Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.

The incidence, natural history, and predictive factors for tissue protrusion after drug-eluting stent implantation.

OBJECTIVES AND BACKGROUND: Although tissue protrusion (TP) between the stent struts after stent implantation has been implicate as a potential factor of stent failure, the incidence, natural history, and predictive factor of TP after stent implantation remains unclear. This prospective study evaluated the fate of TP after drug-eluting stent (DES) deployment using optical coherence tomography (OCT). METHOD AND RESULT: This study analyzed TP for 42 lesions after DES in which three serial OCTs, including preprocedure, postprocedure, and 1-month after the procedure were performed. TP was classified into the five groups: (a) persistent, (b) progressive, (c) healed, (d) regressive, and (e) late-acquired. Immediately after the procedure, 100 TPs in 37 lesions (88%) were identified. Of those, 53 (53%) were persistent, 3 (3%) were progressive, 20 (20%) were healed, and 24 (24%) were regressed at 1-month follow-up. Seven TPs in five patients (13%) were observed only at 1-month follow-up (late-acquired). CONCLUSION: In lesions with late-acquired TP, calcified nodule was identified as an underlying plaque morphology on preprocedural OCT. A serial OCT analysis found TP occurred not only immediately after DES implantation, but also 1-month after DES implantation.

Renoprotective effect of tolvaptan in patients with new-onset acute heart failure.

AIMS: Although tolvaptan has been reported to prevent worsening renal function (WRF) in patients with advanced acute heart failure (AHF), evidence regarding the effect of tolvaptan on renal function in patients with new-onset AHF is not available. This study aimed to investigate the renoprotective effect of tolvaptan in patients hospitalized with new-onset AHF. METHODS AND RESULTS: A total of 122 consecutive patients hospitalized with new-onset AHF between May 2015 and December 2018 were retrospectively evaluated. WRF was defined as an absolute increase in serum creatinine ≥0.3 mg/dL (≥26.4 µmol/L) within 48 h or a 1.5-fold increase in serum creatinine after hospitalization. The furosemide group (n = 75) and the tolvaptan add-on group (n = 47) were compared. The tolvaptan group consists of patients who received tolvaptan as an individual physicians' decision. The incidence of WRF was significantly lower in the tolvaptan add-on group (8.5%) than in the furosemide group (24.0%, P = 0.03). Multivariate logistic regression analysis revealed that tolvaptan treatment was an independent variable related to the prevention of WRF [odds ratio (OR), 0.20; 95% confidence interval (CI), 0.05-0.85]. Furthermore, subgroup analysis revealed a more favourable effect of tolvaptan in patients with serum creatinine ≥1.1 mg/dL on admission (OR, 0.23; 95% CI, 0.06-0.98) and an ejection fraction <50% (OR, 0.19; 95% CI, 0.04-0.90). CONCLUSIONS: A lower incidence of WRF was observed in patients with new-onset AHF who were treated with the tolvaptan add-on therapy, specifically those with left ventricular systolic dysfunction and renal impairment on admission.

Effect of Tofogliflozin on Systolic and Diastolic Cardiac Function in Type 2 Diabetic Patients.

PURPOSE: Recent studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors have a favorable effect on cardiovascular events in diabetic patients. However, the underlying mechanism associated with a favorable outcome has not been clearly identified. The purpose of this study was to investigate the effect of tofogliflozin, SGLT2 inhibitor, on systolic and diastolic cardiac function in patients with type 2 diabetes mellitus (T2DM). METHODS: We enrolled 26 consecutive T2DM out-patients on glucose-lowering drugs who initiated tofogliflozin and underwent echocardiography before and ≥ 6 months after tofogliflozin administration. During this period, we also enrolled 162 T2DM out-patients taking other glucose-lowering drugs as a control group. Propensity score analysis was performed to match the patient characteristics. As a result, 42 patients (tofogliflozin group 21 patients and control group 21 patients) were finally used for analysis. Left ventricular systolic function was assessed by measuring 2D-echocardiographic left ventricular ejection fraction (LVEF) and diastolic cardiac function by pulsed wave Doppler-derived early diastolic velocity (E/e'). RESULTS: There were no significant differences in patient characteristics and echocardiographic parameters at baseline. The change in LVEF from baseline to follow-up was 5.0 ± 6.9% in the tofogliflozin group and - 0.6 ± 5.5% in the control group; difference significant, p = 0.006. The change in E/e' was - 1.7 ± 3.4 in the tofogliflozin group and 0.7 ± 4.1 in the control group; difference significant, p = 0.024. CONCLUSIONS: In addition to conventional oral glucose-lowering drugs, additional tofogliflozin administration had a favorable effect on left ventricular systolic and diastolic function in patients with T2DM.

