Publications by authors named "Kenji Sakamoto"

307 Publications

East Asian variant aldehyde dehydrogenase type 2 genotype exacerbates ischemia/reperfusion injury with ST-elevation myocardial infarction in men: possible sex differences.

Heart Vessels 2021 Jul 14. Epub 2021 Jul 14.

Department of Cardiovascular Medicine, Faculty of Life Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies toxic aldehydes generated during ischemia/reperfusion (I/R) injury in ST-elevation myocardial infarction (STEMI). The deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. Whether ALDH2*2 exacerbates I/R injury of in patients with STEMI is not known. The study subjects comprised 218 Japanese patients with STEMI (158 men and 60 women, mean age 67.9 ± 11.9) who underwent successful percutaneous coronary intervention. Of these, 120 (55.0%) were the carriers of variant ALDH2*2 and 98 (45.0%) those of wild ALDH2*1/*1 on genotyping. There were no differences in clinical characteristics between the ALDH2*2 and ALDH2*1/*1 group except lower alcohol habit (14.2% vs 46.3%, P < 0.001) in the ALDH2*2 group. The peak plasma levels of creatine phosphokinase myocardial binding (CKMB), a marker of myocardial injury, however, were significantly higher in the patients with ALDH2*2 than in those with ALDH2*1/*1 [a median 275.0 (175.8-407.5) vs 177.5 (126.9-344.3) U/L, P = 0.001] among men but not among women (P = 0.811). There was a significant interaction between men (male sex) and ALDH2*2 for I/R injury (χ2 = 4.425, P = 0.040). The variant ALDH2*2 was associated with more severe I/R injury than the wild ALDH2*1/*1 in STEMI patients in men with possible sex differences.
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http://dx.doi.org/10.1007/s00380-021-01907-xDOI Listing
July 2021

Impairment of endothelium-dependent vasodilator function of retinal blood vessels in adult rats with a history of retinopathy of prematurity.

J Pharmacol Sci 2021 Aug 7;146(4):233-243. Epub 2021 May 7.

Department of Molecular Pharmacology, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address:

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease, initiated by delayed retinal vascular growth after premature birth. In the majority of cases, ROP resolves spontaneously; however, a history of ROP may increase the risk of long-term visual problems. In this study, we evaluated the endothelial function of retinal blood vessels in adult rats with a history of ROP. ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8. On P56, vasodilator responses to acetylcholine, GSK1016790A (an activator of transient receptor potential vanilloid 4 channels), NOR3 (a nitric oxide [NO] donor), and salbutamol (a β-adrenoceptor agonist) were assessed. Compared to age-matched controls, retinal vasodilator responses to acetylcholine and GSK1016790A were attenuated in P56 rats with a history of ROP. No attenuation of acetylcholine-induced retinal vasodilator response was observed under inhibition of NO synthase. Retinal vasodilator responses to NOR3 and salbutamol were unaffected. These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood.
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http://dx.doi.org/10.1016/j.jphs.2021.04.008DOI Listing
August 2021

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against -methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague-Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.
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http://dx.doi.org/10.3390/ijms22094439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123037PMC
April 2021

L-Citrulline ameliorates the attenuation of acetylcholine-induced vasodilation of retinal arterioles in diabetic rats.

Heliyon 2021 Mar 21;7(3):e06532. Epub 2021 Mar 21.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

In our previous study, we found that the vasodilation of retinal arterioles induced by acetylcholine and BMS-191011, a large-conductance Ca-activated K (BK) channel opener, were diminished in diabetic rats. Currently, few agents ameliorate the impaired vasodilator responses of retinal blood vessels. Our recent finding that the intravenous infusion of L-citrulline dilated retinal arterioles, suggests that L-citrulline could be a potential therapeutic agent for circulatory disorders of the retina. In this study, we determined the effect of an oral L-citrulline treatment on impaired acetylcholine- and BMS-191011-induced vasodilation in the retinal arterioles of diabetic rats. To induce diabetes, rats were administered an intravenous dose of streptozotocin (65 mg/kg) and a 5% D-glucose solution as drinking water. The L-citrulline (2 g/kg/day) and L-arginine (2 g/kg/day) treatments commenced either 15 days before or just after the streptozotocin injection and continued throughout the experimental period. A 29-day treatment with L-citrulline, but not L-arginine, significantly ameliorated the impaired acetylcholine- and BMS-191011-induced retinal vasodilation in diabetic rats without affecting their plasma glucose levels. The 2-week L-citrulline treatment tended to ameliorate the dysfunction of the acetylcholine-induced retinal vasodilation in diabetic rats. In conclusion, these results showed that the retinal blood vessel dysfunction induced by diabetes mellitus could be prevented by the long-term administration of L-citrulline and suggest that the latter could play a potentially prophylactic role in diabetic retinopathy.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020426PMC
March 2021

Impact of Reactive Oxidative Metabolites Among New Categories of Nonischemic Heart Failure.

J Am Heart Assoc 2021 Apr 18;10(7):e016765. Epub 2021 Mar 18.

