Long-term administration of tolvaptan ameliorates annual decline in estimated glomerular filtration rate in outpatients with chronic heart failure.

Protective effects of tolvaptan against worsening renal function in acute heart failure have been shown. However, long-term effects of its agent on renal function remain to be elucidated. The present study investigated retrospectively whether long-term treatment with tolvaptan exerts renoprotective effects in patients with chronic heart failure, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after tolvaptan administration. From 63 outpatients with chronic heart failure taking diuretics including tolvaptan, 34 patients whose eGFR levels were continuously measured for more than 6 months both before and after administration of tolvaptan (average dose, 7.8 mg/day at the end of the follow-up period) were selected as eligible for the present analyses. All eGFR values were separately plotted before and after the initiation of treatment with tolvaptan (except hospitalization periods) along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. The mean follow-up periods before and after tolvaptan administration were 1197 and 784 days (3.3 and 2.1 years), respectively. Changing rates of eGFR per year were significantly ameliorated after treatment with tolvaptan (mean ± SD, - 8.02 ± 9.35 to - 1.62 ± 5.09 mL/min/1.73m2 /year, P = 0.001). In echocardiographic parameters, inferior vena cava (IVC) diameter significantly decreased after tolvaptan administration, and the decrease in IVC diameter was correlated with the improvement of eGFR decline slope after administration of tolvaptan (P = 0.0075). This longitudinal observational study indicated that long-term treatment with tolvaptan ameliorated annual decline in eGFR in outpatients with chronic heart failure. Our findings suggest that tolvaptan has a protective effect against chronically worsening renal function in heart failure patients.

Usefulness of pre- and post-stent optical frequency domain imaging findings in the prediction of periprocedural cardiac troponin elevation in patients with coronary artery disease.

Cholesterol crystals (CCs) are frequently found in high-risk plaques, such as thin-capped fibroatheromas. The purpose of this study was to investigate the associations of CCs, plaque morphologies, and post-stent optical frequency domain imaging (OFDI) findings with periprocedural cardiac troponin (cTn) elevation in patients treated with percutaneous coronary intervention (PCI). This study consists of 119 patients with stable coronary artery disease (CAD) with normal cTn levels who underwent OFDI-guided PCI. Periprocedural cTn elevation was defined as an elevation of cTn ≥ × 5 times the upper reference limit after PCI. Pre- and post-stent OFDI findings, including fibrous cap thickness (FCT), presence of CCs, and parameters for lipid and calcification were analyzed. A total of 37 (31%) patients were classified into the periprocedural cTn elevation group. Compared with lesions without CCs, lesions exhibiting CCs had thinner FCT, larger lipid arc, and longer lipid length, and were more likely to have irregular protrusion and in-stent thrombus (all p < 0.05). For pre-stent OFDI features, FCT < 82 µm [odds ratio (OR) 4.11; p = 0.003] and CCs (OR 3.23; p = 0.017) were associated with periprocedural cTn elevation. For post-stent OFDI features, in-stent dissection (OR 3.08; p = 0.035) and in-stent thrombus (OR 7.98; p = 0.002) were independent predictors of cTn elevation. The combination of CCs and FCT < 82 µm showed increased risk of periprocedural cTn elevation (OR 7.22; p = 0.002). OFDI-guided PCI provides unique insight into the mechanism for periprocedural cTn elevation in CAD patients.

Prognostic significance of renal dysfunction and its change pattern on outcomes in patients with acute coronary syndrome treated with emergent percutaneous coronary intervention.

Renal dysfunction and its change pattern are associated with short- and long-term mortality. However, it remains to be investigated whether or not worsening renal function (WRF) defined by baseline renal function identified from different time points would provide prognostic implication on outcomes in acute coronary syndrome (ACS) patients. This study consists of 334 ACS patients (mean age 68 ± 11 years, 75% male) treated with emergent percutaneous coronary intervention (PCI). Estimated glomerular filtration rate (eGFR) was evaluated on baseline, during hospitalization, at discharge, and at 3-month follow-up. WRF was defined as a relative decrease of eGFR > 20% at 3 months using baseline eGFR identified from different time points. The primary end point was a composite event of major cardiovascular events (MACE), including all-cause death, ACS, and heart failure hospitalization. The associations of chronic kidney disease (CKD), acute kidney injury (AKI), and WRF with MACE were evaluated. During a mean follow-up of 3.3 ± 1.7 years, a total of 64 MACE were observed. Multivariable analysis revealed that CKD (hazard ratio 2.16; p = 0.018) and AKI (hazard ratio 1.95; p = 0.030) were independent predictors of MACE, but WRF did not remain as an independent predictor of MACE (p = 0.208). The highest risk was observed in AKI patients with CKD when stratified by the presence or absence of CKD and AKI. In ACS patients treated with emergent PCI, this study demonstrated that CKD and AKI were independent predictors of MACE, while there was no independent relationship between WRF and MACE.

