Clinical outcomes of sirolimus-eluting stenting after rotational atherectomy.

BACKGROUND: The efficacy of drug-eluting stents after rotational atherectomy (ROTA) has not been clarified. METHODS AND RESULTS: The 704 consecutive patients who underwent percutaneous coronary intervention (PCI) with a sirolimus-eluting stent (SES) (79 with and 625 without ROTA) were enrolled. The 2-year clinical outcome of these patients was compared with that of a group of 1,123 consecutive patients treated with bare-metal stents (BMS) (144 with and 979 without ROTA). At 2 years after index PCI, the use of SES after ROTA was associated with a lower crude incidence of major adverse cardiac events (MACE) than were BMS after ROTA (30.1% vs 43.1%, P=0.024). The difference was mainly derived from the reduction in target lesion revascularization (TLR) (25.0% vs 39.1%, P=0.022). After adjusting for confounders, ROTA-SES was associated with a reduction in MACE and TLR, with a similar hazard ratio to the non-ROTA group only with SES implantation. In a subgroup of dialysis patients, the incidence of TLR after ROTA with SES and BMS was similarly high. CONCLUSIONS: The use of SES after ROTA is an appropriate method for selected hard lesions, but has a limited effect in dialysis patients, even after lesion preparation with ROTA.

Plasma levels of oxidized low density lipoprotein are associated with stable angina pectoris and modalities of acute coronary syndrome.

The role of plasma levels of oxidized low density lipoprotein (OxLDL) in the development of coronary heart disease (CHD) has not been fully elucidated. We examined the relationship among plasma levels of OxLDL, measured by an enzyme immunoassay using an antibody against OxLDL (FOH1a/DLH3) and apolipoprotein B, CHD, and modalities at the onset of acute coronary syndrome (ACS). A total of 115 individuals who underwent coronary angiography were studied. Of these, 21 patients complicated with extracoronary cardiovascular diseases were excluded. Consequently, 94 patients (63 men) (ACS: 23, stable angina pectoris (SAP): 46, and normal coronary artery (NCA):25) were eligible for inclusion in the study. Elevated plasma levels of OxLDL were associated with CHD, especially with ACS. In patients with NCA, hypertension was associated with plasma OxLDL. Plasma levels of OxLDL were significantly higher in patients with new-onset type ACS than in those with worsening type ACS (2.98 versus 1.53 mg/dL, P = 0.002). In conclusion, plasma levels of OxLDL are associated with CHD and significantly higher in patients with new-onset ACS. The findings of the present study suggest that plasma OxLDL can be a marker of the development of CHD and modalities of ACS.

One-year clinical outcomes of dialysis patients after implantation with sirolimus-eluting coronary stents.

BACKGROUND: The efficacy of sirolimus-eluting stents (SESs) has not been established in dialysis patients. METHODS AND RESULTS: This study was a non-randomized observational single-center registry in a community hospital: data for 80 consecutive dialysis patients who underwent percutaneous coronary intervention (PCI) with SES were compared with those of a historical group of consecutive 124 dialysis patients treated with bare-metal stents (BMS). After 1 year, the cumulative incidence of major adverse cardiac events (MACE), comprising cardiac death, nonfatal myocardial infarction, stent thrombosis, or target lesion revascularization (TLR), was 25.2% in the SES group and 38.2% in the BMS group (p=0.048). In multivariate analysis, use of SES remained an independent predictor of MACE at 1 year after PCI (risk ratio 0.70, 95% confidence interval 0.52-0.93, p=0.015). Rates of TLR were 21.7% in the SES group and 30.9% in the BMS group and (p=0.15). Subgroup analysis showed that use of SES was effective in patients with small vessels, non-diabetic patients, and patients without highly calcified lesions. CONCLUSIONS: In dialysis patients, the implantation of SES was moderately effective in reducing MACE at 1 year after PCI as compared with BMS. However, the TLR rate at 1 year was relatively higher than previously reported.

Induction of heme oxygenase-1 inhibits monocyte chemoattractant protein-1 mRNA expression in U937 cells.

Heme oxygenase-1 (HO-1) is a stress-inducible isoform of HO with potential cytoprotective effects. Monocyte activation/migration mediated by monocyte chemoattractant protein-1 (MCP-1) is one of the earliest and important events in the pathogenesis of atherosclerosis. We examined the effect of HO-1 on the production of lysophosphatidylcholine (Lyso-PC)-induced MCP-1 in the human promonocytic cell line U937. Increased HO-1 induction by hemin resulted in a significant decrease in the Lyso-PC-mediated induction of MCP-1 mRNA expression. SnPP (IX), the specific inhibitor of HO-1 enzymatic activity, prevented the hemin-mediated attenuation of MCP-1 mRNA expression. These results suggest that HO-1 may work as an anti-atherogenic agent through the attenuation of MCP-1 production.

