Development of a model for prediction of coronary atherosclerotic regression: evaluation of high-density lipoprotein cholesterol level and peripheral blood monocyte count.

Monocytes and high-density lipoprotein cholesterol (HDL-C) play important roles in the process of coronary atherosclerosis. We hypothesized that a reasonable predictive model of coronary plaque regression might be constructed using the change in the peripheral monocyte count and the serum HDL-C level. The plaque volume, as assessed by volumetric intravascular ultrasound, was measured at the baseline and after 6 months of pravastatin therapy in 114 patients with coronary artery disease. After 6 months of pravastatin therapy, a significant decrease of the plaque volume by 9.9% (p < 0.0001, vs. baseline) was observed; furthermore, a corresponding increase of the serum HDL-C level and decrease of the peripheral blood monocyte count were also seen (12.5%, p < 0.01 and -7.3%, p < 0.0001). In a multivariate regression analysis using the serum lipids and traditional risk factors as the covariates, the increase in the serum HDL-C (ß -0.56, p < 0.0001) and the decrease in monocyte count (ß 0.23, p = 0.03) were identified as independent predictors of the plaque regression. A model for the prediction of plaque regression according to whether the achieved the change in (Δ) monocyte count and ΔHDL-C were above or below the median values was prepared. Among the four groups, the group with ΔHDL-C ≥8.8% and Δmonocyte count ≤-8.6% showed the largest plaque regression (-20.4%), and the group with ΔHDL-C <8.8% and Δmonocyte count >-8.6% showed the increase of the plaque volume (2.6%). In view of the inflammatory nature of atherosclerosis, the model constructed using the two predictors may be a useful model for the prediction of plaque regression.

Low-density lipoprotein cholesterol/apolipoprotein B ratio may be a useful index that differs in statin-treated patients with and without coronary artery disease: a case control study.

Low density lipoproteins (LDLs) are heterogeneous aggregations of molecules of different particle sizes, and small-size LDLs are more potent risk factors for atherosclerosis. We examined the qualitative characteristics of LDLs in patients with stable coronary artery disease (CAD) receiving statin therapy. LDL-particle size was estimated based on the LDL-cholesterol/apolipoprotein B ratio (LDL-C/apoB) in 214 age-adjusted men receiving statin therapy. The LDL-C/apoB ratio was significantly lower in the CAD (+) group (n = 107) than in the CAD (-) group (n = 107) (median, 1.17 versus 1.19, P = 0.0095). LDL-C/apoB was significantly lower in patients with serum TG ≥ 150 mg/dL than in those with serum TG < 150 mg/dL, and in patients with serum HDL-C < 40 mg/dL than in those with serum HDL-C ≥ 40 mg/dL (1.06 versus 1.18, P = 0.012; 1.08 versus 1.22, P = 0.0023). Stepwise logistic regression analysis revealed that elevated serum TG was an independent predictor for smaller sizes of LDLs, both in the overall subjects (ß : -0.165, P = 0.02) as well as in the subset with serum LDL-C < 100 mg/dL (ß : -0.252, P = 0.011). This study demonstrated that not only the absolute serum LDL-C level, but also the qualitative characteristics of LDL may be monitored for secondary prevention of CAD. Such monitoring is particularly important in patients with elevated serum TG levels, which is associated with smaller sizes of LDL-particles.

Coronary plaque regression and lifestyle modification in patients treated with pravastatin. - Assessment mainly by daily aerobic exercise and an increase in the serum level of high-density lipoprotein cholesterol -.

BACKGROUND: The purpose of this study was to explore the effect of lifestyle modification, mainly daily aerobic exercise, on coronary atherosclerosis in patients with coronary artery disease (CAD). METHODS AND RESULTS: A 6-month prospective observational study was conducted with 84 CAD patients receiving pravastatin treatment in order to evaluate the relationship between lifestyle modification, in particular aerobic exercise, and plaque volume as assessed by intravascular ultrasound (IVUS). Lifestyle during the study period was assessed by the-lifestyle modification score. A significant decrease in plaque volume by 12.9% was observed after 6 months of pravastatin therapy (P<0.0001 vs baseline). The change in plaque volume correlated with the change in the serum level of high-density lipoprotein cholesterol (HDL-C) (r=-0.549, P<0.0001), non-HDL-C (r=0.248, P=0.03), low-density lipoprotein cholesterol/HDL-C (r=0.505, P<0.0001), apolipoprotein (apo) A-1 (r=-0.335, P=0.007) and apoB/apoA-1 (r=0.335, P=0.007), and lifestyle modification score (r=-0.616, P<0.0001). There was a clear positive correlation between a change in the serum HDL-C level and lifestyle modification score. Multivariate regression analysis revealed that the increase in serum HDL-C level and lifestyle modification score were independent predictors of coronary plaque regression. CONCLUSIONS: An appropriate combination of statin therapy and lifestyle modification, in particular, physical activity, may result in coronary plaque regression. This combined treatment strategy, inducing an increase of the serum HDL-C, may contribute to coronary plaque regression.

Treatment of coronary spastic angina with a statin in addition to a calcium channel blocker: a pilot study.

Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (-20.7 +/- 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 +/- 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 +/- 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.

Effect of pravastatin on malondialdehyde-modified low-density lipoprotein levels and coronary plaque regression as determined by three-dimensional intravascular ultrasound.

We hypothesized that a reduction in atherogenic malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels, which may antagonize the action of atheroprotective high-density lipoprotein cholesterol, leads to coronary plaque regression. This study investigated the effects of pravastatin on the serum levels of MDA-LDL and coronary atherosclerosis. In a 6-month prospective study, 75 patients with stable coronary artery disease were randomly assigned to a pravastatin-treatment group (n = 52) or a control group (n = 23). Volumetric analyses were performed in matched coronary artery segments by 3-dimensional intravascular ultrasound. Pravastatin therapy for 6 months resulted in a decrease in coronary plaque volume (14.4%, p <0.0001) and a corresponding reduction in serum MDA-LDL levels (12.7%, p = 0.0001). In the pravastatin treatment group, the percentage of change in plaque volume correlated with changes in the MDA-LDL and high-density lipoprotein cholesterol levels (r = 0.52 and -0.55, respectively, p <0.0001) but not with the changes in any other lipid levels. Multivariate regression analysis revealed that a reduced MDA-LDL level is an independent predictor of plaque regression, as was an increase in high-density lipoprotein cholesterol. In conclusion, these results suggest that the reduction in the MDA-LDL levels induced by pravastatin may serve as a novel marker of coronary atherosclerosis regression.

Effect of exposure to cigarette smoke on carotid artery intimal thickening: the role of inducible NO synthase.

OBJECTIVE: We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS). METHODS AND RESULTS: Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS-/-) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO. Intimal thickening 21 days after cuff placement was significantly greater in mice exposed to CS compared with air (0.023+/-0.013 mm(2) versus 0.009+/-0.008 mm(2); P<0.05). iNOS inhibitor mercaptoethylguanidine-treated WT mice exposed to CS had reduced iNOS activity and intimal thickening (0.006+/-0.005 mm(2); P<0.05). Intimal thickening was significantly less in iNOS-/- mice compared with WT mice (0.006+/-0.005 mm(2); P<0.01) and was not augmented with CS (0.002+/-0.002 mm(2)). The aryl hydrocarbon receptor (AhR) was detected in arteries in vivo and in smooth muscle cells (SMCs) in vitro. CS condensate treatment of SMCs increased AhR binding to the core xenobiotic-responsive element of the iNOS promoter and increased iNOS expression. CONCLUSIONS: Increased arterial expression of iNOS, mediated at least in part by AhR signaling, may be an important mechanism by which CS increases carotid intimal thickening. CS exposure in mice was associated with increased arterial iNOS expression, superoxide production, AP-1 activation, serum NO expression, and intimal thickening. Inhibition or deletion of iNOS abrogated the effects of CS.

