Prognostic Implication of Platelet Reactivity According to Left Ventricular Systolic Dysfunction Status in Patients Treated With Drug-Eluting Stent Implantation: Analysis of the PTRG-DES Consortium.

BACKGROUND: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. METHODS: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3-5. RESULTS: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85-2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39-2.78). The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group, P < 0.01, 95% CI 2.51-3.91). The frequency of major bleeding was not associated with the HPR in either group. CONCLUSION: LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734028.

Effect of rosuvastatin 20 mg versus rosuvastatin 5 mg plus ezetimibe on statin side-effects in elderly patients with atherosclerotic cardiovascular disease: Rationale and design of a randomized, controlled SaveSAMS trial.

BACKGROUND: Current guidelines recommend that patients with established atherosclerotic cardiovascular disease (ASCVD) use high-intensity statin therapy to lower low-density lipoprotein (LDL)-cholesterol levels by at least 50%, irrespective of age. However, in real-world practice, there is reluctance to maintain statin use in response to side-effects, particularly statin-associated muscle symptoms (SAMS). Moreover, no randomized trial has been conducted on the safety of statin therapy in elderly patients. TRIAL DESIGN: This investigator-initiated, multicenter, randomized clinical trial aimed to investigate the incidence of SAMS and its effect on LDL-cholesterol levels in elderly patients with established ASCVD. Eligible patients were aged 70 years or older with established ASCVD. Consecutive patients who met the inclusion criteria were randomized in a 1:1 fashion to receive either intensive statin monotherapy (rosuvastatin 20 mg) or combination therapy (rosuvastatin/ezetimibe, 5/10 mg). The primary endpoint of the study is SAMS at 6 months with regard to treatment strategy. Positive SAMS results are defined as patients with a proposed statin myalgia index score of 7 or higher. The key secondary end-points are target LDL-cholesterol achievement (LDL < 70 mg/dL), incidence of myopathy, rhabdomyolysis, frequency of drug discontinuation, and creatinine kinase, aspartate transaminase, alanine transaminase, total cholesterol, LDL-cholesterol, high-density lipoprotein-cholesterol, triglyceride, and highly sensitive C-reactive protein levels at 6 months. CONCLUSIONS: The SaveSAMS study is a multicenter, randomized trial that will compare the incidence of SAMS in patients with established ASCVD who are 70 years or older on intensive statin monotherapy to that combination therapy.

Effects of metabolic parameters' variability on cardiovascular outcomes in diabetic patients.

BACKGROUND: Metabolic abnormalities such as dyslipidemia, glucose and high blood pressure are common in diabetic patients. Visit-to-visit variabilities in these measures have been reported as potential residual cardiovascular risk factors. However, the relationship between these variabilities and their effects on cardiovascular prognosis have not been studied. METHODS: A total of 22,310 diabetic patients with ≥ 3 measurements of systolic blood pressure (SBP), blood glucose, total cholesterol (TC), and triglyceride (TG) levels during a minimum of three years at three tertiary general hospitals were selected. They were divided into high/low variability groups for each variable based on the coefficient of variation (CV) values. The primary outcome was the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. RESULTS: All high CV groups had a higher incidence of MACE than those with low CV (6.0% vs. 2.5% for SBP-CV groups, 5.5% vs. 3.0% for TC-CV groups, 4.7% vs. 3.8% for TG-CV groups, 5.8% vs. 2.7% for glucose-CV groups). In multivariable Cox regression analysis,, high SBP-CV (HR 1.79 [95% CI 1.54-2.07], p < 0.01), high TC-CV (HR 1.54 [95% CI 1.34-1.77], p < 0.01), high TG-CV (HR 1.15 [95% CI 1.01-1.31], p = 0.040) and high glucose-CV (HR 1.61 [95% CI 1.40-1.86], p < 0.01) were independent predictors of MACE. CONCLUSION: Variability of SBP, TC, TG and glucose are important residual risk factors for cardiovascular events in diabetic patients.

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium.

BACKGROUND: Diabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients. METHODS: The Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and 'high platelet reactivity (HPR)' was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke. RESULTS: Between July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869-1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193-1.902; P < 0.001). CONCLUSION: The levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique identifier: NCT04734028.

Gender Difference of Blood Pressure Control Rate and Clinical Prognosis in Patients With Resistant Hypertension: Real-World Observation Study.

BACKGROUND: There are several differences in the clinical course of hypertension due to the biological and social differences between men and women. Resistant hypertension is an advanced disease state, and significant gender difference could be expected, but much has not been revealed yet. The purpose of this study was to compare gender differences on the current status of blood pressure (BP) control and clinical prognosis in patients with resistant hypertension. METHODS: This is a multicenter, retrospective cohort study using common data model databases of 3 tertiary hospitals in Korea. Total 4,926 patients with resistant hypertension were selected from January 2017 to December 2018. Occurrence of dialysis, heart failure (HF) hospitalization, myocardial infarction, stroke, dementia or all-cause mortality was followed up for 3 years. RESULTS: Male patients with resistant hypertension were younger but had a higher cardiovascular risk than female patients. Prevalence of left ventricular hypertrophy and proteinuria was higher in men than in women. On-treatment diastolic BP was lower in women than in men and target BP achievement rate was higher in women than in men. During 3 years, the incidence of dialysis and myocardial infarction was higher in men, and the incidence of stroke and dementia was higher in women. After adjustment, male sex was an independent risk factor for HF hospitalization, myocardial infarction, and all-cause death. CONCLUSION: In resistant hypertension, men were younger than women, but end-organ damage was more common and the risk of cardiovascular event was higher. More intensive cardiovascular prevention strategies may be required in male patients with resistant hypertension.

Comparison of the effects of triglyceride variability and exposure estimate on clinical prognosis in diabetic patients.

BACKGROUND: Hypertriglyceridemia is an important feature of dyslipidemia in type 1 and type 2 diabetic patients and associated with the development of atherosclerotic cardiovascular disease. Recently, variability of lipid profile has been suggested as a residual risk factor for cardiovascular disease. This study compared the clinical impact of serum triglyceride variability, and their cumulative exposure estimates on cardiovascular prognosis in diabetic patients. METHODS: A total of 25,933 diabetic patients who had serum triglyceride levels measured at least 3 times and did not have underlying malignancy, myocardial infarction (MI), and stroke during the initial 3 years (modeling phase) were selected from three tertiary hospitals. They were divided into a high/low group depending on their coefficient of variation (CV) and cumulative exposure estimate (CEE). Incidence of major adverse event (MAE), a composite of all-cause death, MI, and stroke during the following 5 years were compared between groups by multivariable analysis after propensity score matching. RESULTS: Although there was a slight difference, both the high CV group and the high CEE group had a higher cardiovascular risk profile including male-dominance, smoking, alcohol, dyslipidemia, and chronic kidney disease compared to the low groups. After the propensity score matching, the high CV group showed higher MAE incidence compared to the low CV group (9.1% vs 7.7%, p = 0.01). In contrast, there was no significant difference of MAE incidence between the high CEE group and the low CEE group (8.6% vs 9.1%, p = 0.44). After the multivariable analysis with further adjustment for potential residual confounding factors, the high CV was suggested as an independent risk predictor for MAE (HR 1.19 [95% CI 1.03-1.37]). CONCLUSION: Visit-to-visit variability of triglyceride rather than their cumulative exposure is more strongly related to the incidence of MAE in diabetic patients.

Risks of complicated acute appendicitis in patients with psychiatric disorders.

BACKGROUND: Acute appendicitis often presents with vague abdominal pain, which fosters diagnostic challenges to clinicians regarding early detection and proper intervention. This is even more problematic with individuals with severe psychiatric disorders who have reduced sensitivity to pain due to long-term or excessive medication use or disturbed bodily sensation perceptions. This study aimed to determine whether psychiatric disorder, psychotropic prescription, and treatment compliance increase the risks of complicated acute appendicitis. METHODS: The diagnosis records of acute appendicitis from four university hospitals in Korea were investigated from 2002 to 2020. A total of 47,500 acute appendicitis-affected participants were divided into groups with complicated and uncomplicated appendicitis to determine whether any of the groups had more cases of psychiatric disorder diagnoses. Further, the ratio of complicated compared to uncomplicated appendicitis in the mentally ill group was calculated regarding psychotropic dose, prescription duration, and treatment compliance. RESULTS: After adjusting for age and sex, presence of psychotic disorder (odds ratio [OR]: 1.951; 95% confidence interval [CI]: 1.218-3.125), and bipolar disorder (OR: 2.323; 95% CI: 1.194-4.520) was associated with a higher risk of having complicated appendicitis compared with absence of psychiatric disorders. Patients who are taking high-daily-dose antipsychotics, regardless of prescription duration, show high complicated appendicitis risks; High-dose antipsychotics for < 1 year (OR: 1.896, 95% CI: 1.077-3.338), high-dose antipsychotics for 1-5 years (OR: 1.930, 95% CI: 1.144-3.256). Poor psychiatric outpatient compliance was associated with a high risk of complicated appendicitis (OR: 1.664, 95% CI: 1.014-2.732). CONCLUSIONS: This study revealed a close relationship in the possibility of complicated appendicitis in patients with severe psychiatric disorders, including psychotic and bipolar disorders. The effect on complicated appendicitis was more remarkable by the psychiatric disease entity itself than by psychotropic prescription patterns. Good treatment compliance and regular visit may reduce the morbidity of complicated appendicitis in patients with psychiatric disorders.

Drug Eluting Stent vs. Drug Coated Balloon for Native Femoropopliteal Artery Disease: A Two Centre Experience.

OBJECTIVE: There have been limited clinical trials comparing drug eluting stents (DESs) and drug coated balloons (DCBs) in the treatment of femoropopliteal artery disease. This two centre retrospective and prospective cohort study sought to compare DES with DCB for the treatment of native femoropopliteal artery disease. METHODS: A total of 288 limbs (242 patients) with native femoropopliteal artery disease were treated with DESs (Zilver PTX; 102 limbs) or DCBs (IN.PACT Admiral; 186 limbs) in two Korean endovascular centres between 19 January 2013 and 5 May 2018 and followed for a median duration of 19.6 months. The primary endpoint was primary clinical patency. Propensity score matching (PSM, 162 limbs) and inverse probability weighted (IPW) adjustment were performed to adjust for confounding baseline characteristics. RESULTS: The DCB group had fewer lesions with Trans-Atlantic Inter-Society Consensus (TASC) II type C/D (55.9% vs. 70.6%, p = .021) or total occlusions (43.5% vs. 77.5%, p < .001) and showed shorter lesion lengths (164.2 ± 105.4 mm vs. 194.8 ± 86.8 mm, p = .009) than the DES group. After PSM, baseline clinical and lesion characteristics of the two groups were comparable except for larger reference vessel diameter in the DES group (5.4 ± 0.6 vs. 5.1 ± 0.7, p = .025). Adjunctive atherectomy was performed in 32.1% of the DCB group and in 2.5% of the DES group (p < .001). The provisional stenting was required in 14.8% of the DCB group. At two year follow up, the DCB group showed higher primary clinical patency (74.6% vs. 56.7%, hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.27-0.96, p = .032) and freedom from target lesion revascularisation (85.9% vs. 71.3%, HR 0.39, 95% CI 0.17-0.89, p = .021) than the DES group. Survival from all cause death did not differ between groups (87.6% vs. 92.1%, HR 1.85, 95% CI 0.62-5.52, p = .26). CONCLUSION: In this two centre cohort, DCBs with selective use of adjunctive atherectomy achieved more favourable outcomes than DESs for native femoropopliteal artery disease.

Cardioprotective effects of genetically engineered cardiac stem cells by spheroid formation on ischemic cardiomyocytes.

BACKGROUND: Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. METHODS: Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. RESULTS: The optimal conditions for S-GECS was determined to be 1052 GECS cells/mm2 and a 48 h culture period to produce spheroids. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl2-induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. CONCLUSIONS: Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).

A comparison between drug-eluting stent implantation and drug-coated balloon angioplasty in patients with left main bifurcation in-stent restenotic lesions.

BACKGROUND: The current guidelines recommend both repeat stenting and drug-coated balloons (DCB) for in-stent restenosis (ISR) lesions, if technically feasible. However, real-world clinical data on the interventional strategies in patients with left main bifurcation (LMB)-ISR have not been elucidated. METHODS: Seventy-five patients with LMB-ISR, who underwent percutaneous coronary intervention (PCI) between January 2009 and July 2015, were retrospectively reviewed for the present study (repeat drug eluting stent [DES] implantation [n = 51], DCB angioplasty [n = 24]). RESULTS: Analysis of the baseline characteristics showed that the patients in the DCB group had a lower incidence of non-ST segment elevation myocardial infarction/ST segment elevation myocardial infarction at the index PCI (8.3% vs. 25.5%; p = 0.12), higher low-density lipoprotein-cholesterol level (92.9 mg/dL vs. 81.7 mg/dL; p = 0.09), and more "stent-in-stent" lesions (25% vs. 7.8%; p = 0.07) than those in the DES group. A smaller post-procedural minimal target lesion lumen diameter was also noted in the DCB group than in the DES group (2.71 mm vs. 2.85 mm; p = 0.03). The cumulative incidence rates of major adverse cardiac events (MACEs) were similar between both groups (median follow-up duration, 868 days; MACE rate, 25% in the DCB group vs. 25.5% in the DES group; p = 0.96). The multivariate Cox regression analysis indicated that the true bifurcation of ISR was an independent risk predictor of MACEs (hazard ratio, 4.62; 95% confidence interval, 1.572-13.561; p < 0.01). CONCLUSIONS: DES and DCB showed comparable long-term clinical results in patients with LMB-ISR lesions.

Prospective partially randomized comparison of clopidogrel loading versus maintenance dosing to prevent periprocedural myocardial infarction after stenting for stable angina pectoris: Results from the "Method of Clopidogrel Pre-treatment Undergoing Conventional Coronary Angiogram in Angina Patients (MECCA)" study.

WHAT IS KNOWN AND OBJECTIVE: Pre-treatment of clopidogrel 600 mg is better than 300 mg loading for reducing periprocedural myocardial infarction (PMI). We aimed to evaluate pre-treatment methods for preventing PMI among patients undergoing conventional coronary angiography (CAG) for stable angina pectoris. MATERIALS AND METHODS: The study analyzed 402 patients who underwent percutaneous coronary intervention (PCI) during 2010 - 2011 at three Korean hospitals. Clopidogrel-naïve patients received routine maintenance therapy (75 mg/day for ≥ 5 days) and were randomly assigned to a 300-mg reload (RL) or only the maintenance dose (MD). Patients who received a loading dose (LD; 600 mg at 2 - 24 hours before the procedure) were entered into a non-randomized group. RESULTS: After excluding patients who showed an abnormal creatinine kinase myocardial band (CK-MB) level, the study included 233 patients in the LD group, 85 patients in the RL group and 84 patients in the MD group. The LD group had a significantly higher rate of PMI (LD: 21, RL: 3, MD: 0 cases; p = 0.007) and a significant increase in the mean CK-MB levels after 8 hours (p = 0.016) and 24 h (p = 0.01). However, there was no difference in PMI between the RL and MD groups. Furthermore, no significant differences between the three groups were observed in the P2Y12 reaction unit (PRU) values (p = 0.57). Albeit not significantly, the LD group had a higher rate of moderate-to-severe GUSTO bleeding within 7 days. WHAT IS NEW AND CONCLUSION: Clopidogrel maintenance is better than 600-mg loading for preventing PMI, and the RL protocol did not further prevent PMI.

