective localization of anti-IgM antibody on the membrane of the myocytes in the repetitive CVB3 group. CONCLUSIONS: IgM antibodies against alpha-cardiac actin and HSP60, which were induced by repetitive CVB3 infection, may play an important role in the pathophysiology of the subsequent cardiac dysfunction and dilatation.

Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model.

OBJECTIVES: The present study investigated the effects of tumor necrosis factor (TNF)-alpha and angiotensin II (ANG II) on cardiac remodeling and dysfunction at the early stage of acute myocardial infarction (MI) by using a novel heterotopic cardiac transplantation-coronary ligation model. BACKGROUND: A recent clinical study has demonstrated a possible role of monocytosis in the development of left ventricular (LV) remodeling in patients with acute MI reperfusion. METHODS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce MI in the donor heart and to evaluate the hearts of both donors and recipients in Lewis rats. RESULTS: A significant decrease in LV fractional shortening and positive rate of rise in LV pressure and a significant increase in LV end-diastolic dimension/body weight and LV end-diastolic pressure were observed in the recipient hearts in the ligation group on day 7. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group. In contrast, ANG II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Furthermore, the recipients' transient LV remodeling and dysfunction were completely abolished by the intravenous administration of a TNF-alpha antagonist. CONCLUSIONS; We developed a novel cardiac transplantation-coronary ligation model capable of inducing MI in the absence of downstream hemodynamic effects and allowing differential quantification of indexes of cardiac remodeling in vivo, including the local and remote effects of ANG II and TNF-alpha on cardiac remodeling.

[Induction of left ventricular remodeling and dysfunction in the recipient heart following donor heart myocardial infarction: new insights into the pathological role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation model].

BACKGROUND: Neurohormonal and cytokine activation after acute myocardial infarction contribute to cardiac remodeling. This study aimed to examine the effects of tumor necrotic factor (TNF)-alpha and angiotensin II on cardiac remodeling and dysfunction after acute myocardial infarction. METHODS AND RESULTS: We performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce myocardial infarction in the donor heart, and to evaluate the hearts of both donors and recipients in Lewis rats. The recipients in the ligation group showed significant body-weight loss, hyperthermia, tachycardia, hypotension and leukocytosis at day 7. A significant decrease in left ventricular fractional shortening and + dP/dt, and a significant increase in left ventricular enddiastolic dimension/body weight and left ventricular enddiastolic pressure were also observed in the recipient hearts in the ligation group at day 7. With the exception of the increased perivascular fibrosis, these recipient responses were no longer seen at day 21. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group at day 7. In contrast, angiotensin II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Further, the recipients' transient left ventricular remodeling and dysfunction were completely abolished by the intravenous administration of chimeric TNF-alpha soluble receptor. CONCLUSIONS: We developed a novel heterotopic cardiac transplantation-coronary ligation model capable of inducing myocardial infarction in the absence of downstream hemodynamic effects, and allowing differential quantification of indexes of cardiac remodeling in vivo, such as the local and remote effects of angiotensin II and TNF-alpha on cardiac remodeling. Modification of activated cytokines, such as TNF-alpha induced by cardiac ischemic stress, might be a beneficial strategy for the treatment of cardiac dysfunction and subsequent cardiac remodeling after acute myocardial infarction.

Excessive ventilatory response during exercise in patients with non-hypoxic pulmonary hypertension.

The slope of the regression line between carbon dioxide output (VCO2) and minute ventilation (VE) (SLOPE) is useful for evaluating ventilation-perfusion inequality during exercise. A cardiopulmonary exercise test was carried out in 8 pulmonary hypertension (PH) patients without hypoxemia (group PH), 38 male patients with old myocardial infarction (group OMI), and 20 healthy men (group Ctrl). The average SLOPE for each group was 36.3+/-3.3, 28.7+/-0.9 and 25.6+/-0.5, respectively. There were significant differences among them. Group OMI was divided into 3 groups: OMI class 0: peak oxygen consumption (VO2) > or =21 ml x kg(-1) min(-1); OMI class I: 14 ml x kg(-1) x min(-1) < or =peak VO2<21 ml x kg(-1) min(-1); OMI class II: peak VO2< 14ml x kg(-1) x min(-1). There were no significant differences in peak VO2 between the groups PH and OMI class I, but the SLOPE in the group PH was greater than the SLOPE in OMI class I (p=0.0019). Compared with OMI class II, group PH had a greater peak VO2 (p=0.0215), although their SLOPE was equivalent to that of OMI class II. These results suggest that PH patients have severe ventilation-perfusion inequality despite good exercise capacity. When performing a cardiopulmonary exercise test on PH patients, it is necessary to observe not only VO2 or VCO2, but also VCO2/VE, in order to prevent aggravation of the ventilation-perfusion inequality, which leads to exercise-induced hypoxemia.