Effect of pioglitazone on arteriosclerosis in comparison with that of glibenclamide.

BACKGROUND: Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. OBJECTIVE: To investigate the anti-arteriosclerotic effects of pioglitazone in patients with diabetes mellitus using pulse wave velocity (PWV) as an index of efficacy. METHODS: Twenty-seven patients with type 2 diabetes mellitus were randomly assigned to two groups, and pioglitazone (n=13) or glibenclamide (n=14) was administered for 6 months. The TG, TC, LDL-C, and HDL-C, FPG, HbA1c, IRI levels, HOMA-IR, and ba-PWV data were examined before and after administration of each agent. RESULTS: FPG and HbA1c were significantly improved in both the groups after treatment, but IRI, HOMA-IR and were improved only in the PIO group. The percent change of ba-PWV from the baseline after treatment in the PIO group improved significantly than that in the GC group (-6.3 +/- 5.6% versus 0.8 +/- 5.7%). CONCLUSIONS: The findings in this study suggested that pioglitazone has anti-arteriosclerotic effects. We concluded that drugs for the treatment of diabetes mellitus should be selected taking into consideration such endpoints as blood sugar control, and also the risk of complications such as cardiovascular events in the future.

Aberrant antibody responses to oxidized LDL and increased intimal thickening in apoE-/- mice exposed to cigarette smoke.

Cigarette smoking is associated with increased atherosclerosis and intimal thickening, and has immune-suppressive effects. The immune system modulates atherosclerosis and intimal thickening. We hypothesized that detrimental effects of cigarette smoke (CS) involves modulation of the immune response to oxidized low-density lipoprotein (oxLDL). ApoE-/- mice fed Western diet were exposed to CS starting at 20 weeks of age. Control mice were exposed to air. After 5 weeks of CS, mice were subjected to carotid arterial cuffing for 21 days. Intimal thickening was significantly increased in CS mice compared to control (0.050 +/- 0.034 mm(2) versus 0.023 +/- 0.021 mm(2); P < 0.05). Spleen lymphocyte population, cytokine mRNA expression, and total IgM and IgG levels were similar. Anti-MDA oxLDL IgG was reduced by 40% (P < 0.05) in CS mice compared to control. Copper-oxidized LDL IgG antibodies remained unchanged but IgM increased in CS mice, associated with increased intimal thickening. Anti-phosphorylcholine (PC) IgM was also increased in the CS mice, associated with increased intimal thickening. Lymphocyte signaling molecule lymphotoxin beta (LTbeta) expression was significantly decreased in spleens of CS exposed mice. Our results suggest that immune modulation by CS characterized by aberrant antibody responses to oxLDL and reduced LTbeta mRNA expression is associated with increased intimal thickening after arterial cuffing.

Double left anterior descending artery arising from right and left sinus of Valsalva in patient with acute coronary syndrome.

An aberrant origin of left anterior descending artery (LAD) from right and left sinus of Valsalva is a rare anomaly but clinically important. Coronary angiography (CAG) was performed in patient with acute coronary syndrome, and revealed severe stenosis at the mid of LAD. The distal of LAD was likely to be a total occlusion. It was proved to be a double left anterior descending artery arising from right and left sinus of Valsalva by multidetector-row computed tomography (MDCT) and following CAG. We describe here congenital coronary anomaly case which would be misleading as a total occlusion.

Relation of change in apolipoprotein B/apolipoprotein A-I ratio to coronary plaque regression after Pravastatin treatment in patients with coronary artery disease.