Department of Cardiovascular Medicine Faculty of Life Sciences Graduate School of Medical Science and Center for Metabolic Regulation of Healthy Aging (CMHA) Kumamoto University Kumamoto Japan.

Background We investigated the clinical significance of derivatives of reactive oxygen metabolites (DROMs), a new marker of reactive oxygen species, in patients with nonischemic heart failure (HF) and compared them among new categories of HF. Methods and Results We recruited 201 consecutively hospitalized patients with HF and measured DROM under stable conditions. Then, we divided them according to new categories of HF (HF with reduced ejection fraction [EF], HF with midrangeEF, and HF with preserved EF) without coronary artery disease. In subgroup analysis, we followed EF changes in patients with HF with reduced EF and classified them into HF with recovered EF or nonrecovered EF according to whether EF had improved to >40%. DROMs are significantly and independently associated with HF-related events in patients with NIHF. There were no significant differences in DROM and the probability of HF-related events among HF categories in Kaplan-Meier analysis. However, patients with HF with reduced EF and HF with preserved EF but not HF with midrange EF with HF-related events had higher DROM than those without HF-related events. In subgroup analysis, Kaplan-Meier analysis demonstrated that the probabilities of HF-related events in HF with recovered EF were dramatically decreased. DROM were significantly higher in patients with HF with nonrecovered EF than in HF with recovered EF. In receiver operating characteristic analysis, the cutoff level of DROM for predicting improvements in HF with recovered EF was 347 Carratelli units. Furthermore, the C-statistic value for predicting EF improvement for the DROM levels was 0.703. In multivariable logistic regression analysis, DROM was independently and significantly associated with the prediction of HF with recovered EF. Conclusions DROM measurements can provide important prognostic information for risk stratification in any category of NIHF. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000035827.
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http://dx.doi.org/10.1161/JAHA.120.016765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174381PMC
April 2021

Cardioprotective Effects of Rivaroxaban on Cardiac Remodeling After Experimental Myocardial Infarction in Mice.

Circ Rep 2020 Mar 4;2(3):158-166. Epub 2020 Mar 4.

Department of Cardiovascular Medicine and Center for Metabolic Regulation of Healthy Aging, Graduate School of Medical Sciences, Kumamoto University Kumamoto Japan.

Direct-activated factor X (FXa) plays an important role in thrombosis and is also involved in inflammation via the protease-activated receptor (PAR)-1 and PAR-2 pathway. We hypothesized that rivaroxaban protects against cardiac remodeling after myocardial infarction (MI). MI was induced in wild-type mice by permanent ligation of the left anterior descending coronary artery. At day 1 after MI, mice were randomly assigned to the rivaroxaban and vehicle groups. Mice in the rivaroxaban group were provided with a regular chow diet plus rivaroxaban. We evaluated cardiac function by echocardiography, pathology, expression of mRNA and protein at day 7 after MI. Rivaroxaban significantly improved cardiac systolic function, decreased infarct size and cardiac mass compared with the vehicle. Rivaroxaban also downregulated the mRNA expression levels of tumor necrosis factor-α, transforming growth factor-β, PAR-1 and PAR-2 in the infarcted area, and both A-type and B-type natriuretic peptides in the non-infarcted area compared with the vehicle. Furthermore, rivaroxaban attenuated cardiomyocyte hypertrophy and the phosphorylation of extracellular signal-regulated kinase in the non-infarcted area compared with the vehicle. Rivaroxaban protected against cardiac dysfunction in MI model mice. Reduction of PAR-1, PAR-2 and proinflammatory cytokines in the infarcted area may be involved in its cardioprotective effects.
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http://dx.doi.org/10.1253/circrep.CR-19-0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921351PMC
March 2020

Temporal Change in Longitudinal Strain After Domino Liver Transplantation With Liver Grafts Explanted From Patients With Hereditary Amyloidogenic Transthyretin Amyloidosis.

Circ Rep 2020 Nov 10;2(12):730-738. Epub 2020 Nov 10.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University Kumamoto Japan.

Using transthoracic echocardiography, including 2D speckle tracking imaging (STI), this study examined cardiac function after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary amyloidogenic transthyretin amyloidosis. In all, 14 patients who underwent DLT at Kumamoto University Hospital and for whom 2D STI information was available were enrolled in the study; time-dependent echocardiographic changes were evaluated in 7. Although left ventricular (LV) systolic and diastolic function did not differ between the pre- and post-DLT periods (mean [±SD] 5.4±1.0 years after DLT), there were significant (P<0.05 for all) increases in the post- vs. pre-DLT period in basal longitudinal strain (LS; -13.4±2.3 vs. -19.3±4.4), relative apical LS index (=apical LS/[basal LS+mid LS]; 0.75±0.20 vs. 0.58±0.08), and LV ejection fraction/global LS (3.91±0.58 vs. 3.06±0.44). Age at the time of DLT was significantly higher in the group with impaired (>-14%) than preserved basal LS (57.2±3.5 vs. 39.6±16.0 years; P<0.05). When control subjects (n=14) were added to the enrolled DLT recipients, multivariable logistic regression analysis revealed that a history of DLT was significantly associated with impaired basal LS (>-14%; odds ratio 28.39, 95% confidence interval 1.89-427.45, P<0.05). LV systolic and diastolic function was preserved in the long term after DLT. However, 2D STI revealed subtle cardiac dysfunction in DLT recipients, which may be an early manifestation of cardiac amyloidosis.
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http://dx.doi.org/10.1253/circrep.CR-20-0106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937528PMC
November 2020

Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation.

