京都大学 / 新制・論文博士 / 博士(医学) / 乙第13435号 / 論医博第2234号 / 新制||医||1054(附属図書館) / (主査)教授 石見 拓, 教授 佐藤 俊哉, 教授 湊谷 謙司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Cellular cardiomyoplasty is the method of transplanting myogenic cells into injured myocardium to restore the lost heart muscle cells and to improve ventricular function. Method: Three patients, all with a history of coronary heart disease, underwent coronary artery bypass grafting and implantation of autologous satellite cells. A muscle biopsy of 2-4 g from the right vastus lateralis muscle was obtained for satellite cell (myogenic stem cell from skeletal muscle) isolation and proliferation before implanted into the donor's heart. The cells were suspended in serum-free medium and injected into 30-40 sites at and around the ischemic areas just before reversing the hypothermic cardioplegia to eliminate arrhythmia and to improve retention. After recovery, each patient was maintained at the intensive care unit for 3-4 days with ECG monitoring before transferring to the patient floor. Results: All patients survived the procedure with an uneventful recovery and were discharged from the hospital. At 3-4 months follow-up examination, increased left ventricular ejection fraction of 11% (35-46%), 5.4% (40-45.4%) and 1% (40-41%) and decreased left ventricular diastolic diameter of 4, 2 and 9 mm were observed for the patients, respectively. Arrhythmia was not detected during the follow-up evaluation by ECG. Improved perfusion (99mTC-MIBI) and increased metabolic activity (18F-deoxyglucose) were found at the sites of satellite cell implantation. Significant increase of wall thickness and movement at the areas of cell injection was also observed using 2D-echo. Conclusion: Cellular cardiomyoplasty using autologous satellite cells is a safe procedure with encouraging beneficial outcomes in patients.

Substance P and neurokinin A are tachykinins that are co-localized with calcitonin gene-related peptide (CGRP) in a unique subpopulation of cardiac afferent nerve fibers. These neurons are activated by nociceptive stimuli and exhibit both sensory and motor functions that are mediated by the tachykinins and/or CGRP. Sensory signals (e.g., cardiac pain) are transmitted by peptides released at central processes of these neurons, whereas motor functions are produced by the same peptides released from peripheral nerve processes. This review summarizes our current understanding of intracardiac actions of the tachykinins. The major targets for the tachykinins within the heart are the intrinsic cardiac ganglia and coronary arteries. Intrinsic cardiac ganglia contain cholinergic neurons that innervate the heart and coronary vasculature. Tachykinins can stimulate NK3 receptors on these neurons to increase their excitability and evoke spontaneous firing of action potentials. This action provides a mechanism whereby tachykinins can indirectly influence cardiac function and coronary tone. Tachykinins also have direct effects on coronary arteries to decrease or increase tone. Stimulation of NK1 receptors on the endothelium causes vasodilation mediated by nitric oxide. This effect is normally dominant, but NK2 receptor-mediated vasoconstriction can also occur and is augmented when NK1 receptors are blocked. It is proposed that these ganglion stimulant and vascular actions are manifest by endogenous tachykinins during myocardial ischemia.

Atherosclerosis begins in the teenage years and progresses over time in susceptible individuals. It is unknown, however, whether coronary angiography in middle-aged adults showing no evidence of atherosclerosis identifies individuals at low risk for subsequent development of coronary artery disease (CAD). We identified 4068 patients ≥40 years of age who had at least two coronary angiograms between January 1, 1990 and March 31, 2011. Of these, 227 patients (5.8%) had no CAD and 251 patients (6.4%) had mild atherosclerotic disease (stenosis <30%) on the initial angiogram. Patients in the normal-angiogram group were younger, more often female, and less likely to use tobacco than patients in the mild-atherosclerosis group, while rates of diabetes and hypertension were the same. Angiographic evidence of any CAD and obstructive CAD was apparent in 26% and 4.8%, respectively of the normal-angiogram group on subsequent angiography performed 75 ± 46 months later. Myocardial infarction and revascularization occurred in 4.8% and 3.5%, respectively. Progression of CAD (odds ratio ≤ 10.2), development of obstructive CAD (odds ratio ≤ 8.9), myocardial infarction (odds ratio ≤ 2.7), and revascularization (odds ratio ≤ 8.4) were more frequent in the mild-atherosclerosis group. In summary, 26% of middle-aged adults with a normal coronary angiogram who had subsequent angiography for clinical reasons developed CAD, although the annual rates of myocardial infarction or revascularization were very low. Even mild atherosclerosis on the initial angiogram increased the rate of progression of CAD by 10-fold and the rate of revascularization by 8-fold.

