Mary C. DeVoe

Reactive Oxygen Species Are Involved in Smoking-Induced Dysfunction of Nitric Oxide Biosynthesis and Upregulation of Endothelial Nitric Oxide Synthase An In Vitro Demonstration in Human Coronary Artery Endothelial Cells

Background—Our group has previously shown that human umbilical vein endothelial cells exposed to smokers’ serum decreased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in the presence of increased eNOS expression. In the present study, we examined whether these observations extended to human coronary artery endothelial cells (HCAECs). In addition, the role of reactive oxygen species in the observed alterations was examined. Methods and Results—HCAECs were incubated with serum from 10 nonsmokers and 15 smokers for 12 hours with or without the addition of either polyethylene glycol-superoxide dismutase (PEG-SOD, 300 U/mL), PEG-SOD+PEG-catalase (1000 U/mL), chelerythrine (3 &mgr;mol/L), or tetrahydrobiopterin (20 &mgr;mol/L). At the end of incubation, NO, eNOS protein, and eNOS activity were measured from the same culture. HCAECs incubated with smokers’ serum alone showed significantly lower NO production (P <0.05) and eNOS activity (P <0.005) but higher eNOS expression (P <0.005) compared with nonsmokers. In smokers, addition of PEG-SOD, PEG-SOD+PEG-catalase, or tetrahydrobiopterin significantly (P <0.05) improved NO levels and eNOS activity. Interestingly, in the same smokers, a significant decrease in eNOS expression was only seen with the addition of PEG-SOD+PEG-catalase (P <0.05) and treatment with PEG-SOD alone insignificantly increased eNOS expression. Conclusions—The present study indicates that in vitro, HCAECs show similar changes in NO biosynthesis as human umbilical vein endothelial cells when exposed to smokers’ serum and also confirms that oxidative stress plays a central role in smoking-mediated dysfunction of NO biosynthesis in endothelial cells. Furthermore, these data support other studies suggesting a role for hydrogen peroxide in the upregulation of eNOS.

The impact of plasma levels of C-reactive protein, lipoprotein (a) and homocysteine on the long-term prognosis after successful coronary stenting: The global evaluation of new events and restenosis after stent implantation study

OBJECTIVES The objective of this study was to evaluate the association of high plasma levels of either C-reactive protein (CRP), lipoprotein (a) (Lp[a]) or total homocysteine (tHCY) with the long-term prognosis after successful coronary stenting (CS). BACKGROUND High plasma levels of either CRP, Lp(a) or tHCY may have an impact in coronary artery disease. However, long-term prospective data after coronary stenting (CS) are limited. METHODS Four-hundred and eighty-three consecutive patients with either stable or unstable coronary syndromes were followed for up to three years after successful CS. The composite of cardiac death, myocardial infarction or rehospitalization for rest unstable angina, whichever occurred first, was the prespecified primary end point. Moreover, the one-year incidence of clinical recurrence of symptoms, in-stent restenosis (ISR) and progression of atherosclerosis to a significant lesion (PTSL) were additionally evaluated. PTSL was defined as an increase by at least 25% in the luminal diameter stenosis of a known nonsignificant lesion (<or=50% luminal diameter stenosis) that was located in a nonintervened vessel at restudy, resulting in an angiographically significant lesion (>or=70% luminal diameter stenosis). RESULTS By the end of the follow-up, high plasma levels of either CRP or Lp(a) but not tHCY were independently associated with the primary end point. In particular, CRP >or=0.68 mg/dl (p < 0.001) or Lp(a) >or=25 mg/dl (p = 0.003) conferred a significantly increased risk. By 1 year, a CRP >or=0.68 mg/dl conferred a significantly increased risk for clinical recurrence of symptoms (p < 0.001) or PTSL (p < 0.001). None of the studied biochemical markers was related to ISR. CONCLUSIONS High plasma levels of either CRP or Lp(a) but not tHCY may be associated with a higher incidence of late adverse events after successful CS. PTSL in vessels not previously intervened upon may play a significant role in the underlying pathophysiology as opposed to ISR.

Frequency of and outcome of acute coronary syndromes in patients with human immunodeficiency virus infection

Fifty-one patients with human immunodeficiency virus infection and acute coronary syndromes were identified. Nearly all patients (98%) had traditional coronary risk factors. Revascularization procedures were performed safely with low in-hospital mortality.