Pulse wave velocity predicts cardiovascular mortality: findings from the Hawaii-Los Angeles-Hiroshima study.

BACKGROUND: Arterial stiffness measurements, generally from pulse wave velocity (PWV), are widely used with little knowledge of their relationship to long-term cardiovascular mortality in general populations. METHODS AND RESULTS: We studied a cohort of 492 Japanese-Americans living in Hawaii (mean age: 63.7 +/-8.8 years) to assess the relationship between PWV and cardiovascular disease mortality and all-cause mortality. During the 10-year follow-up, 43 patients died (14 from cardiovascular events). The cohort was divided into 2 groups by the cut-off value of PWV (9.9 m/s) represented in the receiver operating characteristic curve. The risk ratio for PWV values >9.9 m/s to all-cause mortality was 1.28 [95% confidence interval (CI): 1.14-1.42], and adjusted for other risk factors this ratio was 1.42 (95% CI: 0.96-2.11). The corresponding risk ratios for cardiovascular mortality was 4.46 (95% CI: 1.61-12.32) and 4.24 (95% CI: 1.39-12.96), respectively. CONCLUSIONS: The present study demonstrated that an increased PWV value is associated with future cardiovascular disease death in Japanese-Americans living in Hawaii.

Influence of Chlamydia pneumoniae infection on aortic stiffness in healthy young men.

Though Chlamydia pneumoniae infection has been implicated in the pathogenesis of atherosclerosis, its role in early atherogenesis has not been well elucidated. To clarify whether C. pneumoniae infection was related to early atherogenesis, we evaluated the association between serological detection of C. pneumoniae antibodies and aortic stiffness in 102 healthy young male volunteers (mean age 27.1+/-0.4 years). Serum C. pneumoniae IgA and IgG antibodies were measured by the enzyme-linked immunosorbent assay (ELISA). Aortic stiffness was estimated using the brachial-ankle pulse wave velocity (PWV). No significant differences were observed between IgA seropositive and seronegative groups with regard to conventional cardiovascular risk factors. However, the mean PWV value was significantly higher in the IgA seropositive group than the seronegative group. Analyses of subgroups according to C-reactive protein (CRP) level showed that those subjects with IgA seropositivity and a high CRP level (>0.17 mg/l) had the highest PWV values. Multivariate logistic regression analysis revealed that a combination of C. pneumoniae IgA seropositivity and a high CRP level was an independent predictor of high values of PWV. These results suggest that C. pneumoniae infection might contribute to early atherogenesis, which might be associated with chronic inflammation.

Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats.

Ghrelin is a novel growth hormone (GH)-releasing peptide which was isolated from the stomach. We have reported that ghrelin causes vasorelaxation in rats through GH-independent mechanisms. We investigated whether ghrelin improves endothelial dysfunction. Ghrelin was subcutaneously administered to GH-deficient rats for three weeks. After isolation of the thoracic aorta, aortic ring tension was measured to evaluate vasorelaxation. Acetylcholine-induced vasorelaxation was impaired in GH-deficient rats given placebo compared to that in normal rats given placebo. GH-deficient rats treated with ghrelin, however, showed a significant increase in the maximal relaxation as compared with those given placebo. This improvement by ghrelin was inhibited by N(G)-nitro-L-arginine methyl ester, a nonselective nitric oxide synthase (NOS) inhibitor. Western blot analysis demonstrated that treatment with ghrelin increased endothelial NOS (eNOS) expression in the aorta of GH-deficient rats. These results suggest that administration of ghrelin improves endothelial dysfunction and increases eNOS expression in rats through GH-independent mechanisms.

Myocardial velocity gradient reflects the severity of myocardial damage regardless of the presence or absence of mitral regurgitation.