BACKGROUND: Recent studies indicate that the use of ankle-brachial index (ABI) measurements helps identify patients with peripheral arterial disease. Previous research also reveals a relationship between peripheral arterial disease and higher incidence of cardiac mortality and morbidity. PURPOSE: The purpose of this study was to investigate the correlation of a low ABI (<0.90 mm Hg) with coronary artery disease, diabetes, hypercholesterolemia, body mass index greater than 25, a sedentary lifestyle, smoking, and carotid artery disease. METHODS: A descriptive correlational design was used to study a population (N = 810) of fairly healthy women who self-selected to undergo cardiovascular screening that they paid for out of pocket. Cardiac disease and most of the data on risk factors were obtained using questionnaires. Carotid artery stenosis was determined by ultrasound. Hypotheses were tested using χ and independent t test. RESULTS: A statistically significant relationship was found between a low ABI and the presence of moderate to severe carotid artery stenosis (χ = 5.90, P = .015). A low ABI (<0.90 mm Hg) was not significantly related to cardiac disease (χ = 0.83, P = .362), diabetes (χ = 1.82, P = .177), hypercholesterolemia (χ = 0.01, P = .930), claudication (χ = 2.06, P = .151), physical activity (χ = 1.17, P = .884), or body mass index (t = 1.12, P = .270). CONCLUSION: The significant relationship between low ABI and carotid artery stenosis illustrates that atherosclerosis occurs in multiple arterial beds simultaneously. The lack of association between ABI and the other variables probably reflects the self-report nature of the data collected on these variables. Ankle-brachial index measurements may be useful in future research as a tool for early recognition of cardiovascular disease.

Antibody-coated microprobes were inserted into the thoracic (T3-4) spinal cord in urethane-anesthetized Sprague-Dawley rats to detect the differences in the release of immunoreactive substance P-like (irSP) substances in response to differential activation of cardiac nociceptive sensory neurons (CNAN). CNAN were stimulated either by intrapericardial infusion of an inflammatory ischemic exudate solution (IES) containing algogenic substances (i.e., 10 mM each of adenosine, bradykinin, prostaglandin E2, and 5-hydroxytryptamine), or by transient occlusion of the left anterior descending coronary artery (CoAO). There was widespread basal release of irSP from the thoracic spinal cord. Stimulation of the CNAN by IES did not alter the pattern of release of irSP. Conversely, CoAO augmented the release of irSP from T3-4 spinal segments from laminae I-VII. This CoAO-induced irSP release was eliminated after thoracic dorsal rhizotomy. These results indicate that heterogeneous activation of cardiac afferents, as with focal coronary artery occlusion, represents an optimum input for activation of the cardiac neuronal hierarchy and for the resultant perception of angina. Excessive stimulation of cardiac nociceptive afferent neurons elicited during regional coronary artery occlusion involves the release of SP in the thoracic spinal cord and suggests that local spinal cord release of SP may be involved in the neural signaling of angina.