Proposal and Assessment of a De-Identification Strategy to Enhance Anonymity of the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) in a Public Cloud-Computing Environment: Anonymization of Medical Data Using Privacy Models.

BACKGROUND: De-identifying personal information is critical when using personal health data for secondary research. The Observational Medical Outcomes Partnership Common Data Model (CDM), defined by the nonprofit organization Observational Health Data Sciences and Informatics, has been gaining attention for its use in the analysis of patient-level clinical data obtained from various medical institutions. When analyzing such data in a public environment such as a cloud-computing system, an appropriate de-identification strategy is required to protect patient privacy. OBJECTIVE: This study proposes and evaluates a de-identification strategy that is comprised of several rules along with privacy models such as k-anonymity, l-diversity, and t-closeness. The proposed strategy was evaluated using the actual CDM database. METHODS: The CDM database used in this study was constructed by the Anam Hospital of Korea University. Analysis and evaluation were performed using the ARX anonymizing framework in combination with the k-anonymity, l-diversity, and t-closeness privacy models. RESULTS: The CDM database, which was constructed according to the rules established by Observational Health Data Sciences and Informatics, exhibited a low risk of re-identification: The highest re-identifiable record rate (11.3%) in the dataset was exhibited by the DRUG_EXPOSURE table, with a re-identification success rate of 0.03%. However, because all tables include at least one "highest risk" value of 100%, suitable anonymizing techniques are required; moreover, the CDM database preserves the "source values" (raw data), a combination of which could increase the risk of re-identification. Therefore, this study proposes an enhanced strategy to de-identify the source values to significantly reduce not only the highest risk in the k-anonymity, l-diversity, and t-closeness privacy models but also the overall possibility of re-identification. CONCLUSIONS: Our proposed de-identification strategy effectively enhanced the privacy of the CDM database, thereby encouraging clinical research involving multiple centers.

Thymosin ß4-Enhancing Therapeutic Efficacy of Human Adipose-Derived Stem Cells in Mouse Ischemic Hindlimb Model.

Thymosin ß4 (Tß4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tß4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tß4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tß4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tß4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tß4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tß4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tß4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tß4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.

Fimasartan reduces neointimal formation and inflammation after carotid arterial injury in apolipoprotein E knockout mice.

BACKGROUND: The beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on atherosclerosis have been demonstrated in numerous studies. We investigated the effects of fimasartan on reducing neointimal formation and systemic inflammation after carotid artery (CA) injury in Apolipoprotein E knockout (ApoE KO) mice. METHODS: ApoE KO mice were randomly allocated to Group I (without CA injury), Group II (without CA injury + Fimasartan), Group III (CA injury), and Group IV (CA injury + Fimasartan). Fimasartan was orally administered everyday starting 3 days before iatrogenic left CA injury. RESULTS: At 28 days, neointimal hyperplasia and the inflammatory cytokines including TNFα, IL-6, ICAM, and MMP-9 in the peripheral blood were significantly reduced in Groups II and IV compared to Groups I and III, respectively. All fimasartan-administered groups revealed significant increases of CD4+CD25+Foxp3+ regulatory T (Treg) cells with increased plasma levels of IL-10 and TGFß. In addition, increased CD8+ T cells by fimasartan were correlated with reduced smooth muscle cell (SMC) proliferation in the neointima in Groups II and IV. Furthermore, the populations of Treg and CD8+ T cells in total splenocytes were increased in Groups II and IV compared to Groups I and III, respectively. The enlargement of spleens due to CA injury in the Group III was attenuated by fimasartan, as shown in the Group IV. These data indicate that fimasartan significantly reduced SMC proliferation in neointima and increased Treg cells in ApoE KO CA injury mice. CONCLUSIONS: This study suggests fimasartan could be an efficient strategy for reduction of atherosclerotic progression, with a decrease in immune response and systemic inflammation.

Incidence of new-onset diabetes with 1 mg versus 4 mg pitavastatin in patients at high risk of developing diabetes during a 3-year follow-up.

BACKGROUND: Statin therapy reduces the risk of cardiovascular events across a broad spectrum of patients; however, it increases the risk of new-onset diabetes (NOD). Although the highest dose pitavastatin is considered to not be associated with NOD, there are limited data regarding the impact of long-term highest dose pitavastatin use on the development of NOD in patients at high risk of developing diabetes. Therefore, we prospectively compared the differences in the development of NOD between the lowest and the highest dose of pitavastatin in patients at high risk of developing diabetes during a 3-year follow-up. METHODS: This post hoc analysis of a prospective, single-blinded, randomized study compared the risk of NOD between the highest dose of pitavastatin (4 mg) and the lowest dose of pitavastatin (1 mg) over a 3-year follow-up in patients with acute coronary syndrome. Among 1044 patients of the original study, 667 patients at high risk of developing type 2 diabetes mellitus were in the subgroup analysis. The primary endpoint was a comparison of the differences in the cumulative incidence of NOD in the pitavastatin 1 mg and 4 mg groups during a 3-year follow-up. RESULTS: With propensity score matching, there were no significant differences in baseline demographic characteristics between the 2 groups. Incidence of NOD was similar between the pitavastatin 1 mg and 4 mg groups [12 of 289 patients (4.2%) and 8 of 289 patients (2.8%), respectively; p = 0.36]. In a prespecified analysis, there were no significant differences in NOD events according to sex, age, diagnosis, body mass index, glucose intolerance, or dyslipidemia. CONCLUSIONS: Administration of highest-dose pitavastatin did not increase the risk of NOD in patients at high risk of developing diabetes during the 3-year follow-up. Moreover, various risk factors for NOD such as metabolic syndrome components, glucose intolerance, dyslipidemia, obesity, or hypertension did not affect the development of NOD during pitavastatin administration. Thus, the highest dose pitavastatin can be safely used in patients with metabolic syndrome who are at high risk of developing diabetes. Trial registration Clinical Trial registration information. URL: https://clinicaltrials.gov/ct2/show/NCT02545231. Unique identifier: NCT02545231.

Effects of lowest-dose vs. highest-dose pitavastatin on coronary neointimal hyperplasia at 12-month follow-up in type 2 diabetic patients with non-ST elevation acute coronary syndrome: an optical coherence tomography analysis.