Nat Metab 2021 02 18;3(2):196-210. Epub 2021 Feb 18.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Ketone bodies are generated in the liver and allow for the maintenance of systemic caloric and energy homeostasis during fasting and caloric restriction. It has previously been demonstrated that neonatal ketogenesis is activated independently of starvation. However, the role of ketogenesis during the perinatal period remains unclear. Here, we show that neonatal ketogenesis plays a protective role in mitochondrial function. We generated a mouse model of insufficient ketogenesis by disrupting the rate-limiting hydroxymethylglutaryl-CoA synthase 2 enzyme gene (Hmgcs2). Hmgcs2 knockout (KO) neonates develop microvesicular steatosis within a few days of birth. Electron microscopic analysis and metabolite profiling indicate a restricted energy production capacity and accumulation of acetyl-CoA in Hmgcs2 KO mice. Furthermore, acetylome analysis of Hmgcs2 KO cells revealed enhanced acetylation of mitochondrial proteins. These findings suggest that neonatal ketogenesis protects the energy-producing capacity of mitochondria by preventing the hyperacetylation of mitochondrial proteins.
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http://dx.doi.org/10.1038/s42255-021-00342-6DOI Listing
February 2021

Temporal trends in coronary intervention strategies and the impact on one-year clinical events: data from a Japanese multi-center real-world cohort study.

Cardiovasc Interv Ther 2021 Jan 9. Epub 2021 Jan 9.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

Percutaneous coronary intervention (PCI) has significantly advanced over the last 40 years, but it is not clear whether there have been any changes in prognosis in recent years. The Kumamoto Intervention Conference Study Real-World Registry is a multi-center registry that enrolls consecutive patients undergoing PCI in 17 centers in Kyushu, Japan. To elucidate the clinical impact of recent changes in treatment strategies, 8841 consecutive participants (historical PCI: n = 4038, enrolled between January 2013 and December 2014, and current PCI: n = 4803, between January 2015 and March 2017) with 1-year follow-up data were analyzed. The incidences of major adverse cardiovascular and other clinical events were comparable between historical PCI and current PCI, even though complex lesions were more frequent during the more recent period. During this period, the use of radial approaches, drug eluting stents, and coronary imaging was greater. The use of prasugrel was more frequent (P < 0.001) during the time periods. Comparable event rates were associated with the use of clopidogrel (52.7%) and prasugrel (47.3%). In the sub-analysis for acute coronary syndrome (n = 5047), similar clinical event rates were recorded for historical and current PCI. Although the lesions to be treated are becoming more severe and complex, equivalent clinical outcomes have been maintained in recent years, possibly due to advances in the devices and medication used.
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http://dx.doi.org/10.1007/s12928-020-00752-5DOI Listing
January 2021

Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial.

J Atheroscler Thromb 2021 Jan 7. Epub 2021 Jan 7.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University.

Aim: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI.

Methods: This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment.

Results: Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period.

Conclusions: This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.
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http://dx.doi.org/10.5551/jat.59477DOI Listing
January 2021

Role of Epoxyeicosatrienoic Acids in Acetylcholine-Induced Dilation of Rat Retinal Arterioles in Vivo.

Biol Pharm Bull 2021 ;44(1):82-87

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

CYP epoxygenase-derived epoxyeicosatrienoic acids (EETs) contribute to endothelium-dependent hyperpolarization (EDH)-related dilation in multiple vascular beds. The present study aimed to determine the role of EETs in the acetylcholine (ACh)-induced dilation of retinal arterioles in rats in vivo. The vasodilator responses were assessed by determining the change in diameter of the retinal arterioles on images of the ocular fundus. The intravitreal injection of 17-octadecynoic acid (1.4 nmol/eye), an inhibitor of CYP epoxygenase, and 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE-5(Z)-E; 2 nmol/eye), an antagonist of EETs, reduced the ACh (0.3-10 µg/kg/min)-induced dilation of the retinal arterioles. The EET antagonist attenuated the vasodilator response to ACh under blockade of nitric oxide (NO) synthases and cyclooxygenases with N-nitro-L-arginine methyl ester (30 mg/kg) plus indomethacin (5 mg/kg). Intravitreal injection of 14,15-EET (0.5 nmol/eye) dilated retinal arterioles and the response was prevented by iberiotoxin, an inhibitor of large-conductance Ca-activated K (BK) channels (20 pmol/eye). These results suggest that ACh stimulates the production of EETs, thereby dilating the retinal arterioles via activation of BK channels. CYP epoxygenase-derived EETs may be involved in the EDH-related component of the ACh-induced dilation of the retinal arterioles.
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http://dx.doi.org/10.1248/bpb.b20-00635DOI Listing
January 2021

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus.

