Randomized, multicenter, parallel, open, phase 4 study to compare the efficacy and safety of rosuvastatin/amlodipine polypill versus atorvastatin/amlodipine polypill in hypertension patient with dyslipidemia.

The authors performed this study to investigate the efficacy and safety of a rosuvastatin (RSV)/amlodipine (AML) polypill compared with those of atorvastatin (ATV)/AML polypill. We included 259 patients from 21 institutions in Korea. Patients were randomly assigned to 1 of 3 treatment groups: RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, or ATV 20 mg /AML 5 mg. The primary endpoint was the efficacy of the RSV 10.20 mg/AML 5 mg via percentage changes in LDL-C after 8 weeks of treatment, compared with the ATV 20 mg /AML 5 mg. There was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 10 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (full analysis set [FAS]: -7.08%, 95% CI: -11.79 to -2.38, p = .0034, per-protocol analysis set [PPS]: -6.97%, 95% CI: -11.76 to -2.19, p = .0046). Also, there was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 20 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (FAS: -10.13%, 95% CI: -15.41 to -4.84, p = .0002, PPS: -10.96%, 95% CI: -15.98 to -5.93, p < .0001). There was no significant difference in the adverse events rates between RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, and ATV 20 mg/AML 5 mg. In conclusion, while maintaining safety, RSV 10 mg/AML 5 mg and the RSV 20 mg/AML 5 mg more effectively reduced LDL-C compared with the ATV 20 mg /AML 5 mg (Clinical trial: NCT03951207).

Routine Functional Testing or Standard Care in High-Risk Patients after PCI.

BACKGROUND: There are limited data from randomized trials to guide a specific follow-up surveillance approach after myocardial revascularization. Whether a follow-up strategy that includes routine functional testing improves clinical outcomes among high-risk patients who have undergone percutaneous coronary intervention (PCI) is uncertain. METHODS: We randomly assigned 1706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing (nuclear stress testing, exercise electrocardiography, or stress echocardiography) at 1 year after PCI or to standard care alone. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. Key secondary outcomes included invasive coronary angiography and repeat revascularization. RESULTS: The mean age of the patients was 64.7 years, 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents. At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval [CI], 0.61 to 1.35; P = 0.62). There were no between-group differences with respect to the components of the primary outcome. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, -0.01 to 5.99), and 8.1% and 5.8% of patients, respectively, had undergone repeat revascularization (difference, 2.23 percentage points; 95% CI, -0.22 to 4.68). CONCLUSIONS: Among high-risk patients who had undergone PCI, a follow-up strategy of routine functional testing, as compared with standard care alone, did not improve clinical outcomes at 2 years. (Funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical; POST-PCI ClinicalTrials.gov number, NCT03217877.).

Apamin inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration through suppressions of activated Akt and Erk signaling pathway.

The increased proliferation and migration of vascular smooth muscle cells (VSMC) are key process in the development of atherosclerosis lesions. Platelet-derived growth factor (PDGF) initiates a multitude of biological effects that contribute to VSMC proliferation and migration. Apamin, a component of bee venom, has been known to block the Ca(2+)-activated K(+) channels. However, the effects of apamin in the regulation PDGF-BB-induced VSMC proliferation and migration has not been identified. In this study, we investigate the inhibitory effect of apamin on PDGF-BB-induced VSMC proliferation and migration. Apamin suppressed the PDGF-BB-induced VSMC proliferation and migration with no apparent cytotoxic effect. In accordance with these findings, apamin induced the arrest of cell cycle progression at G0/G1 phase. Apamin also decreased the expressions of G0/G1 specific regulatory proteins including proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin-dependent kinases (CDK) 4, cyclin E and CDK2, as well as increased the expression of p21(Cip1) in PDGF-BB-induced VSMC. Moreover, apamin inhibited PDGF-BB-induced phosphorylation of Akt and Erk1/2. These results suggest that apamin plays an important role in prevention of vascular proliferation and migration through the G0/G1 cell cycle arrest by PDGF signaling pathway. Thus, apamin may be a promising candidate for the therapy of atherosclerosis.

Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.

BACKGROUND: Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. METHODS AND RESULTS: We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74-0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52-0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro-B-type natriuretic peptide and troponin) versus enalapril. CONCLUSIONS: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Gender Difference in Arterial Stiffness in a Multicenter Cross-Sectional Study: The Korean Arterial Aging Study (KAAS).