Associations of sensitive cardiac troponin-I with left ventricular morphology, function and prognosis in end-stage renal disease patients with preserved ejection fraction.

Sensitive cardiac troponin I (cTnI) predicts all-cause and cardiovascular mortality in various clinical settings. However, its clinical significance in hemodialysis (HD) patients with preserved left ventricular ejection fraction (LVEF) has not been fully elucidated. This study investigated the association of cTnI with LV morphology and function, and its long-term outcome in HD patients with preserved LVEF. This prospective study consists of 96 HD patients with preserved LVEF (69 ± 8 years and 63% male) who underwent two-dimensional echocardiographic examination and biomarker tests including cTnI, brain natriuretic peptide, and high-sensitive C-reactive protein. The primary endpoint was all-cause death and secondary endpoint was cardiovascular death. Factors independently associated with cTnI were systolic blood pressure (ß = - 0.239, p = 0.011), heart rate (ß = 0.216, p = 0.021), LV mass index (ß = 0.231, p = 0.020), and E to e' ratio (ß = 0.237, p = 0.016). During a mean follow-up of 3.6 years, primary and secondary endpoints were observed in 23 (24%) and 18 (19%) patients, respectively. In the multivariate Cox proportional hazard analysis, the upper cTnI tertile has significantly increased risk of all-cause mortality [hazard ratio (HR), 2.69; 95% confidence interval (CI), 1.139-6.386; p = 0.024] and that of cardiovascular death (HR, 4.56; 95% CI 2.021-16.968; p = 0.006) independent of echocardiographic measures and other serum biomarkers. In HD patients with preserved LVEF, serum cTnI levels were significantly associated with diastolic function and risk of mortality independent of echocardiographic variables and other biomarkers.

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Cardiovascular and cancer events in hyper-high-density lipoprotein cholesterolemic patients: a post hoc analysis of the MEGA study.

BACKGROUND: The prognosis for hyper-high-density lipoprotein (HDL) cholesterolemic patients has not been fully elucidated. We conducted a post hoc analysis of MEGA study data to investigate prospectively the incidence of cardiovascular events and cancer in hyper-HDL cholesterolemic patients. METHODS: A total of 7832 patients with mild hypercholesterolemia were randomly allocated to either the National Cholesterol Education Program step 1 diet alone (n = 3966) or the diet plus pravastatin (n = 3866) and followed for 5 years. The incidences of coronary heart disease (CHD), CHD plus cerebral infarction (CI), cardiovascular disease (CVD), and cancer were calculated using the Cox proportional hazards model according to the level of HDL cholesterol (HDL-C). RESULTS: CHD incidence was lower in patients with HDL-C >60-90 mg/dL (-52%, p = 0.0018) and HDL-C > 90 mg/dL (-46%, p = 0.4007) than in patients with HDL-C ≤ 60 mg/dL. The incidences of CHD, CHD plus CI, and CVD were significantly lower in patients with HDL-C >60-90 mg/dL than in those with HDL-C ≤ 60 mg/dL in both diet-alone and diet-plus-pravastatin groups. Cancer incidence was not increased in patients with HDL-C >60-90 mg/dL. CONCLUSION: Patients not receiving statin therapy should aim for a target HDL-C of between 60 and 90 mg/dL to achieve a significant reduction in CHD without the occurrence of adverse events. TRIAL REGISTRATION: Clinical trials.gov NCT00211705.

[From the Point of View of Health Evaluation and Promotion (Ningen Dock) Facilities].

Since the direct method of LDL measurement is easy and convenient, many health evaluation and promotion facilities adopted it without sufficient discussion after specific health checkups started in Japan. For the purpose of reliable, specific health checkup data, we must review the methods and standardization of LDL measurement. I hope that medical societies, the Ministry of Health, Labour and Welfare, and reagent manufacturers will collaborate.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

BACKGROUND: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING: None.