Some investigations have looked into the ability of measurements of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio to predict cardiovascular events. We hypothesized that a decrease in the apoB/apoA-1 ratio by statin therapy would act on suppression of coronary plaque progression. A 6-month prospective study was conducted of 64 patients with coronary artery disease treated with pravastatin. The plaque volume, assessed by volumetric intravascular ultrasonography, had decreased significantly by 12.6% (p <0.0001 vs baseline). Although a significant decrease of 6.4% and 14.6% was found in the serum level of apoB and the apoB/apoA-1 ratio (p = 0.0001 and p <0.0001, respectively, vs baseline), a significant increase of 14.0% of and 12.0% in the level of apoA-I and apoA-II (both p <0.0001 vs baseline). No significant changes were found in the level of apoC-II or apoE. A stepwise regression analysis revealed that the change in the apoB/apoA-1 ratio was an independent predictor of the change in coronary plaque volume (beta coefficient 0.386; p = 0.0023). In conclusion, our results have indicated that the decrease in the apoB/apoA-I ratio is a simple predictor for coronary atherosclerotic regression: the lower the apoB/apoA-I ratio, the lower the risk of coronary atherosclerosis.

Association of plasma level of malondialdehyde-modified low-density lipoprotein with coronary plaque morphology in patients with coronary spastic angina: implication of acute coronary events.

BACKGROUND: Focal vasospasm is reportedly involved in a high incidence of acute coronary syndrome (ACS) as compared with diffuse vasospasm. No adequate studies have been conducted on the mechanism underlying the higher incidence of ACS involving focal vasospasm than of those involving diffuse vasospasm in patients with coronary spastic angina. METHODS AND RESULTS: Blood samples were collected from the aortic root (Ao) and the coronary sinus (CS) before provoking left coronary vasospasm using intracoronary administration of acetylcholine. After relief of vasospasm, volumetric analyses of vasospastic lesions were evaluated with 3-dimensional intravascular ultrasound in 64 patients. The percent plaque volume was more prominent in focal (n=31) than in diffuse vasospasm (n=33) (40.9+/-9.4 vs. 23.3+/-9.2%, p<0.0001). The Cs-Ao difference of malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, as a marker of atherothrombosis, in focal vasospasm increased significantly as compared with diffuse vasospasm (6.9+/-6.7 vs. 1.2+/-5.7 U/L, p=0.001). In a multiple-logistic regression analysis with the traditional risk factors, the Cs-Ao difference of MDA-LDL level was a variable differing independently between the 2 types of vasospasm. CONCLUSIONS: Higher MDA-LDL levels were observed in the coronary circulation in patients with focal vasospasm than in those with diffuse vasospasm. Under these conditions, the dramatically increased percent plaque volume in cases with focal vasoconstriction may play an important role in the development of acute coronary events.

Effects of enalapril and losartan in left ventricular remodeling after acute myocardial infarction: a possible mechanism of prevention of cardiac events by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high-risk myocardial infarction.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) have been shown to have a significant cardioprotective effect in high-risk patients after myocardial infarction (MI). However, there are few data on the effects of these drugs on left-ventricular (LV) remodeling after MI in Japanese patients. METHODS AND RESULTS: We randomly assigned 100 patients with anterior-wall MI who had received reperfusion therapy to treatment with either enalapril (n=50) or losartan (n=50), and calculated the LV ejection fraction (LVEF) and LV end-diastolic volume index (LVEDVI) in these patients at baseline and after 6 months of treatment. While a significant increase in the LVEF as compared with that at the baseline was observed in both groups, no significant difference was found in the rate of change of this parameter between the two groups. However, inverse correlations were observed between the baseline LVEF and LVEDVI and also the rates of change of the two parameters, suggesting that the greater the compromise of the LV function at baseline, the greater the preventive effect of both classes of drugs on LV remodeling. CONCLUSION: The results of this study suggest that neither enalapril nor losartan is superior to the other in terms of the effect on LV remodeling after MI in Japanese patients. In addition, the suppressive effect of both classes of drugs on LV remodeling was greater in patients with more extensive infarction and greater compromise of LV function at baseline.

Association of body mass index with coronary plaque regression: 6-month prospective study.