Elevated arterial stiffness has emerged as an important risk factor for future cardiovascular (CV) events in men and women. However, gender-related differences in arterial stiffness have not been clearly demonstrated. We thus determine whether gender affects arterial stiffness in subjects with and without CV risk factors. We consecutively enrolled 1,588 subjects aged 17-87 years (mean age: 46.5; 51% women) from the Korean Arterial Aging Study (KAAS), which is a multicenter registry from 13 university hospitals in Korea for the evaluation of arterial stiffness. We compared markers of arterial stiffness - central augmentation index (AIx), aortic pulse wave velocity (PWV), and pulse pressure (PP) amplification - in apparently healthy men and women without risk factors with those in high-risk subjects with a smoking habit, hypertension, diabetes, and dyslipidemia but without drug treatment. Aortic PWV and PP amplification were significantly higher in men than in women (7.78 ± 1.16 vs. 7.64 ± 1.15 m/s, p = 0.015, and 1.39 ± 0.22 vs. 1.30 ± 0.18, p < 0.001, respectively). However, women had a significantly higher central AIx than men (23.5 ± 11.9 vs. 16.1 ± 12.6%, p < 0.001). The central AIx and aortic PWV values were significantly higher in the high-risk group than in the healthy group for both men and women. In men, central AIx and aortic PWV were associated positively with age and blood pressure, and negatively with body mass index. In women, central AIx was positively related to age, diastolic blood pressure, and serum cholesterol levels. Aortic PWV was positively related to age, systolic blood pressure, fasting glucose, and heart rate. PP amplification was associated negatively with age and blood pressure and positively with heart rate in both men and women. In conclusion, arterial stiffness is mainly determined by sex, age, and blood pressure. Markers of arterial stiffness differ between men and women. Dyslipidemia and glucose contribute to a modest increase in arterial stiffness only in women. Therefore, the arteries of women may be more vulnerable to CV risk factors than those of men.

Apamin inhibits THP-1-derived macrophage apoptosis via mitochondria-related apoptotic pathway.

The development of atherosclerotic lesions is mainly due to macrophage death. The oxidative stresses of monocytes/macrophages play a vital role in the initiation and amplification of atherosclerosis. Apamin, a component of bee venom, exerts an anti-inflammatory effect, and selectively inhibits the Ca(2+)-activated K(+) channels. The mechanisms involved in the inhibition of macrophage apoptosis have been fully elucidated. We induced oxidized low-density lipoprotein (oxLDL) in THP-1-derived macrophage and studied the effect of apamin on intercellular lipid levels, mitochondria-related apoptotic pathway and numbers of apoptotic cells. Oil-red O staining indicates that the inhibition of apamin in the condition significantly prevents intracellular lipid deposition. Treatment with apamin significantly decreased the apoptotic macrophages by decreasing the expression of pro-apoptotic genes Bax, caspase-3 and PARP protein levels, as well as through increasing expression of anti-apoptotic genes Bcl-2 and Bcl-xL protein levels in the absence and presence of oxLDL. In vivo, with apamin treatment reduced apoptotic cells death by TUNEL staining. These results indicate that apamin plays an important role in monocyte/macrophage apoptotic processing, which may provide a potential drug for preventing atherosclerosis.

Melittin inhibits atherosclerosis in LPS/high-fat treated mice through atheroprotective actions.

AIM: Atherosclerosis is influenced by multiple environmental factors that involve a complex interaction between blood components and the arterial wall and is characterized by inflammatory reactions. Melittin has been used in treatment of various chronic inflammatory diseases. We investigated the effects of melittin regulated atherosclerotic changes in an animal model of atherosclerosis. METHODS: Atherosclerotic mice were induced by intraperitoneal (i.p) injection of lipopolysaccharide (LPS, 2 mg/kg) three times a week and an atherogenic diet for 12 weeks. RESULTS: Melittin (0.1 mg/kg) treatment was administered with i.p injection. Melittin treatment showed that total cholesterol and triglyceride levels decreased in atherosclerotic mice however, high-density lipoprotein cholesterol (HDL-C) levels were higher in atherosclerotic mice treated with melittin than in atherosclerotic mice. H&E staining showed that heart and descending aorta were significantly recovered by melittin, compared to atherosclerotic mice. In addition, melittin decreased the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, fibronectin and transforming growth factor (TGF)-ß1 in atherosclerotic mice. In vitro, melittin decreased LPS-induced THP-1 cells-derived macrophages TNF-α and IL-1ß expression levels and nuclear factor (NF)-κB signal pathway. CONCLUSIONS: These results demonstrate that melittin has an anti-atherogenic effect by suppression of pro-inflammatory cytokines and adhesion molecules.

Reversible pulmonary hypertension in adolescent with left atrial myxoma.