Usefulness of pravastatin in primary prevention of cardiovascular events in women: analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA study).

BACKGROUND: It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. METHODS AND RESULTS: Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for > or = 5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women > or = 60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone. CONCLUSIONS: Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques: a 2-year follow-up by noninvasive MRI.

BACKGROUND: Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated. DESIGN: A prospective, randomized, open-label trial. METHODS: We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemic patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated. RESULTS: The 20-mg dose markedly reduced LDL-cholesterol levels (-47%) versus 5-mg (-35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (-15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (-14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (-1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64). CONCLUSION: Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment.

Associations between headache and stress, alcohol drinking, exercise, sleep, and comorbid health conditions in a Japanese population.

We conducted a cross-sectional survey of 12,988 subjects aged 20-79 years (5,908 men and 7,090 women) receiving health checkups at a Tokyo clinic. They filled out a self-administered structured questionnaire, and 5.4% of the men and 15.4% of the women reported having headaches. Younger subjects were more prone to having headaches. The likelihood of having headaches increased with stress level and decreased ability to relieve stress in both genders. There was an inverse dose-response relationship between having headaches and alcohol consumption, and less walking/exercise and sleep problems increased the likelihood of headaches in both genders. Headache sufferers of both genders were more likely to report multiple additional poor health conditions. A multivariate stepwise logistic analysis showed that age, self-estimated degree of stress, reported number of additional poor health conditions, and less alcohol consumption were independently correlated with having headaches. In conclusion, although women were more susceptible to headache, Japanese men and women in Tokyo shared factors associated with headache, including age, stress, having other poor health conditions, alcohol consumption, sleep, and exercise.

Ankle-brachial index, arterial stiffness, and biomarkers in the prediction of mortality and outcomes in patients with end-stage kidney disease.

BACKGROUND: Although ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are significant predictors of major adverse cardiovascular event (MACE), their prognostic value in association with biomarkers has not been fully evaluated in patients with end-stage kidney disease (ESKD). HYPOTHESIS: We hypothesized that ABI/baPWV would provide better prognostic value independent of biomarkers in ESKD patients. METHODS: This study included 104 ESKD patients treated with maintenance hemodialysis who underwent ABI and baPWV examinations and laboratory tests, including brain-natriuretic peptide, high-sensitive cardiac troponin T (hs-cTnT), and high-sensitive C-reactive protein (hs-CRP). MACE was defined as a composite event of all-cause death, acute coronary syndrome, and stroke. RESULTS: During a mean follow-up of 3.6 ± 1.7 years, a total of 51 MACE were observed. The independent factors associated with MACE were age >75 years (adjusted hazard ratio [HR], 2.15; P < .05), abnormal ABI (adjusted HR, 2.01; P < .05), left ventricular ejection fraction (LVEF) <50% (adjusted HR, 3.33; P < .001), the upper tertile of hs-cTnT (adjusted HR, 2.77; P < .05), and hs-CRP (HR, 1.96; P < .05). However, baPWV did not remain as an independent predictor of MACE in the entire cohort and also in patients without abnormal ABI. The combination of predictors improves the predictive value of MACE, providing increased HR with 4.00 for abnormal ABI + hs-CRP, 4.42 for abnormal ABI + hs-cTnT, and 7.04 for abnormal ABI + LVEF <50% (all P < .001). CONCLUSION: Abnormal ABI is a robust predictor of MACE independent of biomarkers and their combination provides better risk stratification compared with a single predictor in ESKD patients.

Phytosterols dissolved in diacylglycerol oil reinforce the cholesterol-lowering effect of low-dose pravastatin treatment.