Heparin Induces the Mobilization of Heart-Derived Multipotent Mesoangioblasts During Cardiac Surgery With Cardiopulmonary Bypass or Cardiac Catheterization.

BACKGROUND: We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. CONCLUSIONS: Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.

Intracoronary followed by intravenous administration of the short-acting ß-blocker landiolol prevents myocardial injury in the face of elective percutaneous coronary intervention.

BACKGROUND: Myocardial injury during elective percutaneous coronary intervention (PCI) is associated with higher subsequent cardiac events and mortality. ß-Blockers have been used to reduce myocardial injury during ischemia and reperfusion. We investigated whether intracoronary followed by intravenous administration of the short-acting ß-blocker landiolol prevents myocardial injury in the face of elective PCI. METHODS AND RESULTS: Patients undergoing elective PCI (n=70) were randomly assigned to the landiolol (n=35) or control (n=35) group. Landiolol or saline was administered into target vessels through a balloon catheter for 1min before and after first balloon inflation followed by continuous intravenous administration for 6h after PCI. The incidence of myocardial injury defined by cardiac troponin-I (cTnI) >/=0.05 ng/ml was 79% of the patients in the control group compared to 56% in the landiolol group (p=0.04). The cTnI level at 24h after PCI tended to be lower in the landiolol group (0.57 ± 1.14 versus 1.27 ± 2.48 ng/ml; p=0.07), while the CK-MB level was not significantly different between the landiolol and control groups. The incidence of peri-procedural myocardial infarction defined by cTnI >/=0.12 ng/ml was significantly (p=0.02) lower in the landiolol group (41%) compared to the control group (70%). There was no incidence of coronary spasm, hypotension, bradycardia or heart failure during and after PCI in the two groups. CONCLUSIONS: Brief intracoronary followed by continuous intravenous administration of landiolol is safe and effective for myocardial protection in the face of elective PCI.

Efficacy of intracoronary administration of a short-acting ß-blocker landiolol during reperfusion in pigs.

BACKGROUND: Although ß-blockers are used to prevent myocardial ischemia/reperfusion injury, the risk of heart failure has limited ß-blocker therapy in patients with acute myocardial infarction. This study evaluated efficacy of intracoronary administration of the short-acting ß-blocker, landiolol, during reperfusion in pigs with acute myocardial ischemia. METHODS AND RESULTS: In the non-ischemic model landiolol administered into the left anterior descending coronary artery (LAD) inhibited in a dose-dependent fashion segmental wall thickening (SWT) in the anterior LV wall without altering SWT in the posterior LV wall and without prolonged depression of global LV function except for the highest dose. In the ischemic model with 60 min LAD occlusion followed by reperfusion the medium dose landiolol administered into the LAD 1 min before and for 10 min during reperfusion inhibited initial recovery of SWT in the anterior LV wall but improved SWT in this region and global LV function late after reperfusion. Ultrastructural studies showed inhibition of sub-sarcolemmal bleb formation by treatment with landiolol 10 min after reperfusion associated with the inhibition of CK-MB release and the reduction of infarct size. There was no significant difference in CK-MB release and infarct size between landiolol treatment for 10 min and 180 min during reperfusion. CONCLUSIONS: Selective and brief intracoronary administration of landiolol during reperfusion enhances myocardial salvage without causing deterioration of global LV function.

Retrograde fast pathway ablation with the EnSite NavX mapping system for slow-fast atrioventricular node reentrant tachycardia and a prolonged PR interval during sinus rhythm.

An 84-year-old male had experienced palpitations. He was transported to our hospital for treatment of palpitations. A 12-lead electrocardiogram (ECG) showed regular tachycardia with a wide QRS complex of 153 bpm, and the P wave was not clear. The ECG after the tachycardia stopped showed a sinus rhythm, and there was a prolonged PR interval of 312 ms and complete right bundle branch block. We recorded a prolonged AH interval (235 ms) in electrophysiology study (EPS). As for the St-A interval (185 ms) by consecutive pacing from the right ventricular apex, it was short in comparison with the anterograde conduction. As a result of detailed EPS, we diagnosed the tachycardia as slow-fast atrioventricular nodal reentrant tachycardia. The anterograde conduction depended on the slow pathway (SP), and the fast pathway (FP) was considered to have only retrograde conduction. It was thought that a complete atrioventricular block been caused by the SP ablation. Therefore we carried out FP ablation with three-dimensional computed tomography and the EnSite NavX mapping system (St. Jude Medical, St Paul, MN, USA), which was superior in space resolution power, and were able to effect a radical cure without complications.