Dev Dyn 2021 Apr 2;250(4):497-512. Epub 2020 Nov 2.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.

Background: In mice, a tri-layered (superficial, intermediate, and deep) vascular structure is formed in the retina during the third postnatal week. Short-term treatment of newborn mice with vascular endothelial growth factor (VEGF) receptor inhibitors delays the formation of superficial vascular plexus and this allows us to investigate the developmental process of superficial and deep vascular plexuses at the same time. Using this model, we examined the effect of pharmacological depletion of retinal neurons on the formation of superficial and deep vascular plexuses.

Results: Neuronal cell loss induced by an intravitreal injection of N-methyl-d-aspartic acid on postnatal day (P) 8 delayed vascular development in the deep layer but not in the superficial layer in mice treated with KRN633, a VEGF receptor inhibitor, on P0 and P1. In KRN633-treated mice, neuronal cell loss decreased the number of vertical sprouts originating from the superficial plexus without affecting the number of angiogenic sprouts growing in front. Neuronal cell loss did not impair networks of fibronectin and astrocytes in the superficial layer.

Conclusions: Our results suggest that inner retinal neurons play a crucial role in forming the deep vascular plexus by directing the sprouts from the superficial blood vessels to the deep layer.
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http://dx.doi.org/10.1002/dvdy.263DOI Listing
April 2021

Association of short term exposure to Asian dust with increased blood pressure.

Sci Rep 2020 10 19;10(1):17630. Epub 2020 Oct 19.

Department of Pharmacoepidemiology, Graduate School of Medical and Public Health, Kyoto University, Yoshida, Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.

Air pollution causes hypertension, cardiovascular disease, and mortality. Asian dust (AD) reportedly induces asthma or acute myocardial infarction along with air pollution, but its impact on blood pressure (BP) is unknown. We investigated the association between short-term AD exposure and BP fluctuations in 300,952 individuals whose BP was measured during April 2005-March 2015 and divided them into AD and non-AD groups based on visitation for AD-related events. AD's occurrence, air pollutants' concentration (suspended particulate matter, SO, NO, photochemical oxidants), and meteorological variables (mean ambient temperature, relative humidity) were obtained from a monitoring station; AD events correlated with decreased visibility (< 10 km). We observed 61 AD days, with 3897 participants undergoing medical check-ups. Short-term AD exposure at lag day-0 was significantly associated with higher systolic BP (SBP), diastolic BP (DBP), and pulse rate (PR) risk (β = 1.85, 95% confidence interval (CI) 1.35-2.35 for SBP, β = 2.24, 95% CI 1.88-2.61 for DBP, β = 0.52, 95% CI 0.14-0.91 for PR) using multi-pollutant model. Population-attributable fractions exposed to AD were 11.5% for those with elevated SBP (SBP ≥ 120 mmHg) and 23.7% for those with hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg). This study showed a strong association between short-term AD exposure and increased SBP and DBP.
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http://dx.doi.org/10.1038/s41598-020-74713-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572380PMC
October 2020

The process of revascularization in the neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors.

Cell Tissue Res 2020 Dec 8;382(3):529-549. Epub 2020 Sep 8.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

Misdirected vascular growth frequently occurs in the neovascular diseases in the retina. However, the mechanisms are still not fully understood. In the present study, we created capillary-free zones in the central and peripheral retinas in neonatal mice by pharmacological blockade of vascular endothelial growth factor (VEGF) signaling. Using this model, we investigated the process and mechanisms of revascularization in the central and peripheral avascular areas. After the completion of a 2-day treatment with the VEGF receptor tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5, revascularization started on P8 in the central avascular area where capillaries had been dropped out. The expression levels of VEGF were higher in the peripheral than in the central avascular area. However, the expansion of the vasculature in the peripheral avascular retina remained suppressed until revascularization had been completed in the central avascular area. Additionally, we found disorganized endothelial cell division, misdirected blood vessels with irregular diameters, and abnormal fibronectin networks at the border of the vascular front and the avascular retina. In the central avascular area, a slight amount of fibronectin as non-vascular component re-formed to provide a scaffold for revascularization. Mechanistic analysis revealed that higher levels of VEGF attenuated the migratory response of endothelial cells without decreasing the proliferative activity. These results suggest that the presence of concentration range of VEGF, which enhances both migration and proliferation of the endothelial cells, and the structurally normal fibronectin network contribute to determine the proper direction of angiogenesis.
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http://dx.doi.org/10.1007/s00441-020-03276-9DOI Listing
December 2020

Clinical significance of reactive oxidative metabolites in patients with heart failure with reduced left ventricular ejection fraction.

J Card Fail 2021 Jan 11;27(1):57-66. Epub 2020 Aug 11.

Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Science and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan.

Background: We investigated the clinical significance of the derivative of reactive oxygen metabolites (DROM), a new marker of reactive oxygen species (ROS), in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF).

Methods And Results: Serum DROM concentrations were measured in 201 consecutive patients with HFrEF (EF < 50%) in stable condition. DROM values were significantly higher in patients with HFrEF than in risk-matched patients without HF (P < 0.01). They also correlated significantly with high-sensitivity C-reactive protein and B-type natriuretic peptide. Kaplan-Meier analysis demonstrated significantly higher probabilities of HF-related events in the high-DROM group than in the low-DROM group (log-rank test, P < 0.01). Multivariable Cox hazard analysis revealed that DROM were independent and significant predictors of cardiovascular events. In a subgroup analysis, DROM levels were also measured at the aortic root and coronary sinus in 49 patients. The transcardiac gradient of DROM values was significantly higher in patients with HFrEF than in patients without HF (P = 0.04), indicating an association between DROM production in the coronary circulation and HFrEF development. Changes in DROM following optimal therapy were significantly associated with LVEF improvement (r = 0.34, P = 0.04).

Conclusions: The higher levels of DROM and their association with cardiovascular events suggest the clinical benefit of DROM measurements in the risk stratification of patients with HFrEF.
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http://dx.doi.org/10.1016/j.cardfail.2020.07.020DOI Listing
January 2021

The controlling nutritional status score predicts outcomes of cardiovascular events in patients with heart failure with preserved ejection fraction.

Int J Cardiol Heart Vasc 2020 Aug 26;29:100563. Epub 2020 Jun 26.

Department of Cardiovascular Medicine and Center for Metabolic Regulation of Healthy Aging, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

Backgrounds: The relationship between cardiovascular outcomes and the Controlling Nutritional Status (CONUT) score in heart failure (HF) with preserved ejection fraction (HFpEF) patients is unknown. This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients.

Methods And Results: A total of 506 consecutive HFpEF patients were prospectively observed for up to 1500 days or until the occurrence of cardiovascular events. The mean age was 71.6 ± 9.4 years. Cardiovascular outcomes were compared between the CONUT score 0-1 group with a normal nutritional state (normal group), the CONUT score 2-4 group with a light degree of undernutrition (light group), and the CONUT score 5-8 group with a moderate degree of undernutrition (moderate group). In this study, there were no patients who scored 9-12, which was defined as a severe state of undernutrition. Overall, 238 cardiovascular events were observed during the follow-up period (median: 1159 days). Kaplan-Meier analysis showed that the moderate group was at higher risk of composite cardiovascular events than the normal group  < 0.001) and the light group ( = 0.031). The analysis also showed that the light group was at higher risk of composite cardiovascular events than the normal group ( = 0.038). Multivariable Cox proportional hazards analysis with the significant factors from the univariate analysis showed that the CONUT score (hazard ratio: 1.12, 95% confidence interval: 1.03-1.21,  0.005) significantly predicted future cardiovascular events.

Conclusion: Nutritional screening using the CONUT score may be useful for predicting cardiovascular events in HFpEF patients.
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http://dx.doi.org/10.1016/j.ijcha.2020.100563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326720PMC
August 2020

4-Aminopyridine, a Voltage-Gated K Channel Inhibitor, Attenuates Nitric Oxide-Mediated Vasodilation of Retinal Arterioles in Rats.

Biol Pharm Bull 2020 ;43(7):1123-1127

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Nitric oxide (NO) is an important regulator of the retinal blood flow. The present study aimed to determine the role of voltage-gated K (K) channels and ATP-sensitive K (K) channels in NO-mediated vasodilation of retinal arterioles in rats. In vivo, the retinal vasodilator responses were assessed by measuring changes in the diameter of retinal arterioles from ocular fundus images. Intravitreal injection of 4-aminopyridine (a K channel inhibitor), but not glibenclamide (a K channel blocker), significantly attenuated the retinal vasodilator response to the NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3). Intravitreal injection of indomethacin (a non-selective cyclooxygenase inhibitor) also reduced the NOR3-induced retinal vasodilator response. The combination of 4-aminopyridine and indomethacin produced a greater reduction in the NOR3-induced response than either agent alone. 4-Aminopyridine had no significant effect on pinacidil (a K channel opener)-induced response. These results suggest that the vasodilatory effects of NO are mediated, at least in part, through the activation of 4-aminopyridine-sensitive K channels in the retinal arterioles of rats. NO exerts its dilatory effect on the retinal vasculature of rats through at least two mechanisms, activation of the K channels and enhancement of prostaglandin production.
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http://dx.doi.org/10.1248/bpb.b20-00220DOI Listing
December 2020

Author's reply.

J Cardiol 2020 11 4;76(5):529-530. Epub 2020 Jun 4.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

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http://dx.doi.org/10.1016/j.jjcc.2020.05.002DOI Listing
November 2020

Clinical significance of diastolic late mitral annular velocity in heart failure with preserved ejection fraction.