BACKGROUND AND AIMS: Dietary therapy using phytosterols can reinforce statin treatment; however the value of a low-dose combination of those agents remains to be investigated. Plant sterols (PS), dissolved in diacylglycerol (DAG) oil, (PS/DAG) can be effective at a relatively low dose. The objective of the present study was to examine the effect of PS/DAG oil on blood cholesterol concentrations in hypercholesterolemic outpatients on low-dose pravastatin (10 mg/day). METHODS AND RESULTS: The patients (n=61) were randomly assigned to one of three groups, who consumed TAG (control), DAG or PS/DAG oil. The average intake of PS from the PS/DAG oil during the test period was significantly higher than that for TAG and DAG oils (502 vs. 49 and 38 mg/day, P<0.05). Significant cholesterol-lowering effects from the baseline were observed in the case of the PS/DAG oil treatment alone. Changes in low-density lipoprotein (LDL) cholesterol were inversely correlated with baseline serum campesterol concentrations (r=-0.560, P<0.05), but not baseline LDL cholesterol concentrations. In addition, serum apolipoprotein B concentrations were reduced to a greater extent in subjects with high versus low levels of baseline campesterol (-13.2 mg/dL vs. -3.1 mg/dL, P<0.05). Furthermore, there was a mild, but significant reduction in serum lipoprotein (a) concentration from the baseline (-5.9 mg/dL), which was correlated with the reduction in serum apolipoprotein B concentration (r=0.596, P<0.05). CONCLUSION: A low-dose combination of PS/DAG oil and pravastatin may be a useful strategy for further ameliorating blood cholesterol and lipoprotein (a) concentrations for hypercholesterolemic patients with a low response to pravastatin.

Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.

BACKGROUND: Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. METHODS: In this prospective, randomised, open-labelled, blinded study, patients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. The primary endpoint was the first occurrence of coronary heart disease. Statistical analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00211705. FINDINGS: 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. INTERPRETATION: Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.

Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma.

AIM: The ATP binding cassette transporters A1 and G1 (ABCA1/G1) and scavenger receptor class B type I (SR-BI) are key molecules in cholesterol efflux and atherogenesis. These genes are regulated by peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor (LXR). Telmisartan is an angiotensin type 1 receptor blocker which has been reported to act as a ligand for PPARgamma. We investigated whether PPARgamma-activating ARBs affect the expression of these genes and cholesterol efflux from macrophages. METHODS AND RESULTS: Telmisartan increased ABCA1, ABCG1 and SR-BI mRNA levels in THP-1 macrophages in a dose- and time-dependent fashion. It also increased their protein levels and enhanced apoA-I- and HDL-mediated cholesterol efflux from macrophages. The knockdown of PPARgamma by siRNA abolished the telmisartan-induced expression of these genes. The knockdown of LXRalpha resulted in the complete and partial abolishment of telmisartan-induced ABCA1 and ABCG1 expression, respectively. We also demonstrated that telmisartan-induced SR-BI expression was dependent on the PPARgamma pathway but not on the LXRalpha pathway. A luciferase assay using an ABCA1 promoter construct showed that telmisartan activated ABCA1 transcription, which was abolished if the LXR binding element was mutated, indicating that increased ABCA1 transcription by telmisartan is LXR-dependent. CONCLUSION: Our results showed that telmisartan enhanced both apoA-I- and HDL-mediated cholesterol efflux from macrophages by increasing ABCA1, ABCG1 and SR-BI expression via PPARgamma-dependent and LXR-dependent/independent pathways.

Glucocorticoid receptor regulates ATP-binding cassette transporter-A1 expression and apolipoprotein-mediated cholesterol efflux from macrophages.

OBJECTIVE: The ATP-binding cassette transporter-A1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis. The objective of this study was to investigate the effect of dexamethasone (Dex) and other glucocorticoid receptor (GR) ligands on apolipoprotein AI-mediated cholesterol efflux from macrophages and ABCA1 expression in them. METHODS AND RESULTS: Dex, a GR agonist, decreased ABCA1 mRNA levels in a dose- and time-dependent fashion, and RU486, a GR antagonist, reversed the inhibitory effect of Dex. The effects of Dex and RU486 on ABCA1 protein levels and apolipoprotein AI-mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels. Transfected RAW264.7, together with a human ABCA1 promoter-luciferase construct, inhibited transcriptional activity by Dex and overexpression of human GR. Transrepression by GR was not mediated by liver X receptor (LXR), because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations, and no changes were brought about in ABCG1 and ABCG4 expression by GR ligands. CONCLUSIONS: Our results showed that GR ligands affected ABCA1 expression and cholesterol efflux from macrophages, which are regulated by GR through a LXR-independent mechanism.

A possible association between coronary plaque instability and complex plaques in abdominal aorta.