AIM: Obesity is a well known strong risk factor for coronary artery disease (CAD). We prospectively investigated the influence of body mass index (BMI) on the inhibitory effects of pravastatin against the development of coronary atherosclerosis. METHODS: In 56 patients with stable CAD, 3-dimensional intravascular ultrasound was performed in matched coronary segments at the baseline and after 6-month treatment with pravastatin. RESULTS: The plaque volume was significantly reduced by 11% after treatment (p<0.001 vs. baseline). The percent plaque volume was positively correlated with the baseline BMI (r=0.37, p<0.001), and negatively correlated with the serum total cholesterol / high-density lipoprotein cholesterol ratio (r=0.27, p<0.05) and total leukocyte count (r=0.27, p<0.05). Multivariate regression analysis showed that BMI was an independent predictor of the change in plaque volume (beta coefficient: 0.326; 95% CI: 0.003 to 0.037; p<0.05). No correlations were found between BMI and changes in the serum levels of any other lipids, apolipoproteins, or hs-CRP. CONCLUSION: The present study demonstrated that an increase in BMI attenuated pravastatin-induced coronary atherosclerosis regression. The results may provide new insight into the framework for the treatment of obese patients with CAD.

Association of leukocyte subtype counts with coronary atherosclerotic regression following pravastatin treatment.

The purpose of this study was to clarify the relation between differential leukocyte counts and inhibition of the development of coronary atherosclerosis in patients with coronary artery disease. A 6-month prospective study was conducted in 84 patients treated with pravastatin. Plaque volume, as assessed by volumetric analysis using intravascular ultrasound, decreased significantly by 12.6% (p <0.0001 vs baseline) after treatment; furthermore, a corresponding decrease of total leukocyte count (8.9%, p <0.01 vs baseline) was seen. Change in plaque volume was correlated with changes in monocyte (r = 0.35, p = 0.002) and lymphocyte (r = 0.25, p = 0.03) counts but not with changes in neutrophil, eosinophil, or basophil counts. In a multivariate regression analysis with changes in serum lipids, traditional risk factors, and medications as covariates, the decrease in monocyte count was identified as an independent predictor of coronary plaque regression (beta coefficient 0.313, 95% confidence interval 0.089 to 0.353, p = 0.0014). No correlation was found between change in monocyte count and changes in any other lipid levels. This study demonstrated that monocyte count was the only leukocyte type significantly and independently associated with coronary atherosclerotic regression, even after adjustment for changes in any lipid levels. In conclusion, the decrease in monocyte count as a nonlipid-lowering effect of statins may be used as a novel marker of coronary atherosclerotic regression.

Association of circulating leukocyte count with coronary atherosclerosis regression after pravastatin treatment.

Epidemiological studies have demonstrated that the peripheral blood leukocyte count could be used as a marker of the progression of atherosclerosis. Few data exist regarding the relationship between inhibition of the progression of coronary atherosclerosis and the anti-inflammatory effects of statins, especially the drugs' effects on the leukocyte count in patients with coronary artery disease. A 6-month prospective study was, therefore, conducted in 50 patients treated with pravastatin. The plaque volume, as assessed by volumetric analysis using intravascular ultrasound, reduced significantly by 14% (p<0.0001, vs. baseline) following the treatment, furthermore, a corresponding decrease of the leukocyte count (8.9%, p<0.01, vs. baseline) was also seen. No correlation was found between the change in the leukocyte count and any of the changes in the lipid levels; changes in either of these are known to be associated with the rate of progression of atherosclerosis. A multivariate regression analysis using other traditional risk factors and medications as covariates revealed that the decrease in the leukocyte count was an independent predictor of inhibition of the progression of coronary atherosclerosis. In conclusion, a reduction of the leukocyte count as one of the non-lipid-lowering effects of pravastatin may be a novel marker of regression of coronary atherosclerosis.

A case of vasospastic angina showing resolution of coronary vasospasm in acetylcholine provocation test corresponding to regression of coronary atherosclerosis.