The case of successful catheter ablation using only the approach from the upper part of the subject's body, with meandering aorta and implanted IVC filter.

A 79-year-old female had paroxysmal supraventricular tachycardia. However, she was implanted with an inferior vena cava filter and her descending aorta had significant meandering. It was thought that the insertion of the catheters would be difficult from the femoral vessels. Therefore we inserted electrode catheters from the right subclavian vein and internal jugular vein. As a result of an electrophysiology study, we diagnosed atrioventricular reciprocating tachycardia with a left lateral concealed accessory pathway (AP). An ablation catheter was introduced retrogradely through the left brachial artery and it was pushed forward under the mitral valve. Furthermore, it was put into the part where the earliest retrograde atrial deflection was recorded under the right ventricular apex pacing, and we succeeded in ablation of the AP. All catheters were inserted only from the upper part of the person's body. As for catheter operability, electric potential, operation time, and fluoroscopy time, there was no change in the case of either approach from the femoral vessels. Because we did not puncture the inguinal region, the patient was able to return to her ward on foot after the operation. In addition, we were able to perform a radical cure without complications.

Percutaneous coronary intervention for left main trunk ostial stenosis in a patient with Takayasu's arteritis.

Takayasu's arteritis with coronary artery involvement is a rare event especially in men. We will report on a male case of Takayasu's arteritis undergoing stent implantation for left main trunk (LMT) ostial stenosis. The case was that of a 25-year-old man who had been diagnosed with Takayasu's arteritis but there was no significant large vessel involvement. He presented with effort angina and a multidetector computed tomography (MDCT) revealed severe ostial stenosis in the LMT. A coronary angiography confirmed this finding and a virtual histology intravascular ultrasound (VH-IVUS) showed fibrous thickening of the intima and media with little necrotic lipid core and calcification. We performed a bare metal stent implantation for this lesion. No restenosis was found in the MDCT at the 6 month follow-up. Our experience suggests that the VH-IVUS is useful for examining the gross structure and component of the coronary vascular wall and for determining the choice of treatment in patients with Takayasu's arteritis.

Comparison of neointimal morphology of in-stent restenosis with sirolimus-eluting stents versus bare metal stents: virtual histology-intravascular ultrasound analysis.

Sirolimus-eluting stents (SES) have reduced the incidence of restenosis and target lesion revascularization compared to bare metal stents (BMS). However, inhibition of endothelialization and neointimal formation after SES implantation may produce vulnerable plaques. The present study compared the neointimal morphology of in-stent restenosis (ISR) between SES and BMS using virtual histology-intravascular ultrasound (VH-IVUS). Thirty ISR lesions (SES n = 15, BMS n = 15) demonstrated by coronary angiography in 30 patients with stable angina pectoris were analyzed with VH-IVUS between 6 months to 3 years after stent implantation. Tissue maps were reconstructed from radiofrequency data using VH-IVUS software. ISR lesions after SES implantation consisted of a significantly increased necrotic core (NC) compared to BMS (12.9 vs. 5.6% of neointimal volume, p < 0.01). However, the NC in ISR lesions after SES implantation was covered with a thick fibrous cap. An increase in the size of NC covered with a thick fibrous cap is a characteristic morphological feature of ISR after SES implantation. Further studies are needed to clarify whether such a morphological change is related to the attenuation of stent thrombosis after SES implantation.

Three-dimensional echocardiographic assessment of left ventricular function in takotsubo cardiomyopathy.

We evaluated left ventricular (LV) function by three-dimensional echocardiography (3DE) in a patient with takotsubo cardiomyopathy (TC). An 82-year-old man was admitted to our hospital with a suspicion of acute myocardial infarction but was diagnosed as TC by coronary angiography and left ventriculography (LVG). Three-dimensional echocardiography showed circular asynergy from the midventricle to the apex associated with hyperkinesis of the base and volumetric data very close to those obtained by LVG. Thus, 3DE is a useful tool in evaluating regional wall motion abnormalities and LV volume in patients with TC.