Purpose of Review: This article reviews the latest data on unprotected left main (ULM) percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery, with a focus on the NOBLE and EXCEL trials. Recent Findings: In EXCEL trial, the primary endpoint at 3 years was 15.4% in the PCI group and 14.7% in the CABG group (p = 0.02 for non-inferiority of PCI versus CABG). In NOBLE, the primary endpoint at 5 years was 28% and 18% for PCI and CABG, respectively (HR 1.51, CI 1.13–2.0, which did not meet the criteria for non-inferiority of PCI to CABG; p for superiority of CABG was 0.0044). Higher repeat revascularization and non-procedural myocardial infarction were noted in PCI group but there was no difference in all-cause or cardiac mortality between the two groups. Summary: A heart team approach with appropriate patient selection, careful assessment of LM lesions, and meticulous procedural technique makes PCI a valid alternative to CABG for ULM stenosis.

Purpose of Review: Patients with stable coronary artery disease (CAD) and a high risk of bleeding are not ideal candidates for a polymer-based drug-eluting stent (DES) because it requires 6–12 months of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI). The purpose of this review is to assess the angiographic and clinical outcomes of polymer-free drug-coated stents (PF-DCS) in stable CAD patients with a high bleeding risk. Recent Findings: Several randomized controlled trials (RCTs) have compared angiographic and clinical outcomes of PF-DCS with bare-metal stents (BMS), permanent polymer (PP)-DES, or biodegradable polymer (BP)-DES. However, none of these studies particularly recruited patients with stable CAD and a high risk of bleeding. Furthermore, there are limited data available on duration of DAPT following PF-DCS placement. Summary: PF-DCS has a better efficacy and similar safety as compared with BMS. PF-DCS with dual drug is noninferior to currently available PP-DES. Further RCTs are needed to assess the safety and efficacy of PF-DCS to BP-DES and PP-DES comparing shorter to standard durations of DAPT.

Indiana University-Purdue University Indianapolis (IUPUI) / Metabolic syndrome (MetS) affects 1/3 of all Americans and is the clustering of three or more of the following cardiometabolic risk factors: obesity, hypertension, dyslipidemia, glucose intolerance, and insulin resistance. MetS drastically increases the incidence of coronary artery disease (CAD), which is the leading cause of mortality globally. A cornerstone of CAD is arterial remodeling associated with coronary smooth muscle (CSM) cytodifferentiation from a contractile phenotype to proliferative and osteogenic phenotypes. This cytodifferentiation is tightly coupled to changes in intracellular Ca2+ handling that regulate several key cellular functions, including contraction, transcription, proliferation, and migration. Our group has recently elucidated the time course of Ca2+ dysregulation during MetS-induced CAD development. Ca2+ transport mechanisms, including voltage-gated calcium channels, sarcoplasmic reticulum (SR) Ca2+ store, and sarco-endoplasmic reticulum Ca2+ ATPase (SERCA), are enhanced in early, mild disease and diminished in late, severe disease in the Ossabaw miniature swine. Using this well-characterized large animal model, I tested the hypothesis that this Ca2+ dysregulation pattern occurs in multiple etiologies of CAD, including diabetes and aging. The fluorescent intracellular Ca2+ ([Ca2+]i) indicator fura-2 was utilized to measure [Ca2+]i handling in CSM from lean and diseased swine. I found that [Ca2+]i handling is enhanced in mild disease with minimal CSM phenotypic switching and diminished in severe disease with greater phenotypic switching, regardless of CAD etiology. We are confident of the translatability of this research, as the Ca2+ influx, SR Ca2+ store, and SERCA functional changes in CSM of humans with CAD are similar to those found in Ossabaw swine with MetS. Single-cell RNA sequencing revealed that CSM cells from an organ culture model of CAD exhibited many different phenotypes, indicating that phenotypic modulation is not a discreet event, but a continuum. Transcriptomic analysis revealed differential expression of many genes that are involved in the osteogenic signaling pathway and in cellular inflammatory responses across phenotypes. These genes may be another regulatory mechanism common to the different CAD etiologies. This study is the first to show that CSM Ca2+ dysregulation is common among different CAD etiologies in a clinically relevant animal model.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19549号 / 医博第4056号 / 新制||医||1012(附属図書館) / 32585 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福原 俊一, 教授 吉村 長久, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM