β(2)-Adrenergic and M(2)-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure

L-Lype Ca2+ channels (LTCC) play a crucial role in cardiac excitation-contraction coupling. We previously found that in failing ventricular myocytes of mice chronically treated with isoproterenol, basal t-tubular (TT) LTCC activity was halved by activation of protein phosphatase (PP)2A whereas basal surface sarcolemmal (SS) LTCC activity was doubled by inhibition of PP1. Interestingly, chronic treatment of these mice with pertussis toxin almost completely normalized TT and SS LTCC densities and cardiac contractility. In the present study, we therefore sought to identify the G(i/o) protein coupled receptors in cardiac myocytes (i.e. beta(2)-adrenergic, M-2-muscarinic and A(1)-adenosine receptors) that are responsible for these abnormalities in heart failure by chronically administrating mice a selective antagonist of each receptor (ICI118,551, atropine and 8-cyclopentyl-1,3-dipropilxanthine (DPCPX), respectively) with isoproterenol. Compared with mice treated with isoproterenol alone, mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX showed significantly lower lung weight/tibial length, higher fractional shortening, lower left ventricular end-diastolic pressure and higher dP/dt(max) and dP/dt(min). In addition, ventricular myocytes of mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX exhibited significantly higher TT and lower SS LTCC current densities than those of mice treated with isoproterenol alone due to normalization of the PP activities. These results indicate that beta(2)-adrenergic, M-2-muscarinic, but not A(1)-adenosine receptors contribute to reduced ventricular contractility at least partially by decreasing basal TT LTCC activity in heart failure. Therefore, antagonists of beta(2)-alrenergic and/or M-2-muscarinic receptors can be good adjuncts to beta(1)-adrenergic receptor antagonists in the treatment of heart failure.ArticleEUROPEAN JOURNAL OF PHARMACOLOGY. 724:122-131 (2014)journal articl

Iodine-123 Metaiodobenzylguanidine Scintigraphic Assessment of Myocardial Sympathetic Innervation in Patients With Familial Amyloid Polyneuropathy

AbstractObjectives. This study attempted to assess myocardial sympathetic innervation using iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging in patients with familial amyloid polyneuropathy.Background. Signs and symptoms of cardiac autonomic dysfunction are commonly seen in patients with cardiac amyloidosis. However, the incidence and magnitude of abnormalities in myocardial sympathetic nerve function by means of I-123 MIBG imaging and their relation to clinical findings, cardiac function and the results of thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) myocardial scanning have not yet been clarified.Methods. We performed M-mode, two-dimensional and Doppler echocardiography and I-123 MIBG, Tl-201 and Tc-99m PYP imaging of the heart in 12 patients with familial amyloid polyneuropathy and biopsy-proved cardiac amyloidosis.Results. Ten of 12 patients had no clinical evidence of overt heart disease, but left ventricular (LV) wall thickening was observed in 4 of these 10. Left ventricular percent fractional shortening and Doppler transmitral flow velocity patterns were found to be normal in all 12 patients. Eight of 12 patients showed no myocardial MIBG accumulation, with limited uptake in the remaining 4 demonstrated only in the LV anterior wall. Diffuse but mild myocardial uptake of Tc-99m PYP occurred in only 4 of 12 patients, and all 12 had normal results on Tl-201 myocardial scanning. Complete defects on myocardial MIBG scans were found in five of eight patients with negative findings on Tc-99m PYP myocardial scanning. The incidence and magnitude of myocardial uptake of MIBG were independent of clinical findings, extent of endomyocardial amyloid deposition, electrocardiographic QRS voltage and ventricular wall thickness.Conclusions. Patients with familial amyloid polyneuropathy show a high incidence of myocardial adrenergic denervation with viable myocardium that can be identified very early in cardiac amyloidosis, before the development of clinically apparent heart disease, ventricular wall thickening, significant LV systolic and diastolic dysfunction and positive findings on Tc-99m PYP myocardial scanning.(J Am Coll Cardiol 1997;29:168–74)