Int J Cardiol 2020 10 2;316:145-151. Epub 2020 Apr 2.

Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.

Objectives: Because diastolic late mitral annular velocity (a') obtained by transthoracic-echocardiography (TTE) represents left atrial (LA) function, we investigated the clinical significance of a' in heart failure (HF) with a preserved left ventricular (LV) ejection fraction (HFpEF).

Methods: We enrolled 448 consecutive HFpEF patients (sinus rhythm: 66.3%, atrial fibrillation [AF] rhythm: 33.7%) and performed TTE under stable conditions after optimal therapy. In patients with sinus rhythm, a' values were measured at septal mitral annuli.

Results: A' had weak but significant negative correlations with the natural-logarithm-B-type natriuretic peptide (Ln-BNP), LA diameter, LV mass index and tricuspid regurgitation pressure gradient. Receiver operating characteristic (ROC) curve analysis showed that the best cut-off value of a' and systolic mitral annular velocity (s') for the prediction of HF-related events were 7.45 cm/s and 6.5 cm/s with areas under the curve (AUC) of 0.841 and 0.682, respectively. The AUC of ROC analysis for the logistic regression model of a' plus s' was improved to 0.97. In Kaplan-Meier analysis, HFpEF patients with low-a' (<7.45 cm/s) had a significantly higher risk of total cardiovascular and HF-related events (both p < .01 by log-rank test) than those with high-a' (≥ 7.45 cm/s) and were prognostically equivalent to those with AF. Multivariate Cox proportional hazard analysis identified low-a' as an independent predictor of both total cardiovascular (hazard ratio [HR]: 0.823, 95% confidence interval [CI]: 0.714-0.949, p = .007) and HF-related events (HR: 0.551, 95% CI: 0.422-0.720, p < .001).

Conclusion: A' value measurement is a non-invasive and useful method for risk stratification in HFpEF.
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http://dx.doi.org/10.1016/j.ijcard.2020.03.077DOI Listing
October 2020

Involvement of Gi protein-dependent BK channel activation in β-adrenoceptor-mediated dilation of retinal arterioles in rats.

Naunyn Schmiedebergs Arch Pharmacol 2020 11 5;393(11):2043-2052. Epub 2020 Jun 5.

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

Circulating catecholamines contribute to the regulation of retinal vascular tone. Our previous studies have demonstrated that the activation of large-conductance Ca-activated K (BK) channels is involved in the β-adrenoceptor-mediated dilation of retinal arterioles in rats. The present study aimed to examine the role of Gi protein in the β-adrenoceptor-mediated activation of BK channels in the retinal arterioles. Images of in vivo rat ocular fundi were captured, and the diameters of retinal arterioles were measured. Systemic blood pressure and heart rate were recorded continuously. Intravenous infusion of formoterol (0.01-0.3 μg/kg/min), a β-adrenoceptor agonist, increased the diameter of retinal arterioles but decreased mean arterial pressure in a dose-dependent manner. Intravitreal injection of iberiotoxin (20 pmol/eye), an inhibitor of BK channels, significantly attenuated the formoterol-induced dilation of retinal arterioles. Similar results were obtained when salbutamol (0.03-3 μg/kg/min), another β-adrenoceptor agonist, was used instead of formoterol. However, iberiotoxin had no significant effect on retinal vasodilator responses to intravenous infusion of denopamine (1-30 μg/kg/min; a β-adrenoceptor agonist), CL316243 (0.3-10 μg/kg/min; a β-adrenoceptor agonist), prostaglandin I (0.03-10 μg/kg/min; a prostanoid IP receptor agonist), and forskolin (1-10 μg/kg/min; an adenylyl cyclase activator). Intravitreal injection of pertussis toxin (66 ng/eye; a Gi protein inhibitor) significantly attenuated the dilation of retinal arterioles induced by formoterol but not by denopamine and CL316243. In the presence of pertussis toxin, iberiotoxin had no inhibitory effect on formoterol-induced dilation of retinal arterioles. These results suggest that stimulation of β-adrenoceptors dilates retinal arterioles through pertussis toxin-sensitive Gi protein-dependent activation of BK channels in rats in vivo.
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http://dx.doi.org/10.1007/s00210-020-01895-1DOI Listing
November 2020

Long-Term Prognosis of Patients with Myocardial Infarction Type 1 and Type 2 with and without Involvement of Coronary Vasospasm.

J Clin Med 2020 Jun 2;9(6). Epub 2020 Jun 2.

Department of Cardiology, Sakakibara Heart Institute, Tokyo 183-0003, Japan.

