Akihiro Yoshizawa

Detection of periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction.

BACKGROUNDS Numerous reports have demonstrated that periodontal bacteria are present in plaques from atherosclerotic arteries. Although periodontitis has recently been recognized as a risk factor for coronary artery disease, the direct relationship between periodontal bacteria and coronary artery disease has not yet been clarified. It has been suggested that these bacteria might contribute to inflammation and plaque instability. We assumed that if periodontal bacteria induce inflammation of plaque, the bacteria would be released into the bloodstream when vulnerable plaque ruptures. To determine whether periodontal bacteria are present in thrombi at the site of acute myocardial infarction, we tried to detect periodontal bacteria in thrombi of patients with acute myocardial infarction by polymerase chain reaction (PCR). METHODS We studied 81 consecutive adults with ST-segment elevation acute myocardial infarction who underwent primary percutaneous coronary intervention (PCI). All patients underwent removal of thrombus with aspiration catheters at the beginning of percutaneous coronary intervention, and a small sample of thrombus was obtained for PCR. RESULTS The detection rates of periodontal bacteria by PCR were 19.7% for Aggregatibacter actinomycetemcomitans, 3.4% for Porphyromonas gingivalis, and 2.3% for Treponema denticola. CONCLUSIONS Three species of periodontal bacteria were detected in the thrombi of patients with acute myocardial infarction. This raises the possibility that such bacteria are latently present in plaque and also suggests that these bacteria might have a role in plaque inflammation and instability.

Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy.

Background: Certain cardiac‐specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high‐profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. Methods and Results: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either β1‐adrenergic or M2‐muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin‐6 and tumor necrosis factor‐α did not change after each session of IA. Six‐minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). Conclusions: Our initial experience demonstrated safety and short‐term efficacy of IA using a new IgG3‐specific tryptophan column for patients with advanced HF due to DCM. Long‐term follow‐up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients. J. Clin. Apheresis, 2011.

A Pilot Study on the Role of Autoantibody Targeting the β1-Adrenergic Receptor in the Response to β-blocker Therapy for Congestive Heart Failure

BACKGROUND Autoantibodies directed against the beta1-adrenergic receptor exert agonist-like actions by inducing receptor uncoupling and cause myocardial damage as well as fatal ventricular arrhythmias. Previous studies have shown that beta-blockers can modulate these actions of the autoantibodies. We investigated the influence of such autoantibodies in patients with congestive heart failure (CHF) receiving beta-blocker therapy. METHODS AND RESULTS Eighty-two CHF patients were randomly assigned to treatment with metoprolol or carvedilol for 16 weeks. Autoantibodies were detected in 20 patients (24%) by enzyme-linked immunosorbent assay. Left ventricular function in response to beta-blocker therapy did not differ significantly by the presence of the autoantibody in global analysis. However, changes of the left ventricular end-diastolic dimension (P = .04), end-systolic dimension (P < .01), and ejection fraction on radionuclide ventriculography (P = .02) were significantly larger in autoantibody-positive patients than antibody-negative patients. Changes in the plasma level of brain natriuretic peptide tended to be larger in autoantibody-positive patients (P = .09). The increase of heart rate normalized by the increase of plasma norepinephrine during exercise (an index of adrenergic responsiveness) showed a greater decrease in autoantibody-positive patients than autoantibody-negative patients (P = .035). CONCLUSION Our data suggest that beta-blocker therapy might be more effective in CHF patients with autoantibodies targeting the beta1-adrenergic receptor.

Carvedilol Exerts More Potent Antiadrenergic Effect than Metoprolol in Heart Failure

SummaryBackground: It is still uncertain whether or not there is a difference between metoprolol and carvedilol for the treatment of congestive heart failure. We attempted to determine the difference between the two β-blockers in terms of their antiadrenergic effect during exercise in patients with heart failure and their efficacy based on the baseline plasma brain natriuretic peptide concentration. Methods: Fifty-three patients with mild to moderate heart failure with a radionuclide left ventricular ejection fraction <40% received open label metoprolol or carvedilol in a randomized fashion. The increase in the heart rate normalized to the increase in the plasma norepinephrine concentration during exercise, was calculated as an index of adrenergic responsiveness during exercise. Results: The increase in heart rate normalized by the increase in plasma norepinephrine concentration, decreased after the initiation of β-blockers in the carvedilol group, but not in the metoprolol group. The change in cardiac function was more favorable for carvedilol than metoprolol in patients who exhibited a higher baseline brain natriuretic peptide concentration. Conclusions: Carvedilol exerts a more potent antiadrenergic effect than metoprolol during stress in patients with mild to moderate heart failure. Carvedilol appears to be more efficacious than metoprolol in patients who exhibit higher baseline brain natriuretic peptide concentrations. These differences should be kept in mind when selecting appropriate pharmacologic agents in the treatment of heart failure.