Current ACC/AHA guidelines recommend high-dose statin therapy after coronary stenting, especially in diabetic patients; however, pitavastatin 4 mg or pitavastatin 1 mg are frequently used after coronary stenting in Asia, even in patients with acute coronary syndrome. We compared the effects of highest-dose and lowest-dose pitavastatin therapy on coronary neointimal hyperplasia at 12-month follow-up in diabetic patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) using optical coherence tomography. A total of 72 diabetic patients with NSTE-ACS were randomized to lowest-dose pitavastatin [1 mg (n = 36)] or highest-dose pitavastatin [4 mg (n = 36)] after everolimus-eluting stent implantation. The primary endpoint was to compare the normalized neointimal volume at 12-month follow-up. Normalized neointimal volume was significantly lower in the pitavastatin 4 mg group (4.00 ± 2.80 vs. 8.24 ± 2.83 mm3/mm, p < 0.01) at 12-month follow-up. There was also significant difference in neointimal area between the pitavastatin 4 mg group and pitavastatin 1 mg group (0.41 ± 0.28 vs. 0.74 ± 0.23 mm2, p < 0.01). Improvement of brachial artery flow-mediated dilation (baFMD) was significantly higher in the pitavastatin 4 mg group than in pitavastatin 1 mg group (0.15 ± 0.15 vs. - 0.03 ± 0.19 mm, p < 0.001). In addition, the improvement of adiponectin levels was significantly greater in the pitavastatin 4 mg group than in the pitavastatin 1 mg group (2.97 ± 3.98 vs. 0.59 ± 2.80 µg/mL, p < 0.05). Pitavastatin 4 mg significantly improved inflammatory cytokines and lipid profiles compared to pitavastatin 1 mg during the 12-month follow-up, contributing to the reduction of neointimal hyperplasia and to the improvement of baFMD in diabetic patients with NSTE-ACS requiring coronary stenting. Thus, the administration of pitavastatin 4 mg can be safely and effectively used in high-risk patients requiring coronary stenting. Trial registration NCT02545231 (Clinical Trial registration information: https://clinicaltrials.gov/ct2/show/NCT02545231 ).

Association between epicardial adipose tissue, high-sensitivity C-reactive protein and myocardial dysfunction in middle-aged men with suspected metabolic syndrome.

BACKGROUND: As body fat composition and metabolism differ between men and women, we evaluated sex-related differences in the association among epicardial adipose tissue (EAT), secretome profile, and myocardial function of subjects with suspected metabolic syndrome. METHODS: We evaluated 277 participants (men, n = 140; 56.1 ± 4.7 years) who underwent conventional echocardiography and two-dimensional speckle tracking from the Seoul Metabolic Syndrome cohort. EAT was measured from the right ventricular free wall perpendicular to the aortic annulus at end systole. Global longitudinal strain (GLS) was obtained from 18 apical segments. Apolipoprotein A1, apolipoprotein B, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) levels were measured using immunoturbidimetry assay. RESULTS: Mean age, body mass index, and hs-CRP level did not differ by sex. Waist circumference, fasting blood glucose level, and triglyceride/high-density lipoprotein cholesterol ratio were higher, and apolipoprotein AI and adiponectin levels were lower in men. No significant difference in mean EAT thickness was found (7.02 ± 1.81 vs. 7.13 ± 1.70 mm, p = 0.613). Men had a higher left ventricular (LV) mass index and lower GLS. EAT thickness was associated with hs-CRP level in men alone (ß = 0.206, p = 0.015). LV mass index (ß = 2.311, p = 0.037) and function represented by e' (ß = - 0.279, p = 0.001) and GLS (ß = - 0.332, p < 0.001) were independently associated with EAT thickness in men alone. CONCLUSIONS: In middle-aged subjects with suspected metabolic syndrome, EAT was associated with inflammation represented by hs-CRP level, LV mass, and subclinical myocardial dysfunction only in men, suggesting that the inflammatory activity of EAT induced myocardial remodeling and dysfunction in middle-aged subjects but was attenuated in women. Trial registration NCT02077530 (date of registration: November 1, 2013).

Clinical outcomes of patients with coronary artery aneurysm after the first generation drug-eluting stent implantation.