While prognoses in relation to myocardial infarction (MI) type have been elucidated in past reports, the results were not consistent, perhaps due to occurrence of Type 2 MI with CVS and its mortality. The Japanese registry of acute Myocardial Infarction diagnosed by Universal Definition (J-MINUET) is a prospective multicenter registry in Japan. In contrast to thromboembolic event-related Type 1 myocardial infarction (MI), clinical features of Type 2 MI, including coronary vasospasm (CVS), are varied due to the heterogeneous nature of its development. To elucidate the MI type-related all-cause mortality, 2989 consecutive patients with AMI were stratified as Type 1 MI, Type 2 MI with CVS, and Type 2 MI with non-CVS. Most patients ( = 2834; 94.8%) were classified as Type 1 MI and 155 patients (5.2%) were classified as Type 2 MI. Of the Type 2 MI patients, 87 (56% of Type 2 MI) were diagnosed as MI with CVS. Although the 3-year mortality was comparable between Type 1 and Type 2 MI patients, significant differences were observed between Type 2 MI with CVS and with non-CVS (3.4% and 22.1%, < 0.001). Among Japanese patients with AMI, mortality rates between Type 1 MI and Type 2 MI are comparable, but further stratification of Type 2 MI (with or without CVS) may be useful in predicting the prognosis of patients with Type 2 MI.
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http://dx.doi.org/10.3390/jcm9061686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356040PMC
June 2020

Effects of Statin Plus Ezetimibe on Coronary Plaques in Acute Coronary Syndrome Patients with Diabetes Mellitus: Sub-Analysis of PRECISE-IVUS Trial.

J Atheroscler Thromb 2021 Feb 20;28(2):181-193. Epub 2020 May 20.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences and Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University.

Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM.

Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9-12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) <70 mg/dL.

Results: In DM patients, the monotherapy group (n=13) and the DLLT group (n=12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: -2.77±3.47% vs. -0.77±2.51%, P=0.11; non-DM: -2.01±3.36% vs. -0.08±2.66%, P=0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r=0.52, P=0.008).

Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.
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http://dx.doi.org/10.5551/jat.54726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957031PMC
February 2021

Coronary artery perforation into the upper gastrointestinal cavity due to gastric ulceration.

Catheter Cardiovasc Interv 2021 Feb 19;97(2):E237-E240. Epub 2020 May 19.

The Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

An 82-year-old man who had previously undergone a proximal gastrectomy with jejunal interposition surgery for stomach cancer was transferred to our hospital for massive hematemesis and hypotension. His electrocardiogram showed ST-segment elevation in lead ΙΙ, ΙΙΙ, aVF, which confirmed inferior myocardial infarction. Due to active hematemesis, upper endoscopy was performed initially. A visible vessel of gastric ulceration was discovered, and hemostasis was achieved using hemoclips. Subsequently, coronary angiography was performed since the right coronary artery (RCA) segment 4 atrioventricular (AV) was occluded. After thrombectomy and intravascular ultrasound (IVUS), 2.0 mm balloon angioplasty was done, and coronary perforation occurred. During coronary angiography, extravasation of the contrast material into the gastrointestinal cavity was noted. A covered stent was placed across segment 3 to segment 4 descending posteriorly (PD) to stop the blood supply to the perforation site of segment 4 AV. After stenting, adequate re-hemostasis was achieved. The patient was discharged after 28 days. This is the first report of a coronary artery perforation into the gastrointestinal cavity.
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http://dx.doi.org/10.1002/ccd.28945DOI Listing
February 2021

Abnormal Vascular Phenotypes Associated with the Timing of Interruption of Retinal Vascular Development in Rats.

Biol Pharm Bull 2020 ;43(5):859-863

Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.

Pathological angiogenesis is a leading cause of blindness in several retinal diseases. The key driving factor inducing pathological angiogenesis is the pronounced hypoxia leading to a marked, increased production of vascular endothelial growth factor (VEGF). The aim of this study was to determine whether the abnormal vascular growth occurs in a manner dependent on the degree of the vascular defects. Vascular defects of two different degrees were created in the retina by subcutaneously treating neonatal rats with the VEGF receptor (VEGFR) tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5 (P4/5) or P7 and P8 (P7/8). The structure of the retinal vasculature changes was examined immunohistochemically. Prevention of vascular growth and regression of some preformed capillaries were observed on the next day, after completion of each treatment (i.e., P6 and P9). The vascular regrowth occurred as a result of eliminating the inhibitory effect on the VEGFR signaling pathway. KRN633 (P4/5)-treated rats exhibited a retinal vasculature with aggressive intravitreal neovascularization on P21. On the other hand, the appearance of tortuous arteries is a representative vascular pathological feature in retinas of KRN633 (P7/8)-treated groups. These results suggest that an interruption of the retinal vascular development at different time points induces different vascular pathological features in the retina. Pharmacological agents targeting the VEGF signaling pathway are useful for creating an abnormal retinal vasculature with various pathological features in order to evaluate the efficacy of anti-angiogenic compounds.
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http://dx.doi.org/10.1248/bpb.b19-01065DOI Listing
January 2021

Optical Coherence Tomography-Guided Percutaneous Coronary Intervention With Low-Molecular-Weight Dextran - Effect on Renal Function.

Circ J 2020 05 29;84(6):917-925. Epub 2020 Apr 29.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University.