Complicating mitral regurgitation (MR) apparently enhances left ventricular ejection fraction, thereby leading to the underestimation of myocardial damage by routine echocardiography. We sought to assess the significance of myocardial velocity gradient (MVG) derived from Doppler tissue imaging as an indicator of the severity of myocardial damage in the presence or absence of MR. Peak systolic and diastolic MVG was obtained from 39 participants: 12 healthy participants, 10 patients with dilated cardiomyopathy complicating moderate to severe MR [MR (+) group], and 17 patients with dilated cardiomyopathy without significant MR [MR (-) group]. MVG was compared with standard echocardiographic and Doppler transmitral flow velocity indices. Plasma brain natriuretic peptide levels were measured in all patients. Left ventricular dimension and fractional shortening was similar between MR (+) and MR (-) groups. Plasma brain natriuretic peptide levels were significantly increased in MR (+) group (440 +/- 417 pg/mL) as compared with MR (-) group (122 +/- 107 pg/mL, P <.05). Peak systolic MVG was significantly attenuated in dilated cardiomyopathy group with or without MR [MR (+) group = 1.3 +/- 0.5 seconds(-1), MR (-) group = 2.1 +/- 0.5 seconds(-1), where normal = 4.0 +/- 0.9 seconds(-1), P <.01, respectively]. Peak systolic MVG was further attenuated in MR (+) group than in MR (-) group (P <.01). Plasma brain natriuretic peptide levels were negatively correlated with peak systolic MVG (r = -0.66, P <.0005). Peak diastolic MVG was attenuated in MR (+) and also in MR (-) groups [MR (+) group = -4.5 +/- 2.0 seconds(-1), MR (-) group = -4.4 +/- 1.1 seconds(-1), where normal = -8.7 +/- 2.4 seconds(-1), P <.01, respectively], whereas transmitral flow indices failed to distinguish MR (+) group from normal as a result of pseudonormalization. MVG may reflect the severity of myocardial damage regardless of the presence or absence of complicating MR.

Increased plasma ghrelin level in lung cancer cachexia.

PURPOSE: Ghrelin, a novel growth hormone-releasing peptide,has been shown to cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in cachexia associated with lung cancer. EXPERIMENTAL DESIGN: Plasma ghrelin level was measured in 43 patients with lung cancer and 21 control subjects. Patients with lung cancer were divided into two groups: patients with cachexia (n = 21) and those without cachexia (n = 22). RESULTS: Plasma ghrelin level did not significantly differ between all patients with lung cancer and controls (157 +/- 10 versus 132 +/- 8 fmol/ml, P = 0.1). However, plasma ghrelin level was significantly higher in patients with cachexia than in those without cachexia (180 +/- 17 versus 135 +/- 10 fmol/ml, P = 0.011). Furthermore, plasma ghrelin level increased significantly in patients with decreased food intake after chemotherapy (from 136 +/- 11 fmol/ml to 170 +/- 16 fmol/ml on day 8, 179 +/- 20 fmol/ml on day 21 after start of chemotherapy), although plasma ghrelin level did not significantly change in those without decreased food intake. CONCLUSIONS: Baseline plasma ghrelin level was elevated in cachectic patients with lung cancer, and follow-up plasma ghrelin level increased in patients with anorexia after chemotherapy. Considering the positive energy effects induced by ghrelin, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with lung cancer.

Hypertension and insulin disorders.

Insulin resistance and/or compensatory hyperinsulinemia are associated with hypertension, obesity, dyslipidemia, and glucose intolerance. Insulin resistance and hyperinsulinemia are considered to increase blood pressure through sympathetic nervous system activation, renin-angiotensin system stimulation, and vascular smooth muscle cell proliferation. Leptin, magnesium ions, nitric oxide, endothelin, peroxisome proliferator-activated receptor gamma, and tumor necrosis factor-alpha also modulate blood pressure. Decreasing insulin resistance by lifestyle modification including diet, weight loss, and physical exercise has been shown to reduce blood pressure. Angiotensin-converting enzyme inhibitors have a beneficial effect on insulin resistance. On the other hand, the angiotensin II antagonist, losartan, does not affect insulin sensitivity. The selective alpha1-blockers have a favorable metabolic profile producing increases in insulin sensitivity. A short-acting type calcium channel blocker seems to decrease insulin sensitivity. On the other hand, long-acting type calcium channel blockers improve insulin sensitivity. Thiazide diuretics and most of the beta-blockers decrease insulin sensitivity. Vasodilatory beta-blockers have been reported to improve insulin sensitivity. Use of low-dose diuretics avoids the adverse effects seen with conventional doses.

Predictive value of preprocedural fibrinogen concerning coronary stenting.

Elevated fibrinogen levels after coronary balloon angioplasty have been reported to be useful in predicting restenosis. Therefore, we sought to evaluate the relationship between preprocedural fibrinogen levels and the 6-12-month outcomes of patients undergoing coronary stenting. Plasma levels of fibrinogen were measured in 390 consecutive patients prior to coronary stenting. The primary end point was binary restenosis (percent diameter stenosis of >/=50%). The secondary combined end point was death due to cardiac causes, myocardial infarction related to the target vessel and target lesion revascularization. Patients were grouped into tertiles according to fibrinogen levels. Both at baseline and immediately after procedure, clinical and angiographic characteristics were almost identical in the fibrinogen tertiles. An increase in restenosis rate was observed across the tertiles (18.6, 23.9, 38.1%, P<0.001, respectively). In addition, the frequency of the secondary end point increased in the highest tertile (14.9, 21.5, 37.2%, P<0.001, respectively). Multivariate analysis revealed that high levels of fibrinogen (per 100 mg/dl, OR 1.82, P<0.001) and stent length (P=0.034) were independent predictors for restenosis. An elevated preprocedural fibrinogen level should be considered as a stronger predictor for restenosis after coronary stenting, which might be associated with coagulation and inflammation.

Atherosclerotic plaque characterization by quantitative analysis using intravascular ultrasound: correlation with histological and immunohistochemical findings.

The aim of this study was to clarify whether atherosclerotic plaque morphology, as defined by quantitative analysis with intravascular ultrasound (IVUS) images, was related to the immunohistochemical findings. Twenty-five coronary lesions in 25 patients who had ultrasound guidance during directional coronary atherectomy (DCA) were enrolled. The lesions retrieved by DCA were analyzed and divided into 3 groups (lesions infiltrated with both macrophages and lymphocytes: group IML; lesions infiltrated with macrophages but not lymphocytes: group IM; and non-infiltrated lesions: group NI). The mean plaque echo level divided by the mean adventitia echo level (MPEL/MAEL) and the heterogeneity of the distribution of plaque echo levels (HDPEL) were calculated. The proportion of patients with acute coronary syndromes was significantly different among the groups: IML (n=14), IM (n=5), and NI (71%, 0% and 17%, respectively; p<0.01). The pre-DCA HDPEL value was highest in group IML and lowest in group NI; however, no significant differences in MPEL/MAEL values were found. The results suggest that plaque morphology, as defined by IVUS images, was related to the immunohistochemical findings. The increase in HDPEL correlated with the presence of immune inflammation.

Influence of type 2 diabetes mellitus on cardiovascular disease mortality: findings from the Hawaii-Los Angeles-Hiroshima study.

The present study addressed whether diabetes mellitus was a strong risk factor for cardiovascular disease (CVD) death. Between 1976 and 1984, 927 (404 men) Japanese-Americans in Hawaii aged 40-79 years participated at baseline examination including a 75 g oral glucose tolerance test. Diabetes was defined as fasting serum glucose >or=140 mg/dl, 2 h postload glucose >or=180 mg/dl, or the use of drugs for diabetes. Causes of death were classified by ICD-9 codes on the reports from the Hawaii State Public Health Bureau. Until 1994, 178 individuals suffered death; 81 were attributed to CVD and 43 to coronary heart disease (CHD). The age-adjusted and coronary risk factors-adjusted relative risks for CHD and CVD mortality were significant for diabetes both in men and women. The impact of diabetes on CHD mortality was greater for women. However, no gender difference in the contribution of diabetes to fatal CVD was observed. Serum fasting glucose levels tended to be associated with CHD death and were associated with CVD death in diabetic subjects. In conclusion, diabetes is a strong independent risk factor for CVD mortality in Japanese-American men and women. Hyperglycemia is associated with CVD mortality in diabetic subjects.

Influence of angiotensinogen M253T gene polymorphism and an angiotensin converting enzyme inhibitor on restenosis after percutaneous coronary intervention.

We studied the relation between renin-angiotensin system (RAS) related gene polymorphisms, such as angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M253T and angiotensin II type 1 receptor (AT1R) A1166C, and the effect of quinapril, an ACE inhibitor with high tissue-binding affinity, on preventing restenosis after percutaneous coronary intervention (PCI). A total of 253 patients successfully treated for coronary artery disease were randomly assigned to quinapril or control. Of the 215 patients who completed the follow-up, we determined gene polymorphisms in 204 patients with 241 lesions who provided blood samples for genotype determination. In the control, the ACE D homozygotes showed a smaller minimal lumen diameter (MLD) at follow-up (P=0.063). The other two genotypes of AGT and AT1R did not affect restenosis after PCI. According to quinapril treatment, the AGT T homozygotes significantly showed a beneficial effect of quinapril on MLD (P=0.013) and late lumen loss (P=0.013). The ACE I homozygotes also exhibited beneficial effects of quinapril on larger MLD (P=0.065). The AT1R genotype did not influence the quinapril effect. In conclusion, the AGT T homozygotes might benefit from effects of quinapril on preventing restenosis after PCI.