Role of non-electrocardiogram-gated contrast-enhanced computed tomography in the diagnosis of acute coronary syndrome

Non-electrocardiogram-gated contrast-enhanced computed tomography (non-ECG-gated CT) is available in most hospitals where patients with chest and/or back pain are admitted to the emergency department. Although it has been established as the initial diagnostic imaging modality for acute aortic dissection (AAD) and pulmonary thromboembolism (PE), its diagnostic ability for acute coronary syndrome (ACS) in the emergency department has not been elucidated. We retrospectively investigated 154 consecutive patients who required non-ECG-gated CT to differentiate AAD and PE in the emergency department, but had no evidence of them on CT. Furthermore, a subanalysis was performed in the patients who were subsequently suspected of ACS and underwent emergent invasive coronary angiography followed by CT. We evaluated left ventricular enhancement to detect myocardial perfusion deficit by calculating Hounsfield units, and the results were compared with ultimate diagnoses and angiography findings. A perfusion deficit was detected in 43 patients, among whom 26 were ultimately diagnosed with acute myocardial infarction (AMI); 24 patients required emergent revascularization. The subanalysis indicated that perfusion abnormalities corresponded with the territory of the culprit artery in all except one patient. In the remaining 111 patients without perfusion deficit, only two required emergent revascularization, and their levels of creatine kinase MB were not elevated. The sensitivity, specificity, and positive and negative predictive values of non-ECG-gated CT in predicting AMI/emergent revascularization were 93 %, 87 %, 61 %, and 98 %/92 %, 85 %, 56 %, and 98 %, respectively. Non-ECG-gated CT facilitates the diagnosis of ACS and the decision on emergent catheterization, providing information on the ischemic myocardial area by detection of a localized decrease in left ventricular enhancement.

Autoimmunity against M 2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy-like phenotype

Patients with dilated cardiomyopathy (DCM) often have autoantibodies against cardiac antigens including the M2 muscarinic acetylcholine receptor (M2R). To elucidate the role of autoimmunity against M2R in disease development, we induced an immune response against M2R by adoptive transfer into Rag2–/– mice of splenocytes from M2R–/– mice immunized with a recombinant M2R protein. T lymphocytes transiently infiltrated the heart in recipient mice followed by morphological changes in cardiomyocytes. These mice produced IgG antibodies against M2R, which bound to cardiomyocytes in vivo and decreased the amplitude of calcium signals in isolated rat cardiomyocytes in vitro. Recipient mice showed increased heart weights associated with increased intraventricular diameter, decreased systolic function, and increased action potential duration, which are characteristics of DCM. Our results suggest that myocarditis and DCM associated with the presence of anti‐M2R antibodies are autoimmune diseases with a risk of progressing to the terminal stage. Our mouse model will be useful in the analysis of the molecular mechanisms of disease progression and the development of new therapies for DCM.

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity

The GTPase-activating protein Tagap enables thymocytes to properly migrate within the thymus to undergo selection. Letting thymocytes go During the process of T cell development, thymocytes must travel from the cortex of the thymus to the medulla, where any potentially autoreactive cells are removed by negative selection. This translocation is mediated by interactions between sema3E, which is secreted from the medulla, and its receptor plexin-D1, which is present on thymocytes in the cortex. Duke-Cohan et al. found that mouse thymocytes lacking the GTPase-activating protein Tagap had defective sema3E/plexin-D1 signaling and thus failed to detach from the cortex. Given that single-nucleotide polymorphisms in the gene encoding TAGAP are associated with autoimmune disorders, these data suggest that Tagap facilitates the trafficking required for the efficient negative selection of autoreactive cells. Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)–activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes’ adhesion to the cortex through their β1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1–mediated release of thymocytes that adhered within the cortex through β1-containing integrins. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection.