Atropine sulfate may be effective to recover the unstable hemodynamics in coronary artery spasms related to atrial fibrillation ablation procedures.

Coronary artery spasms related to atrial fibrillation ablation procedures could cause lethal ventricular fibrillation or cardiopulmonary arrest. It may be useful to try intravenous atropine sulfate while preparing urgent coronary artery angiography in hemodynamically unstable coronary artery spasms cases to prevent development of the lethal arrhythmias.

Optimizing Guideline-Directed Medical Therapy During Hospitalization Improves Prognosis in Patients With Worsening Heart Failure Requiring Readmissions.

BACKGROUND: We previously demonstrated that higher simple guideline-directed medical therapy (GDMT) scores (comprising renin-angiotensin system inhibitors, ß-blockers, mineralocorticoid antagonists, and sodium-glucose cotransporter 2 inhibitors) at discharge were correlated with improved prognosis in heart failure (HF) patients. HF readmissions are linked to adverse outcomes, emphasizing the need for enhanced optimization of GDMT. METHODS AND RESULTS: Using the simple GDMT score, we evaluated the effect of revising and modifying in-hospital GDMT on the prognosis of patients with HF readmissions. In this retrospective analysis of 2,100 HF patients, we concentrated on 1,222 patients with HF with reduced ejection/moderately reduced ejection fraction, excluding patients with HF with preserved ejection fraction, on dialysis, or who died in hospital. A higher current GDMT score was associated with better HF prognosis. Of the 1,222 patients in the study, we analyzed 372 cases of rehospitalization, calculating the simple GDMT scores at admission and discharge. Patients were divided into groups according to score improvement. Multivariate analysis showed a significant association between improved in-hospital simple GDMT score and the composite outcome (HF readmission+all-cause mortality; hazard ratio 0.459; 95% confidence interval 0.257-0.820; P=0.008). Even after propensity score matching to adjust for background, among rehospitalized patients, those with an improved in-hospital simple GDMT score had a better prognosis. CONCLUSIONS: Our results highlight the potential of robust interventions and score elevation during hospitalization leading to improved outcomes.

A scoring evaluation for the practical introduction of guideline-directed medical therapy in heart failure patients.

AIMS: The guideline-directed medical therapy (GDMT) has been recommended for heart failure (HF) with reduced ejection fraction (HFrEF) based on the accumulating clinical evidence. However, it is difficult to implement all the trial-proven medications for every patient in the real world. METHODS AND RESULTS: A simple GDMT score was created, according to the combination of GDMT drugs (renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose transporter 2 inhibitors) administration and their dosage (0-9 points). Its impact on the prognosis of HF patients was investigated. Admitted HF patients [HFrEF and HF with mildly reduced ejection fraction (HFmrEF), n = 1054] were retrospectively analysed (excluding those with in-hospital death and dialysis). A simple GDMT score ≥5, but not the number of medications, was significantly associated with a reduction of all-cause death, HF readmission, and composite outcome (HF readmission and all-cause death) (P < 0.001). Subgroup analysis showed that almost all groups with a simple GDMT score of 5 or higher had a better prognosis. CONCLUSIONS: The developed simple GDMT score was associated with prognosis in HFrEF and HFmrEF patients. Even if all four drugs cannot be introduced for some reason, a regimen with a simple GDMT score ≥5 may lead to a prognosis in HF patients.

Early Initiation of Sodium-Glucose Cotransporter 2 Inhibitor Leads to a Shorter Hospital Stay in Patients With Acute Decompensated Heart Failure.

Background: The efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with acute chronic heart failure (HF) is increasingly being reported. However, it is not clear when SGLT2i should be initiated in patients with acute decompensated HF (ADHF) after hospitalization. We retrospectively analyzed ADHF patients with newly prescribed SGLT2i. Methods and Results: Among the 694 patients hospitalized due to HF between May 2019 and May 2022, data were extracted for 168 patients with newly prescribed SGLT2i during the index hospitalization. These patients were divided into 2 groups: and early group (92 patients who started SGLT2i within 2 days of admission) and a late group (76 patients who started SGLT2i after 3 days). Clinical characteristics were comparable between the 2 groups. The date of cardiac rehabilitation initiation was significantly earlier in the early than late group (2.5±1.2 vs. 3.8±2.2 days; P<0.001). Hospital stay was significantly shorter in the early group (16.4±6.5 vs. 24.2±16.0 days; P<0.001). Although there were significantly fewer HF readmissions within 3 months in the early group (2.1% vs. 10.5%; P=0.044), the association disappeared in a multivariate analysis including clinical confounders. Conclusions: Early initiation of SGLT2i may shorten hospital stays.

Bigeminal superior vena cava activity with potent arrhythmogenicity.

Superior vena cava is one of the important AF triggers. Superior vena cava bigeminy acts as a trigger of AF. Attention should be paid to the bigeminal activities of the thoracic veins in AF catheter ablation.

Intra- and Postprocedural Management of Coronary Artery Perforation During Percutaneous Coronary Intervention.

Background: Little is known regarding the postprocedural management of coronary artery perforation (CAP). Methods and Results: The characteristics, outcomes, and management of 115 CAP cases among 13,453 patients undergoing percutaneous coronary intervention (PCI) between 2001 and 2017 at Miyazaki Medical Association Hospital were analyzed retrospectively. The incidence of CAP was 0.85% (25 [0.19%] coronary ruptures [CRs], 90 [0.67%] wire perforations [WPs]). The most prevalent causes of CRs and WPs were rotational atherectomy (36.0%) and polymer-jacketed wires (41.1%), respectively. Fifty-two percent of CRs were treated using prolonged balloon inflation, whereas 50% of WPs were treated through embolization. Immediate and delayed cardiac tamponade (CT) occurred in 20% and 24% of CRs, respectively, and in 2.2% and 10% of WPs, respectively. The mean (±SD) right atrial pressure (RAP) during delayed CT in the CR and WP groups was 16.0±1.2 and 14.0±3.0 mmHg, respectively. New-onset atrial fibrillation developed in 24.0% and 11.1% of patients in the CR and WP groups, respectively, whereas late-onset coronary artery aneurysm (CAA) occurred in 24.0% and 0% of patients, respectively. One-year mortality rates in patients with immediate and delayed CT were 28.6% and 20.0%, respectively. Conclusions: Special attention should be paid to delayed CT, new-onset atrial fibrillation, and late-onset CAA after CAP treatment. Continuous monitoring of RAP after CAP during PCI may be useful for the early detection of delayed CT.

Use of a Cutting Balloon Reduces the Incidence of Distal Embolism in Acute Coronary Syndrome Requiring Predilatation Before Stenting.

Background: Acute coronary syndrome (ACS) patients with solid lesions often require predilatation before stenting. Predilatation with high pressure may increase the risk of distal embolism, whereas direct stenting increases the risk of stent underexpansion. We recently reported that, in severely calcified lesions, using a cutting balloon (CB) can provide greater acute gain compared with other scoring balloons. Therefore, we hypothesized that predilatation with CB may reduce the incidence of distal embolism in ACS patients with solid lesions. Methods and Results: This study retrospectively analyzed data for 175 ACS patients who required predilatation, either with a conventional balloon (n=136) or CB (n=39). The occurrence of distal embolism was significantly lower in the CB than conventional balloon group (10.3% vs 32.4%, respectively; P=0.007). Multivariate analysis showed that the occurrence of distal embolism was positively associated with Thrombolysis in Myocardial Infarction (TIMI) grade and the presence of attenuated plaque, but negatively associated with the use of a CB. To support this clinical observation, we compared thrombus dispersal using a CB and non-compliant balloon in an ex vivo experimental model using a pseudo-thrombus. In this model, pseudo-thrombus dispersal was significantly smaller when a CB rather than non-compliant balloon was used (1.8±1.0% vs 2.6±1.2%, respectively; n=20, for each; P=0.002). Conclusions: In ACS patients with solid lesions that require predilatation, predilatation with a CB may reduce the incidence of distal embolism.

Non-rheumatic giant left atrium: An illustrative case successfully treated by surgical intervention.

A 45-year-old male presented to us with decompensated heart failure. He had been diagnosed as having atrial fibrillation when he was 31 years old. Transthoracic and transesophageal echocardiography revealed an excessive left atrial (LA) enlargement with left ventricular dysfunction and severe functional mitral regurgitation. There were no specific findings of rheumatic valve disease. He underwent surgical mitral valve replacement and LA volume reduction surgery after optimal medical therapy. Surgically-removed specimens of the LA and the anterior mitral leaflet were examined and there were no specific histopathological findings suggesting the specific etiology of the giant LA in this patient. The patient's condition significantly improved after the surgery without any cardiac events ever since. .

Early follow-up at outpatient care after discharge improves long-term heart failure readmission rate and prognosis.

AIMS: It has been reported that congestive heart failure (CHF) readmission has not decreased in the last decade. It is also reported that CHF readmission is likely to occur shortly after discharge. We investigated whether an early follow-up at outpatient care within 2 weeks after discharge affects the long-term readmission rate and prognosis. METHODS AND RESULTS: We reviewed consecutive 1002 patients admitted to our hospital due to CHF. Two-hundred and fifty-nine patients who died in-hospital or were transferred to another hospital or readmitted within 2 weeks were excluded and 743 of discharged patients were analysed. We extracted contributing variables associated with heart failure (HF) readmission and the composite adverse outcome (all cause death or HF readmissions) by univariate and multivariate analysis. Multivariate analysis showed that the early follow-up was independently associated with freedom from HF readmission and the composite outcome. We divided these patients into two groups, with/without early follow-up and performed a propensity score-matching analysis (n = 259 each). HF readmission during 2 year follow-up was significantly less in the early follow-up group [P = 0.02, hazard ratio (HR) = 0.647, 95% confidence interval (CI) = 0.447-0.935] as well as the composite outcome was less in the early follow-up group (P = 0.01, HR = 0.643, 95% CI = 0.456-0.908). Medication adjustments were done in only 33.2% of the patients. Rates of HF readmissions were comparable regardless of whether or not medication adjustment was done at the early follow-up (P = 0.505, HR = 1.208, 95% CI = 0.692-2.106). CONCLUSIONS: The present study demonstrates that an early follow-up approach after discharge in CHF patients may improve the long-term prognosis. These results may not depend on medication adjustment but rather on modifying patient factors early after discharge.

Combination of echocardiography and emergency endomyocardial biopsy for suspected myocarditis in the cardiovascular emergency medical care.

Myocarditis is a fatal inflammatory disease of myocardium, diagnosed with clinical and histopathological findings by endomyocardial biopsy (EMB). Myocarditis has a variety of clinical presentations and a dynamic and sometimes rapid process of severity. Echocardiography plays an important role in the management of myocarditis because it has noninvasiveness and portability. Once acute myocarditis is suspected by an echocardiography, pathological information should be required as early as possible. In our cardiovascular center, emergency EMB suspecting myocarditis was performed in 19 cases (1.3%) among consecutive 1469 cases (70.1 ± 12.6 years old, male 67.5%) undergoing emergency coronary angiograms from April 2014 to September 2017. Hematoxylin-eosin stain of the biopsy specimens were prepared with microwave-accelerated histoprocessing within 3-5 hours after EMB for rapid pathological diagnosis of myocarditis. We reviewed the value of emergency echo-EMB combination leading to the early decision making of intensive care, corticosteroids and proper mechanical circulatory support prior to the possible sudden collapse in patients with myocarditis.

Institutional Characteristics and Prognosis of Acute Myocardial Infarction With Cardiogenic Shock in Japan　- Analysis From the JROAD/JROAD-DPC Database.

BACKGROUND: The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. CONCLUSIONS: A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.

Impact of frailty on outcomes in elderly patients with acute myocardial infarction who undergo percutaneous coronary intervention.

AIMS: Frailty is characterized by reduced biological reserves and weakened resistance to stressors, and is common in older adults. This study evaluated the prognostic implications of frailty at hospitalization in elderly patients with acute myocardial infarction (AMI) who undergo percutaneous coronary intervention (PCI). METHODS AND RESULTS: We prospectively analysed 546 AMI patients aged ≥80 years undergoing PCI from 2009 to 2017. Frailty was classified based on impairment in walking (unassisted, assisted, and wheelchair/non-ambulatory), cognition (normal, mildly impaired, moderately to severely impaired), and basic activities of daily living. Impairment in each domain was scored as 0, 1, or 2, and patients were categorized into the following three groups based on total score: no frailty (0), mild frailty (1-2), moderate-to-severe frailty (≥3). The median follow-up period was 589 days. Of the 546 patients, 27.8% were frail (mild or moderate-to-severe), and this proportion significantly increased to 35.5% at discharge (P < 0.001). Compared to non-frail patients, frail patients were older, less likely to be male, and had a higher rate of advanced Killip class. Major bleeding (no frailty, 9.6%; mild frailty, 16.9%; moderate-to-severe frailty, 31.8%; P < 0.001) and in-hospital mortality (no frailty, 8.4%; mild frailty, 15.4%; moderate-to-severe frailty, 27.3%; P < 0.001) increased as frailty worsened. After adjusting for confounders, frailty was independently associated with higher mid-term all-cause mortality (hazard ratio, 1.81; 95% confidence interval, 1.23-2.65; P = 0.002). CONCLUSION: Frailty in AMI patients aged ≥80 years undergoing PCI was associated with major bleeding, in-hospital death, and mid-term mortality.