Background: The excessive volume of contrast needed is a significant limitation of optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI). Low-molecular-weight dextran (LMWD) has been used for OCT image acquisition instead of contrast media. This study compared the effects of OCT-guided PCI using LMWD on renal function and clinical outcomes to those of intravascular ultrasound (IVUS)-guided PCI.Methods and Results:In all, 1,183 consecutive patients who underwent intracoronary imaging-guided PCI were enrolled in this single-center, retrospective, observational study. After propensity score matching, 133 pairs of patients were assigned to undergo either OCT-guided PCI using LMWD or IVUS-guided PCI. There was no significant change from baseline in the primary endpoint, serum creatinine concentrations, after the procedure in either group. There were no significant differences between the OCT and IVUS groups in the volume of contrast medium, the incidence of contrast-induced nephropathy (1.5% vs. 2.3%; P=0.65), and major adverse cardiovascular events (MACE) at 30 days (2.3% vs. 6.0%; P=0.12) and 12 months (2.3% vs. 3.0%; P=0.70) after the procedure. Kaplan-Meier analysis at the 12-month follow-up revealed no significant difference in the incidence of MACE between the 2 groups (P=0.75).

Conclusions: OCT-guided PCI using LMWD did not negatively affect renal function and achieved similar short- and long-term clinical outcomes to IVUS-guided PCI.
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http://dx.doi.org/10.1253/circj.CJ-20-0093DOI Listing
May 2020

Prognostic impact of the presence of on-duty cardiologist on patients with acute myocardial infarction admitted during off-hours.

J Cardiol 2020 08 19;76(2):184-190. Epub 2020 Mar 19.

Department of Cardiovascular Medicine, Graduate School of Medicine, Kumamoto University, Kumamoto, Japan.

Background: Owing to reduced staffing, patients hospitalized for acute myocardial infarction (AMI) during off-hours (nights, weekends, and holidays) have poorer outcomes than those admitted during regular hours. Whether the presence of an on-duty cardiologist in a hospital during off-hours is related to better outcomes for patients with AMI remains unclear. The Miyazaki Prefectural Nobeoka Hospital had a unique medical care system in that cardiologists were on call for half of the week and on duty for the other half during off-hours, thus providing an opportunity to assess the relationship between the presence of an on-duty cardiologist and patient outcomes. We examined clinical outcomes of patients admitted for AMI during off-hours according to the presence of an on-duty cardiologist.

Methods: We recruited 225 consecutive patients with AMI hospitalized during off-hours, who underwent stent implantation at Miyazaki Prefecture Nobeoka Hospital from 2013 to 2017. The endpoints were in-hospital death or long-term major adverse cardiac events (MACE) including cardiovascular death, non-fatal MI, non-fatal stroke, stent thrombosis, ischemia-driven target-lesion revascularization, admission owing to unstable angina, or admission owing to heart failure.

Results: Based on the presence of an on-call cardiologist at admission, we divided patients into the cardiologist on-call group (n = 112) or cardiologist on-duty group (n = 113). The presence of an on-duty cardiologist did not affect door-to-reperfusion time (p = 0.776), level of peak creatine kinase (p = 0.971), or in-hospital death (p = 0.776). The Kaplan-Meier curve analysis showed similar prognosis for the cardiologist on-duty and cardiologist on-call groups (p = 0.843), and multivariable Cox regression analysis showed that the presence of an on-duty cardiologist was not associated with MACE.

Conclusions: The presence of an on-duty cardiologist is not a prognostic factor for patients hospitalized for AMI during off-hours in our medical system. Further prospective multicenter studies should confirm our results.
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http://dx.doi.org/10.1016/j.jjcc.2020.02.016DOI Listing
August 2020

Cytotoxin-associated gene-A-seropositivity and polymorphisms influence adverse cardiovascular events.

Int J Cardiol Heart Vasc 2020 Apr 7;27:100498. Epub 2020 Mar 7.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.

Aims: Although the bacterial virulent factor of cytotoxin-associated gene-A (CagA)-seropositivity and the host genetic factors of polymorphisms have been suggested to influence -related diseases, the underlying mechanisms of the association between infection and acute coronary syndrome (ACS) remain unknown.

Methods And Results: Among 341 consecutive ACS patients, the clinical outcomes after ACS included composite cardiovascular events within the 2-year follow-up period.A significantly higher probability of primary outcomes was observed in positive patients than in negative patients. There were no significant differences in the rate of cardiovascular events between positive and negative patients in the absence of an -polymorphism, while there were significant differences in the presence of an -polymorphism. There were significant differences in the rate of cardiovascular events among CagA positive, CagA negative/ positive and CagA negative/ negative patients. Moreover, via immunohistochemical staining, aortic CagA positive cells were confirmed in the vasa vasorum in CagA positive patients, whereas they could not be identified in CagA negative patients.

Conclusions: The bacterial virulence factor CagA and host genetic polymorphisms influence the incidence of adverse cardiovascular events, possibly through infection of atherosclerotic lesions. University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). UMIN000035696.
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http://dx.doi.org/10.1016/j.ijcha.2020.100498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062927PMC
April 2020
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