心房細動における細動波の振幅とTIMI frame count を用いた冠血流の関係

内容の要旨, 審査の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Coronary angioscopic findings 9 months after everolimus-eluting stent implantation compared with sirolimus-eluting stents

AbstractObjectivesWe assessed angioscopic findings after everolimus-eluting stents (EES) implantation, compared with sirolimus-eluting stents (SES).BackgroundCoronary angioscopy (CAS) provides an opportunity to assess neointimal coverage over stent struts, thrombus, and plaque color by direct visualization. CAS is a useful tool for evaluating stent struts after drug-eluting stent implantation. Angioscopic findings after EES implantation have not been reported before.MethodsWe performed CAS in 23 patients who were treated with EES and 41 patients with SES. CAS was performed 8.5 months after stent implantation. We assessed neointimal coverage, thrombus, and plaque color. We classified neointimal coverage in 4 grades: grade 0=struts were completely exposed; grade 1=struts were visible with dull light reflexion; grade 2=there was no light reflexion from slightly visible struts; grade 3=struts were completely covered.ResultsThere was no significant difference in minimum, maximum, dominant grade of neointimal coverage, and heterogeneity index between EES and SES. Thrombus was less frequently observed in EES than SES (4% vs 29%, p=0.02). When we divided study patients into acute coronary syndrome (ACS) or stable angina pectoris (SAP), there was a tendency toward less thrombus in EES than SES, in both ACS and SAP. Maximum color grade of the plaques was less advanced in EES than SES (p<0.01). Yellow plaques of grade 2 or 3 were less frequent in EES than SES (35% vs 76%, p<0.01).ConclusionsThis study suggested that EES were associated with lower risk of thrombus formation than SES

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation

Use of the augmentation index from applanation tonometry of the radial artery for assessing the extent of coronary artery calcium as assessed by coronary computed tomography

Background: The augmentation index (AI) obtained from applanation tonometry of the radial artery is technically the easiest and quickest of available methods for assessing arterial stiffness. We tested the hypothesis that the radial AI is associated with the extent of coronary artery calcium (CAC) as assessed by coronary computed tomography (CCT). Methods and Results: This study included 161 patients with known or suspected coronary artery disease undergoing central hemodynamic measurements and CCT. Radial AI was recorded and was corrected in accordance with heart rate (radial AI@75). Thirty-seven patients had no CAC (CAC score = 0), 85 had low-grade CAC (CAC score = 1–399), and 39 had high-grade CAC (CAC score ≥400). Coronary risk factors, except for age and serum creatinine, were similar among the three groups. There were significant differences in brachial systolic blood pressure (SBP) (p = 0.011) and radial AI@75 (%) (p = 0.006). Multivariate analysis showed that age (β = 0.27, p = 0.001), serum creatinine (β = 0.18, p = 0.03), and radial AI@75 (β = 0.24, p = 0.005) were significantly associated with ln (CAC score + 1), whereas brachial SBP was not. Additionally, serum creatinine (odds ratio: 11.91, 95% confidence interval: 1.46–112.0, p = 0.02) and radial AI@75 (per 10%) (odds ratio: 1.76, 95% confidence interval: 1.22–2.64, p = 0.002) were independent factors associated with high-grade CAC. Conclusions: Our results suggest that the radial AI is better for estimating CAC than brachial SBP in patients with known or suspected coronary artery disease

TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling

Abstract: Reactive oxygen species (ROS) produced by NADPH oxidase 2 (Nox2) function as key mediators of mechanotransduction during both physiological adaptation to mechanical load and maladaptive remodeling of the heart. This is despite low levels of cardiac Nox2 expression. The mechanism underlying the transition from adaptation to maladaptation remains obscure, however. We demonstrate that transient receptor potential canonical 3 (TRPC3), a Ca2+-permeable channel, acts as a positive regulator of ROS (PRROS) in cardiomyocytes, and specifically regulates pressure overload-induced maladaptive cardiac remodeling in mice. TRPC3 physically interacts with Nox2 at specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca2+-dependent Nox2 activation through TRPC3-mediated background Ca2+ entry. Nox2 also stabilizes TRPC3 proteins to enhance TRPC3 channel activity. Expression of TRPC3 C-terminal polypeptide abolished TRPC3-regulated ROS production by disrupting TRPC3-Nox2 interaction, without affecting TRPC3-mediated Ca2+ influx. The novel TRPC3 function as a PRROS provides a mechanistic explanation for how diastolic Ca2+ influx specifically encodes signals to induce ROS-mediated maladaptive remodeling and offers new therapeutic possibilities

TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy

Angiotensin (Ang) II participates in the pathogenesis of heart failure through induction of cardiac hypertrophy. Ang II-induced hypertrophic growth of cardiomyocytes is mediated by nuclear factor of activated T cells (NFAT), a Ca(2+)-responsive transcriptional factor. It is believed that phospholipase C (PLC)-mediated production of inositol-1,4,5-trisphosphate (IP(3)) is responsible for Ca(2+) increase that is necessary for NFAT activation. However, we demonstrate that PLC-mediated production of diacylglycerol (DAG) but not IP(3) is essential for Ang II-induced NFAT activation in rat cardiac myocytes. NFAT activation and hypertrophic responses by Ang II stimulation required the enhanced frequency of Ca(2+) oscillation triggered by membrane depolarization through activation of DAG-sensitive TRPC channels, which leads to activation of L-type Ca(2+) channel. Patch clamp recordings from single myocytes revealed that Ang II activated DAG-sensitive TRPC-like currents. Among DAG-activating TRPC channels (TRPC3, TRPC6, and TRPC7), the activities of TRPC3 and TRPC6 channels correlated with Ang II-induced NFAT activation and hypertrophic responses. These data suggest that DAG-induced Ca(2+) signaling pathway through TRPC3 and TRPC6 is essential for Ang II-induced NFAT activation and cardiac hypertrophy