Clinical characteristics and prognostic factors in acute coronary syndrome patients complicated with cardiogenic shock in Japan: analysis from the Japanese Circulation Society Cardiovascular Shock Registry.

Cardiogenic shock frequently leads to death even with intensive treatment. Although the leading cause of cardiogenic shock is acute coronary syndrome (ACS), the clinical characteristics and the prognosis of ACS with cardiogenic shock in the present era still remain to be elucidated. We analyzed clinical characteristics and predictors of 30-day mortality in ACS with cardiogenic shock in Japan. The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 495 ACS patients with cardiogenic shock were analyzed. The primary endpoint was 30-day all-cause mortality. The median [interquartile range; IQR] age was 71.0 [63.0, 80.0] years. The median [IQR] value of systolic blood pressure (SBP) and heart rate were 75.0 [50.0, 86.5] mm Hg and 65.0 [38.0, 98.0] bpm, respectively. Multivariable analysis showed an odds ratio (OR) of 4.76 (confidence intervals; CI 1.97-11.5, p < 0.001) in the lowest SBP category (< 50 mm Hg) for SBP ≥ 90 mm Hg. Moreover, age per 10 years increase (OR 1.38, CI 1.18-1.61, p = 0.002), deep coma (OR 3.49, CI 1.94-6.34, p < 0.001), congestive heart failure (OR 3.81, CI 2.04-7.59, p < 0.001) and left main trunk disease (LMTD) (OR 2.81, CI 1.55-5.10, p < 0.001) were independent predictors. Severe hypotension, older age, deep coma, congestive heart failure, and LMTD were independent unfavorable factors in ACS complicated by cardiogenic shock in Japan. A prompt assessment of high-risk patients referring to those predictors in emergency room could lead to appropriate treatment without delay.

Predictors of Recurrent In-Stent Restenosis After Paclitaxel-Coated Balloon Angioplasty.

BACKGROUND: Although paclitaxel-coated balloon (PCB) angioplasty is an effective procedure for in-stent restenosis (ISR) after coronary stenting, recurrent ISR after PCB angioplasty still occurs. The aim of this study was to evaluate the predictors of recurrent ISR after PCB angioplasty for ISR.Methods and Results:A total of 157 ISR lesions treated with PCB angioplasty from January 2014 to May 2015 were retrospectively examined. Recurrent ISR was judged on 6-month follow-up angiography. Clinical, angiographic and procedural parameters were evaluated as possible predictors of recurrent ISR. Recurrent ISR occurred in 13.9% of lesions after PCB angioplasty. On multivariate analysis the following independent predictors of recurrent ISR were identified: (1) smaller acute gain after initial ballooning (OR, 3.06; 95% CI: 1.08-8.71; P=0.04); (2) geographic mismatch between PCB position and initial ballooning (OR, 5.59; 95% CI: 1.64-19.1; P=0.006); and (3) use of percutaneous transluminal coronary rotational atherectomy (PTCRA) at primary percutaneous coronary intervention (PCI; OR, 5.53; 95% CI: 1.89-16.2; P=0.002). CONCLUSIONS: Optimal expansion at initial ballooning before PCB angioplasty and careful positioning of PCB are important technical tips to prevent recurrent ISR after PCB angioplasty. Recurrent ISR occurred more frequently in severely calcified lesions that required PTCRA at primary PCI.

Unroofed coronary sinus detected by 2D/3D echocardiography in a patient referred to catheter ablation for atrial fibrillation.

A 67-year-old female visited our echo lab for a preoperative screening exam before radiofrequency catheter ablation for atrial fibrillation. Transthoracic echocardiography revealed abnormal color flow signal in the right atrium, and following 2D/3D transesophageal echocardiography proved partial type of unroofed coronary sinus. Absence of associated congenital abnormalities was ruled out by Doppler and contrast echo examinations. Surgical findings confirmed exactly the same anatomical abnormalities as preoperative 2D/3D echocardiography. Echocardiography plays an important role in finding unexpected underlying cardiac diseases in patients who are referred to arrhythmia clinics. In the present case with atrial fibrillation, we could accurately diagnose an unroofed coronary sinus syndrome during preoperative transthoracic and transesophageal echocardiography prior to planned radiofrequency catheter ablation. .

Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.

Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1ß, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.

Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.

BACKGROUND: Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-α (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling. METHODS AND RESULTS: Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-ß and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-α synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features. CONCLUSIONS: Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.