We experienced a case of vasospastic angina showing resolution of vasospasm in the acetylcholine provocation test corresponding to regression of coronary atherosclerotic plaque following treatment with a combination of benidipine and pravastatin.

Coronary artery abnormalities after Kawasaki disease in an adult: depiction at whole heart coronary magnetic resonance angiography.

Whole heart coronary magnetic resonance angiography (MRA) was performed in a 57-year-old man with a provisional diagnosis coronary artery aneurysm due to Kawasaki disease. MRA revealed aneurysms in the left anterior descending artery and the left circumflex artery. It also revealed stenosis in the left anterior descending artery and occlusion in the right coronary artery with a collateral vessel connecting between the proximal and distal sites of the occlusion.

Increasingly well-preserved left ventricular function in hospital survivors with acute myocardial infarction: effect of early and complete reperfusion strategy on left ventricular remodeling.

BACKGROUND: Progress in reperfusion therapy for acute myocardial infarction (AMI) has greatly reduced acute phase mortality, but few data exist regarding the time trends in left ventricular (LV) remodeling in hospital survivors of AMI. METHODS AND RESULTS: The study enrolled 813 patients with AMI who had received reperfusion therapy and survived to hospital discharge. The patients were divided into chronological groups: first treatment received between 1989 and 1992, n=196; 1993 and 1995, n=193; 1996 and 1998, n=211; and 1999 and 2002, n=213. A comparison was made of LV ejection fraction (LVEF) and LV end-diastolic volume index (LVEDVI) at 6 months after symptom onset. Along with the temporal improvements reperfusion therapy, LVEF and LVEDVI improved over time (55+/-14, 58+/-13, 59+/-13, 61+/-13%, p<0.001; 98+/-30, 94+/-27, 90+/-31, 76+/-27 ml/m2, p<0.0001). Multiregression analysis revealed that shortening of the door-to-Thrombolysis In Myocardial Infarction (TIMI)-3 time (time interval from arrival at the emergency room until patients achieved TIMI-3 flow) and achieving substantial TIMI-3 flow were independent predictors for LV remodeling. CONCLUSION: Although this was a retrospective analysis, the results demonstrated that the change in reperfusion therapy aiming at complete reperfusion at an earlier stage after AMI onset has contributed to improving post-MI remodeling.

Pure ventricular septal myocardial infarction in a young man with coronary artery ectasia.

The case of a 30-year-old man with myocardial infarction localized in the interventricular septum is described. Coronary angiography performed on day 28 after the onset of symptoms revealed ectasia in the right and left coronary arteries, but no overt stenotic or occlusive lesions were present. Spasm was induced in the first septal branch of the left anterior descending artery by an acetylcholine provocation test, and single photon emission computed tomography myocardial perfusion imaging showed a reduced thallium-201 uptake localized in the interventricular septum.

Regulation of arginine vasopressin in the human heart.

BACKGROUND: The role of arginine vasopressin (AVP) in the heart has yet to be determined. The present study was designed to examine whether AVP is regulated in the human heart. METHODS AND RESULTS: The subjects were 93 patients who underwent coronary angiography and left ventriculography. Blood samples were collected at the aortic root (AO) and the coronary sinus (CS) to measure the plasma levels of AVP. The patients who showed increases in AVP levels at the CS and AO were assigned to the increased AVP group and those who showed no change or a decrease were assigned to the non-increased AVP group. Cardiac function was compared between these 2 groups. There was a significant difference (p<0.0234) in left ventricular end-diastolic volume index between the increased AVP group (125.5 +/-53.4 ml/m2) and the non-increased AVP group (102.2+/-30.6 ml/m2). There was also a significant difference (p<0.0137) in left ventricular stroke volume index between the increased AVP group (66.6+/-23.2 ml/m2) and the non-increased AVP group (54.4+/-18.6 ml/m2). CONCLUSION: These results suggest that both the production of AVP and synthesis with its receptors may be enhanced at regional sites of the human heart in the volume load.