We report a patient of left atrial huge myxoma presenting with severe pulmonary hypertension in adolescents. A patient was a 14-year-old boy presented with sudden onset dyspnea. Transthoracic echocardiographic study revealed the presence of a nodular, 4.34 × 8.11 cm sized, mobile, hyperechoic mass in the left atrium and severe pulmonary hypertension with tricuspid insufficiency. After surgical therapy, tricuspid regurgitation and pulmonary hypertension was decreased and the patient was stabilized and had an uneventful clinical course.

The culprit lesion score on multi-detector computed tomography can detect vulnerable coronary artery plaque.

Vulnerable plaques are characterized by large lipid cores, positive remodeling and small coronary calcium deposits. Multi-detector computed tomography (MDCT) has recently been shown to be able to characterize coronary artery plaques. The aim of this study was to evaluate culprit coronary lesions for differentiating acute coronary syndrome (ACS) from stable angina pectoris (SAP) using MDCT. 64-slice MDCT was conducted on 71 patients (ACS: 35, SAP: 36). The culprit coronary lesions were assessed according to the type and plaque attenuation (PA) of the plaque and the remodeling index (RI) as the ratio of the lesion and the reference area. The culprit lesion score (CLS) was defined as the sum of every score as 1.2 for a PA ≤ 60 Hounsfield units (HU), 1.1 for a RI ≥ 1.05 and 1.2 for a non-calcified or spotty calcification. More spotty calcification (95.0% vs. 23.1%, P < 0.001), a lower PA (40.17 ± 20.08 HU vs. 96.96 ± 58.19 HU, respectively, P < 0.001) and a higher RI (1.44 ± 0.43 vs. 0.90 ± 0.44, respectively, P < 0.001) were observed in the ACS patients. Also, the CLS of the ACS patients was significantly higher than that of the SAP patients (3.07 ± 0.63 vs. 1.18 ± 1.12, respectively, P < 0.001). A CLS more than 2.0 helped us to differentiate ACS from SAP with a sensitivity of 97.1% and a specificity of 67.6%. The CLS might be a useful tool for differentiating ACS from SAP.

Effect of NF-κB decoy oligodeoxynucleotide on LPS/high-fat diet-induced atherosclerosis in an animal model.

Atherosclerosis is a chronic inflammatory process occurring in the walls of arteries, in large part due to the accumulation of inflammatory cells. This study was conducted to determine the effect of nuclear factor (NF)-κB decoy oligodeoxynucleotide (ODN) in an atherosclerosis animal model. The mice received i.p. injections of lipopolysaccharide (LPS, 2 mg/kg) three times a week to induce atherosclerotic change, and fed an atherogenic diet for 12 weeks. NF-κB decoy ODN (0.4 mg/kg) was injected into the tail vein. Treatment with NF-κB decoy ODN decreased pro-inflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß and inflammatory markers, vascular adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, in the LPS/Fat-induced mice. In addition, the expression of proteins related to fibrosis, transforming growth factor (TGF)-ß1 and fibronectin were markedly decreased in the mice treated with NF-κB decoy ODN compared with the LPS/Fat-induced mice without decoy ODN treatment. These data suggest that NF-κB decoy ODN may exert an inhibitory effect on the expression levels of pro-inflammatory cytokines and cell adhesion molecules in atherosclerotic mice.

Outcomes of medically treated patients with aortic intramural hematoma.

PURPOSE: Aortic intramural hematoma has been considered a precursor of aortic dissection, and the same treatment strategy, usually involving surgery, has been applied to both conditions. However, the outcomes of patients with aortic intramural hematoma who are treated medically, including the remodeling process that occurs after an acute event, are not known. SUBJECT AND METHODS: A total of 124 patients with acute aortic intramural hematoma (41 in the proximal aorta and 83 in the distal aorta) was enrolled from five institutions in South Korea. Patients received medical treatment without surgery. A follow-up imaging study was performed in 105 patients. RESULTS: Pericardial (59% [n = 24] vs. 11% [n = 9], P <0.004) and pleural effusions (63% [n = 26] vs. 45% [n = 37], P = 0.05) were more common in patients with the proximal type than in those with the distal type. In-hospital mortality was somewhat higher with proximal hematomas (7% [n = 3 deaths] vs. 1% [n = 1 death], P = 0.11). A follow-up imaging study in 36 patients with proximal hematomas confirmed resorption of the hematoma in 24 patients (67%) and development of aortic dissection in 9 (25%). Resorption was confirmed in 54 (78%) of the 69 patients with distal hematomas who underwent follow-up imaging; localized aortic dissection developed in 11 (16%) of these patients. The 3-year survival rate was 78% in the proximal type and 87% in the distal type (P = 0.10). CONCLUSION: Patients with aortic intramural hematoma had a high rate of resorption with medical treatment regardless of the affected site. Further investigation is necessary to determine the optimal treatment strategy and timing of surgical intervention, especially for patients with proximal hematomas.