Prolyl hydroxylase domain protein 2 plays a critical role in diet-induced obesity and glucose intolerance.

BACKGROUND: Recent studies suggest that the oxygen-sensing pathway consisting of transcription factor hypoxia-inducible factor and prolyl hydroxylase domain proteins (PHDs) plays a critical role in glucose metabolism. However, the role of adipocyte PHD in the development of obesity has not been clarified. We examined whether deletion of PHD2, the main oxygen sensor, in adipocytes affects diet-induced obesity and associated metabolic abnormalities. METHODS AND RESULTS: To delete PHD2 in adipocyte, PHD2-floxed mice were crossed with aP2-Cre transgenic mice (Phd2(f/f)/aP2-Cre). Phd2(f/f)/aP2-Cre mice were resistant to high-fat diet-induced obesity (36.7±1.7 versus 44.3±2.0 g in control; P<0.01) and showed better glucose tolerance and homeostasis model assessment-insulin resistance index than control mice (3.6±1.0 versus 11.1±2.1; P<0.01). The weight of white adipose tissue was lighter (epididymal fat, 758±35 versus 1208±507 mg in control; P<0.01) with a reduction in adipocyte size. Macrophage infiltration into white adipose tissue was also alleviated in Phd2(f/f)/aP2-Cre mice. Target genes of hypoxia-inducible factor, including glycolytic enzymes and adiponectin, were upregulated in adipocytes of Phd2(f/f)/aP2-Cre mice. Lipid content was decreased and uncoupling protein-1 expression was increased in brown adipose tissue of Phd2(f/f)/aP2-Cre mice. Knockdown of PHD2 in 3T3L1 adipocytes induced a decrease in the glucose level and an increase in the lactate level in the supernatant with upregulation of glycolytic enzymes and reduced lipid accumulation. CONCLUSIONS: PHD2 in adipose tissue plays a critical role in the development of diet-induced obesity and glucose intolerance. PHD2 might be a novel target molecule for the treatment of obesity and associated metabolic abnormalities.

Resveratrol attenuates angiotensin II-induced senescence of vascular smooth muscle cells.

Resveratrol (3,5,4'-trihydroxystilbene), a polyphenol abundant in red wine, is known to extend the life span of diverse species. On the contrary, it was reported that angiotensin (Ang) II enhances senescence of vascular smooth muscle cells (VSMCs). We, therefore, examined whether resveratrol attenuates Ang II-induced senescence of VSMC. Senescence-associated ß-galactosidase (SA ß-gal) assay showed that Ang II induced senescence of VSMC. The Ang II-induced senescence was inhibited by losartan, an Ang II type 1 receptor (AT1R) antagonist but not by PD123319, Ang II type 2 receptor antagonist, indicating that AT1R is responsible for the induction of senescence. Resveratrol suppressed Ang II-induced senescence of VSMC in a dose-dependent manner. In addition, resveratrol suppressed Ang II-induced induction of p53 and its downstream target gene p21, both of which play an important role in the induction of senescence. Resveratrol suppressed senescence of VSMC possibly through inhibition of AT1R-dependent induction of p53/p21. Suppression of p53 induction may be involved in the longevity by resveratrol.

Beraprost sodium, a stable prostacyclin analogue, improves insulin resistance in high-fat diet-induced obese mice.

Obesity induces hypertrophy of adipocyte resulting in production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP1 (CCL2)). These cytokines play an important role in the development of insulin resistance. Beraprost sodium (BPS), a prostaglandin I2 analogue, is reported to attenuate inflammation. In this study, we examined the effect of BPS on glucose metabolism in mice fed a high-fat diet (HFD). Four-week-old C57/B6 male mice were fed a HFD for 12 weeks (HFD group) and the treatment group received oral BPS (300 µg/kg per day) for the same period. Then, glucose metabolism, histological changes, and gene expression of white adipose tissue (WAT) were examined. Body weight was increased, and glucose intolerance and insulin resistance were developed in the HFD group. Treatment with BPS improved glucose tolerance and insulin action without body weight change. Histological analysis of WAT showed an increase in the size of adipocyte and macrophage infiltration in the HFD group, which was attenuated by BPS treatment. BPS reduced HFD-induced expression of MCP1 and TNF-α in WAT. BPS also attenuated hepatic steatosis induced by the HFD. These results suggest that BPS improved glucose intolerance possibly through suppression of inflammatory cytokines in WAT. BPS may be beneficial for the treatment of obesity-associated glucose intolerance.