OBJECTIVE: Coronary plaque instability causes myocardial infarction (MI). Angiographic lesions with such instability are complex lesions. Complex carotid plaques were reported to be prevalent in unstable angina. We investigated associations between coronary plaque instability, such as MI and angiographic complex coronary lesions, and aortic plaques. METHODS AND RESULTS: Aortic MRI was performed in 146 patients undergoing coronary angiography, of whom 108 had coronary artery disease (CAD) and 44 also had MI. Prevalence of plaques in thoracic and abdominal aortas was higher in patients with than without CAD (73% and 94% versus 32% and 79%), but it was similar in CAD patients with and without MI. Notably, complex plaques in abdominal aorta were more prevalent in CAD patients with than without MI (36% versus 14%; P<0.025). In multivariate analysis, abdominal complex plaques were associated with MI (odds ratio [OR], 4.5; 95% CI, 1.5 to 13.8). Among patients without MI, thoracic and abdominal complex plaques were more prevalent in patients with than without complex coronary lesions (22% and 33% versus 2% and 7%; P<0.05). Abdominal complex plaques were also associated with complex coronary lesions (OR, 9.8; 95% CI, 1.1 to 85.9). CONCLUSIONS: Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

Preventive effect of pravastatin on the development of hypertension in patients with hypercholesterolemia: A post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.

BACKGROUND: It remains unclear whether treatment of dyslipidemia with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reduces the risk of developing hypertension. OBJECTIVE: In this post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, a large-scale primary prevention trial with pravastatin, we examined the preventive effect of pravastatin on the future development of hypertension in patients with hypercholesterolemia. METHODS: Of the overall (MEGA) Study population, 3397 nonhypertensive patients at baseline were enrolled in this study. The patients were randomly assigned to either the diet alone group (n = 1722) or the diet plus pravastatin group (n = 1675) and then were followed-up for a median of 36 months to determine new-onset hypertension. RESULTS: During the follow-up period, 1595 patients developed hypertension (49.1% in the diet alone group and 44.7% in the diet plus pravastatin group). After adjusting for multiple covariates, the diet plus pravastatin group showed a 10% reduction in the risk of developing hypertension (hazard ratio 0.90, 95% confidence interval 0.81-0.998), compared with the diet alone group. Subgroup analyses revealed that the preventive effect of pravastatin on the development of hypertension was pronounced in patients aged ≥60 years, men, those with chronic kidney disease or diabetes mellitus and those without obesity. CONCLUSIONS: Pravastatin reduced the risk of developing hypertension in Japanese patients with hypercholesterolemia. The risk reduction of cardiovascular disease with statins could be partly explained by their preventive effect on the development of hypertension.

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging.

OBJECTIVES: We sought to elucidate the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques. BACKGROUND: Regression of thoracic aortic plaques by simvastatin was demonstrated using magnetic resonance imaging (MRI). However, the effects of different doses of statin have not been assessed. METHODS: Using MRI, we investigated the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques in 40 hypercholesterolemic patients who were randomized to receive either dose. Treatment effects were evaluated as changes in vessel wall thickness (VWT) and vessel wall area (VWA) of atherosclerotic lesions from baseline to 12 months of treatment. RESULTS: The 20-mg dose induced a greater low-density lipoprotein (LDL) cholesterol reduction than did the 5-mg dose (-47% vs. -34%, p < 0.001). Although 20 mg and 5 mg reduced C-reactive protein (CRP) levels (-47% and -28%), the degree of CRP reduction did not differ between the two doses. The 20-mg dose reduced VWT and VWA of thoracic aortic plaques (-12% and -18%, p < 0.001), whereas 5 mg did not (+1% and +4%). Regarding abdominal aortic plaques, even 20 mg could not reduce VWT or VWA (-1% and +3%), but instead progression was observed with 5-mg treatment (+5% and +12%, p < 0.01). Notably, the degree of plaque regression in thoracic aorta correlated with LDL cholesterol (r = 0.64) and CRP (r = 0.49) reductions. Although changes in abdominal aortic plaques only weakly correlated with LDL cholesterol reduction (r = 0.34), they correlated with age (r = 0.41). CONCLUSIONS: One-year 20-mg atorvastatin treatment induced regression of thoracic aortic plaques with marked LDL cholesterol reduction, whereas it resulted in only retardation of plaque progression in abdominal aorta. Thoracic and abdominal aortic plaques may have different susceptibilities to lipid lowering.