Effects of pravastatin and atorvastatin on HDL cholesterol and glucose metabolism in patients with dyslipidemia and glucose intolerance: the PRAT study.

AIMS: While statins have the property of increasing high-density lipoprotein cholesterol (HDL-C) in addition to lowering low-density lipoprotein cholesterol (LDL-C), a potential adverse effect on glucose metabolism has raised a concern over statin therapy. In a comparative trial, we investigated the effects of low-dose pravastatin and atorvastatin on HDL-C and glucose metabolism in patients with elevated LDL-C levels and glucose intolerance. METHODS: Eligible patients were men aged ≥20 years or postmenopausal women who had LDL-C ≥140 mg/dL, HDL-C <80 mg/dL, and triglycerides <500 mg/dL and who had glucose intolerance. The patients were randomly allocated to either pravastatin (10 mg/day) or atorvastatin (10 mg/day) treatment for 12 months in an unblinded fashion. The percent changes from the baseline were compared between the treatments. RESULTS: Of 202 patients who were randomized to either of the two treatments, 195 patients started the study medication, and 187 patients underwent the follow-up measurements at 6 or 12 months (pravastatin, n= 93; atorvastatin, n= 94). HDL-C increased by 4.3% (p= 0.03) in the pravastatin group and by 5.8% (p=0.0005) in the atorvastatin group and showed no between-group difference (p= 0.38). LDL-C decreased substantially in both groups (pravastatin, 21.5%; atorvastatin, 35.5%), and the decrease was much greater in the atorvastain group (p<0.0001). HbA1c slightly increased in both groups, but showed no measurable difference in the increase between the two treatments (p=0.30). CONCLUSION: Pravastatin and atorvastatin of 10 mg per day each increased HDL-C by almost the same extent. These two statins did not show a differential effect on glucose metabolism.

Double-dose pravastatin versus add-on ezetimibe with low-dose pravastatin - effects on LDL cholesterol, cholesterol absorption, and cholesterol synthesis in Japanese patients with hypercholesterolemia (PEAS study).

AIM: This study compared the effect of doubling the dose of pravastatin with that of adding ezetimibe to low-dose pravastatin on the LDL cholesterol (LDL-C) level and on cholesterol absorption and synthesis markers. The tolerability of the 2 regimens was also compared. METHODS: This was a multicenter, open-label, parallel-group trial. Subjects were aged from 20 to 74 years and had an LDL-C ≥ 120 mg/dL despite pravastatin therapy at 5-10 mg/day. They were randomly allocated to receive either add-on ezetimibe (10 mg/day) or double-dose pravastatin, and follow-up was performed for 12 weeks. The primary endpoints were the changes of LDL-C and apolipoprotein (apo) B levels after 12 weeks of treatment. Cholesterol absorption and synthesis markers were also determined. RESULTS: LDL-C and apo B decreased by 16% and 14% in the ezetimibe add-on group versus 5.9% and 4.4%, respectively, in the pravastatin double-dose group. The between-group differences of these decreases were highly significant. Cholesterol absorption markers (sitosterol, campesterol, and cholestanol) were reduced by 48%, 36%, and 10%, respectively, in the ezetimibe add-on group, and were increased by 17%, 14%, and 6%, respectively, in the pravastatin double-dose group. Lathosterol (a cholesterol synthesis marker) increased by 76% in the ezetimibe add-on group and by 24% in the pravastatin double-dose group. The difference was statistically significant. No serious adverse effect was observed in either group. CONCLUSIONS: Adding ezetimibe to low-dose pravastatin achieves greater decreases in LDL-C, apo B, and cholesterol absorption markers than doubling the dose of pravastatin.

The long-term effect of angiotensin II type 1a receptor deficiency on hypercholesterolemia-induced atherosclerosis.