OBJECTIVES: We sought to investigate the long-term clinical outcomes of patients with coronary artery aneurysm (CAA) after drug-eluting stent (DES) implantation, compared with patients without CAA. BACKGROUND: CAA developed after DES implantation is a rare but associated with poor clinical outcome. METHODS: We retrospectively compared 78 patients with CAA after DES implantation with 269 patients without CAA who underwent DES implantation for complex lesions (controls). The primary endpoint was defined as major adverse cardiac events (MACE), the composite of all-cause death, nonfatal myocardial infarction (MI), and target lesion revascularization (TLR). RESULTS: Morphologically, CAAs were saccular (32%), fusiform (13%), or microform (55%). The stent types involved were Cypher (n = 56, 71.8%) and Taxus (n = 22, 28.2%). During a median follow-up period of 1164 days, the incidence of MACE was significantly higher in the CAA group (26.9 vs. 2.2%, P < 0.001); the difference was driven mainly by nonfatal MI (11.5 vs. 0%, P < 0.001) and TLR (20.5 vs. 1.9%, P < 0.001). The incidence of stent thrombosis was higher in the CAA group (12.8 vs. 0.74%, P < 0.001), irrespective of the maintenance of dual antiplatelet therapy. In the CAA group, Cox regression analysis showed significantly higher hazard ratios of CAA for MACE during the follow-up period. Further analyses after propensity-score matching of 65 pairs also showed similar results. CONCLUSIONS: The incidence of MACE was higher in patients with CAA compared with patients without CAA after DES implantation. This difference was driven by TLR and nonfatal MI and widened over time.

Impact of hyperuricemia on clinical outcomes after percutaneous coronary intervention for in-stent restenosis.

BACKGROUND: There have been limited data on the impact of hyperuricemia on long-term clinical outcomes after percutaneous coronary intervention (PCI) for in-stent restenosis (ISR). METHODS: From January 2009 to July 2015, 317 patients who underwent repeat PCI for ISR were divided into two groups: patients with normal serum uric acid (UA) levels (normal UA group) and patients with higher serum UA levels (higher UA group). The higher UA group included patients with serum UA levels > 6.8 mg/dL or patients who were taking anti-hyperuricemic medication. RESULTS: During a median follow-up period of 1088 days, the cumulative incidence rates of major adverse event (MAE), including a composite of all-cause death, non-fatal myocardial infarction, and any revascularization, were similar between the two groups (higher UA 36.4% vs. normal UA 29.9%, p = 0.389, log-rank p = 0.367). Follow-up angiographic data showed similar outcomes of late lumen loss (0.8 ± 0.9 mm vs. 0.8 ± 1.1 mm, p = 0.895) and binary restenosis rate (28.1% vs. 34.7%, p = 0.622). Multivariate Cox regression analysis indicated higher levels of low-density lipoprotein cholesterol (hazard ratio [HR] 1.011, 95% confidence interval [CI] 1.003-1.019, p = 0.006) and lower left ventricular ejection fraction (HR 0.972, 95% CI 0.948-0.996, p = 0.022), but not UA levels, to be the independent risk predictors of MAE. CONCLUSION: Hyperuricemia is not associated with poor clinical outcomes after repeat PCI for ISR lesions.

The Relationship between Pulse Wave Velocity and Coronary Artery Stenosis and Percutaneous Coronary Intervention: a retrospective observational study.

BACKGROUND: Arterial stiffness has been suggested as a valuable predictor of coronary artery stenosis (CAS). However, little data are available on aortic stiffness and CAS in patients who have previously undergone percutaneous coronary artery intervention (PCI). The aim of this study was to investigate the association of arterial stiffness to CAS in patients with a history of PCI and those without a history of PCI. METHODS: We retrospectively studied 1093 consecutive patients who had undergone coronary angiography (CAG). Arterial stiffness was determined by brachial-ankle pulse wave velocity (baPWV) measured prior to CAG. RESULTS: In patients without a history of PCI, baPWV significantly increased in patients with CAS compared to that in patients without CAS (p < 0.001). However, among patients with a history of PCI, there was no significant difference in baPWV. Multivariate logistic regression analysis demonstrated that baPWV was an independent risk predictor for CAS in patients without a history of PCI, but not in those with a history of PCI (OR 1.106, 95% CI 1.039-1.177, p = 0.002). In CAS patients without a history of PCI, increased baPWV was significantly associated with multiple cardiovascular risk factors, multivessel involvement, and anatomical severity. CONCLUSIONS: Prediction of CAS by baPWV is significantly attenuated in patients with a history of PCI.