The Traditional Japanese Medicine (Kampo) Boiogito has a Dual Benefit in Cardiorenal Syndrome: A Pilot Observational Study

Article信州医学雑誌 62(2):89-97(2014)journal articl

Serum High-density Lipoprotein Cholesterol Level and Lifestyle Habits among Japanese Junior High School Students

Article信州医学雑誌 61(4):205-215(2013)journal articl

High concentrations of omega-3 fatty acids are associated with the development of atrial fibrillation in the Japanese population

The favorable effect of fish oils rich in n-3 polyunsaturated fatty acids (PUFAs) on the development of atrial fibrillation (AF) is controversial. The relationship between the serum concentrations of n-3 PUFAs and the incidence of AF is unclear; therefore, in the present study, we aimed to elucidate this relationship. We evaluated the serum concentrations of n-3 PUFAs in 110 patients with AF, 46 patients with ischemic heart disease (IHD) and no AF, and 36 healthy volunteers. Thirty-six patients had a history of IHD (IHD-AF group) and 74 did not (L-AF group). The eicosapentaenoic acid (EPA) levels in the L-AF group were higher than those in the IHD-AF and control groups (117 +/- A 64, 76 +/- A 30, and 68 +/- A 23 mu g/ml, respectively); the docosahexaenoic acid (DHA) levels showed the same pattern (170 +/- A 50, 127 +/- A 27, and 126 +/- A 35 mu g/ml, respectively). In both the L-AF and IHD-AF groups, the EPA levels in patients with persistent and permanent AF were higher than those in patients with paroxysmal AF (L-AF 131 +/- A 74 vs. 105 +/- A 51 mu g/ml; IHD-AF 82 +/- A 28 vs 70 +/- A 33 mu g/ml). Multivariate analysis showed that cases of AF were associated with higher levels of EPA but not DHA. In this Japanese population study, the EPA and DHA levels in patients with L-AF were higher than those in normal subjects. In particular, the EPA level was associated with the incidence of AF. These findings suggest that an excess of EPA might be a precipitating factor of AF.ArticleHEART AND VESSELS. 28(4):497-504 (2013)journal articl

Nonalcoholic fatty liver disease in Japanese junior high school students: its prevalence and relationship to lifestyle habits

The original publication is available at www.springerlink.comDespite the increase in nonalcoholic fatty liver disease (NAFLD) in Japanese adults, its prevalence in adolescents remains unclear. This prompted us to evaluate the incidence and clinical characteristics of NAFLD among junior high school students. A population-based cross-sectional study was conducted among students in a single junior high school in Nagano prefecture. Serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (gamma GT) measurements and abdominal ultrasonography were performed in 249 and 288 students in 2004 and 2007, respectively. In the latter survey, student lifestyle habits were also assessed, using questionnaires. The prevalence of NAFLD was 4.4% and 4.5% in 2004 and 2007, respectively, which was lower than that of obesity (10.0% and 5.9%). Body mass index and ALT and gamma GT levels increased significantly with hepatic steatosis severity. Multivariate logistic regression analysis demonstrated that the presence of obesity and an ALT level of 30 U/L or more were independent predictors of NAFLD (odds ratio 16.9, P < 0.001 and odds ratio 16.6, P = 0.001, respectively). The ratios of students commuting to and from school by car and not doing sports outside of school were higher in NAFLD students compared with non-NAFLD ones. Such tendencies were observed independently of the presence of obesity. Additionally, one obese student with severe steatosis and liver dysfunction was diagnosed as having nonalcoholic steatohepatitis (NASH). Approximately 4% of junior high school students had NAFLD that was primarily associated with obesity and reduced daily physical activity. Serum ALT measurement during school check-ups is recommended for the early detection of young adolescent NAFLD/NASH.ArticleJOURNAL OF GASTROENTEROLOGY. 45(6):666-672 (2010)journal articl