Angiotensin II type 1 receptor may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. In the present study, we investigated the long-term effect of angiotensin II type 1a receptor (AT1a) deficiency on hypercholesterolemia-induced atherosclerosis by the use of AT1a-knockout (AT1a-KO) mice and apolipoprotein E-knockout (apoE-KO) mice. AT1a-KO were crossed with apoE-KO, generating double-knockout (D-KO) mice. Mice were fed a standard diet and analyzed at 25- or 60-weeks-old. The quantification of atherosclerotic volume in the aortic root revealed that the atherosclerotic lesions of D-KO mice were significantly smaller than those of apoE-KO mice at 25-week-old (0.81+/-0.16 mm2 vs. 1.05+/-0.21 mm2, p<0.001) and at 60-week-old (0.89+/-0.11 mm2 vs. 2.44+/-0.28 mm2, p<0.001). Surprisingly, there was no significant difference in atherosclerotic lesion size of D-KO mice at 25- and 60-week-old, suggesting that AT1a deficiency completely protected against the age-related progression of atherosclerosis. The amounts of collagen and elastin, the expression of p22phox, serum amyloid P (SAP), matrix metalloproteinase (MMP)-2, and MMP-9, and the number of apoptotic cells of D-KO mice were lower than those of apoE-KO mice. Furthermore, we confirmed that the expression of procollagen alpha1(I), procollagen alpha1(III), tropoelastin, p22phox, SAP, MMP-2, and MMP-9 decreased in cultured vascular smooth muscle cells from D-KO mice compared with those of apoE-KO mice. In conclusion, AT1a deficiency reduces atherosclerotic lesion size of apoE-KO mice and protects against the age-related progression of atherosclerosis. Reduction of oxidative stress, apoptosis, and MMP expression in atherosclerotic lesions by AT1a deficiency may contribute to plaque size.

A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance.

BACKGROUND: Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared. OBJECTIVES: This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared. METHODS: This was a multicenter, open-label, parallel-group trial. Patients with LDL-C levels>or=140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable. RESULTS: Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack of >or=6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P=0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P=0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (-40.1 vs -33.0, respectively; P=0.002), as were the percent changes in non-HDL-C (-37.4 vs -31.1; P=0.004), Apo B (-35.1 vs -28.2; P<0.001), and Apo E (-28.1 vs -17.8; P<0.001). The significant results for these parameters were unchanged when all 189 subjects who received>or=1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group (P=NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value>3 times the upper limit of normal (P=NS). CONCLUSIONS: In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.

Association of coronary shear stress with endothelial function and vascular remodeling in patients with normal or mildly diseased coronary arteries.

BACKGROUND: The relationship between coronary remodeling, shear stress and endothelial function remains unclear. OBJECTIVE: The present study investigated the effects of mechanical factors on structure and function of epicardial coronary arteries. METHODS: Patients (group 1: %area stenosis<40%, n=55; or group 2: %area stenosis>or=40%, n=17) with a discrete mildly stenotic lesion (%diameter stenosis<30%) underwent intravascular ultrasound examination of the left anterior descending coronary artery for determination of vessel area, lumen area, plaque area, cross-sectional areas at reference segments, and remodeling index (the ratio of vessel area at the culprit lesion to vessel area at the proximal reference site). Further, vascular reactivity was examined using intracoronary administration of acetylcholine, papaverine, and nitroglycerin. RESULTS: Vessel area significantly correlated with plaque area in both groups (r=0.65, P<0.0001 and r=0.85, P<0.0001). Group 1 showed significantly greater acetylcholine-induced percentage changes in coronary blood flow (67+/-70 vs. 16+/-75%, P<0.05) and coronary artery diameter (-7+/-18 vs.-32+/-31%, P<0.01) and also significantly smaller coronary wall shear stress (65+/-27 vs. 81+/-32 dynes/cm, P<0.05) than group 2. The percentage increase in coronary blood flow induced by acetylcholine was significantly and positively correlated with remodeling index in group 1 (r=0.64, P<0.0001) but not in group 2 (r=-0.03, P=0.90) and was also significantly and positively correlated with coronary wall shear stress in group 1 (r=0.46, P<0.001) but not in group 2 (r=-0.33, P=0.19). CONCLUSIONS: Endothelium-dependent vasodilation in the resistance coronary artery correlates with remodeling via increased wall shear stress when target lesions %area stenosis is <40%.

Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia.

BACKGROUND: Nitric oxide (NO), constitutively produced by endothelial NO synthase (eNOS), plays roles in angiogenesis. Having reported that thermal therapy up-regulated the expression of arterial eNOS in hamsters, we investigated whether this therapy increased angiogenesis in mice with hindlimb ischemia. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced in apolipoprotein E-deficient mice, which were divided into control and thermal therapy groups. The latter mice were placed in a far-infrared dry sauna at 41 degrees C for 15 min and then at 34 degrees C for 20 min once daily for 5 weeks. Laser Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls (0.79+/-0.04 vs 0.54+/-0.08, p<0.001). Significantly greater capillary density was seen in thermal therapy group (757+/-123 /mm2 vs 416+/-20 /mm2, p<0.01). Western blotting showed thermal therapy markedly increased hindlimb eNOS expression. To study possible involvement of eNOS in thermally induced angiogenesis, thermal therapy was given to mice with hindlimb ischemia with or without N(G)-nitro-L-arginine methyl ester (L-NAME) administration for 5 weeks. L-NAME treatment eliminated angiogenesis induced using thermal therapy. Thermal therapy did not increase angiogenesis in eNOS-deficient mice. CONCLUSION: Angiogenesis was induced via eNOS using thermal therapy in mice with hindlimb ischemia.

Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury.

Lectin-like oxidized LDL receptor-1 (LOX-1) is an oxidized LDL receptor, and its role in restenosis after angioplasty remains unknown. We used a balloon-injury model of rabbit aorta, and reverse transcription-polymerase chain reaction revealed that LOX-1 mRNA expression was modest in the non-injured aorta, reached a peak level 2 days after injury, and remained elevated until 24 weeks after injury. Immunohistochemistry and in situ hybridization showed that LOX-1 was not detected in the media of non-injured aorta but expressed in both medial and neointimal smooth muscle cells (SMC) at 2 and 24 weeks after injury. Low concentrations of ox-LDL (10 microg/mL) stimulated the cultured SMC proliferation, which was inhibited by antisense oligonucleotides of LOX-1 mRNA. Double immunofluorescence staining showed the colocalization of LOX-1 and proliferating cell nuclear antigen in human restenotic lesion. These results suggest that LOX-1 mediates ox-LDL-induced SMC proliferation and plays a role in neointimal formation after vascular injury.

Mechanism of persistent ischemic mitral regurgitation after annuloplasty: importance of augmented posterior mitral leaflet tethering.

BACKGROUND: We hypothesized that surgical annuloplasty for ischemic mitral regurgitation (MR) that displaces the posterior annulus anteriorly can potentially augment posterior leaflet (PML) tethering, leading to persistent MR. Relationships between leaflet configurations and persistent ischemic MR after the annuloplasty were investigated. METHODS AND RESULTS: In 31 patients with surgical annuloplasty for ischemic MR and 20 controls, posterior and apical displacement of the leaflet coaptation, the anterior leaflet (AML) and PML tethering angles relative to the line connecting annuli, coaptation length (CL), and the MR grade were quantified before and early after surgery in echocardiographic left ventricular long-axis views. Six of the 31 patients showed persistent MR despite annuloplasty. Compared with patients without persistent MR, those with MR showed no improvement in the left ventricular ejection fraction and systolic volume, similar reduction in the annular area, significant increase in posterior displacement of the coaptation (P<0.01), no improvement in AML tethering, greater worsening in PML tethering (P<0.01), and no increase in the CL. All tethering variables were significantly correlated with both preoperative and postoperative MR in univariate analysis, and reduced CL was the primary independent determinant of both preoperative and postoperative MR. Although increased AML tethering was the primary determinant of the preoperative CL (r2=0.46, P<0.0001), increased PML tethering was the primary determinant afterward (r2=0.60, P<0.0001). CONCLUSIONS: Although tethering of both leaflets is the major determinant of ischemic MR before surgical annuloplasty, both leaflets tethering but with predominant and augmented PML tethering is related to persistent ischemic MR after the annnuloplasty.

Correlation between distal left anterior descending artery flow velocity by transthoracic Doppler echocardiography and corrected TIMI frame count before mechanical reperfusion in patients with anterior acute myocardial infarction.

BACKGROUND: This study was designed to determine the utility of transthoracic Doppler echocardiography (TTDE) in evaluating angiographic Thrombolysis in Myocardial Infarction (TIMI) frame count as a quantitative index of coronary reperfusion in patients with anterior acute myocardial infarction (AMI) before mechanical reperfusion. METHODS AND RESULTS: Color and pulsed TTDE was performed to evaluate distal left anterior descending coronary artery (LAD) reperfusion in 56 consecutive patients with a first anterior AMI before coronary intervention, and these findings were compared with the corrected TIMI frame count (cTFC) by subsequent angiography. Twenty-four of the 56 patients had LAD reperfusion (TIMI 2 or 3) by angiography. Visual antegrade distal LAD flow by color TTDE was detected in 21 of these 24 patients. In the 21 patients, diastolic peak velocity of the distal LAD flow by pulsed TTDE showed a significant correlation with cTFC by angiography (r = -0.74, p < 0.001). The diagnosis of high risk with angiographic cTFC >40 by distal LAD peak velocity <21 cm/s using TTDE had a sensitivity, specificity, and accuracy of 82%, 93%, and 91%, respectively. CONCLUSION: TTDE enables noninvasive and quantitative evaluation of distal LAD reperfusion in patients with anterior AMI in the acute phase before mechanical reperfusion.