Omega-3 fatty acids plus rosuvastatin improves endothelial function in South Asians with dyslipidemia

Background: The present study was undertaken to investigate the effect of statins plus omega-3 polyunsaturated fatty acids (PUFAs) on endothelial function and lipid profile in South Asians with dyslipidemia and endothelial dysfunction, a population at high risk for premature coronary artery disease. Methods: Thirty subjects were randomized to rosuvastatin 10 mg and omega-3-PUFAs 4 g or rosuvastatin 10 mg. After 4 weeks, omega-3-PUFAs were removed from the first group and added to subjects in the second group. All subjects underwent baseline, 4-, and 8-week assessment of endothelial function and lipid profile. Results: Compared to baseline, omega-3-PUFAs plus rosuvastatin improved endothelial-dependent vasodilation (EDV: −1.42% to 11.36%, p = 0.001), and endothelial-independent vasodilation (EIV: 3.4% to 17.37%, p = 0.002). These effects were lost when omega-3-PUFAs were removed (EDV: 11.36% to 0.59%, p = 0.003). In the second group, rosuvastatin alone failed to improve both EDV and EIV compared to baseline. However, adding omega-3-PUFAs to rosuvastatin, significantly improved EDV (−0.66% to 14.73%, p = 0.001) and EIV (11.02% to 24.5%, p = 0.001). Addition of omega-3-PUFAs further improved the lipid profile (triglycerides 139 to 91 mg/dl, p = 0.006, low-density lipoprotein cholesterol 116 to 88 mg/dl, p = 0.014). Conclusions: Combined therapy with omega-3-PUFAs and rosuvastatin improves endothelial function in South Asian subjects with dyslipidemia and endothelial dysfunction.

Endogenous free radical generating sources are involved in smoking-mediated dysfunction of nitric oxide biosynthesis in human coronary artery endothelial cells: An in vitro demonstration

Background: Vulnerable plaques contain abundant macrophages. We developed a novel photodynamic agent, chlorin, conjugated with maleylated albumin, (ce6-mal-alb) that concentrates in macrophage-rich plaques and has a high fluorescent yield. As such, we tested hypothesis that experimental atherosclerotic lesions (ATHERO) can be detected using ce6-mal-alb and an intravascular fluorescence spectroscopy catheter. Methods: ATHERO were induced in New Zealand rabbits by infradiaphragmatic aortic balloon-injury followed by high cholesterol diet. At IO weeks, ce6-mal-alb was administered to 7 atherosclerotic and 7 control animals. 24 hours later, aortic uptake of the ce6mal-alb uptake was measured in situ, using an intravascular fluorescence spectroscopy catheter. Thereafter, the aortas were excised and dissolved in NaOH/SDS for spectrofluorimetric determination of ce6 content. Results: Intravascular measurements of ce6-mal-alb fluorescence were higher in ATHERO vs. non-athero segments, (8.8i4.8 vs. 2.2k2.2 X103AU, P<O.OOl, figure). Further, ce6-mal-alb concentration was higher within the ATHERO aortas (5.2t3.2 vs. 1.9+1.2, ce6 fluorescencelgm tissue x IOs, p=<O.Ol). Conclusion: CeG-mal-alb can be employed for intravascular characterization of atherosclerotic plaques. Because this novel PDT compound is selectively toxic to macrophages when light-activated, this agent may be useful for both the detection and therapeutic modification of macrophage-rich plaques.

C-reactive protein and ST-segment monitoring by continuous 12-lead electrocardiogram in patients with primary unstable angina pectoris

In conclusion, high plasma CRP levels are associated with more myocardial ischemia early in primary UAP. Although the underlying mechanisms are not well understood, these data could have important pathophysiologic and clinical implications. Whether the increased CRP represents a marker either for the extent of atherosclerosis or an inflammatory process in the coronary arteries or directly exerts a pro-inflammatory or prothrombotic effect on the vessel wall leading to the increased ischemia is currently unknown.

Acute coronary lesions and troponin elevation in unstable angina pectoris or non-ST elevation acute myocardial infarction

Angiographic studies support an association between troponin elevation, intracoronary thrombus, and presumed embolization, but previous studies have indicated that only 20% to 25% of patients with positive troponin levels had angiographic evidence of intracoronary thrombus compared with 5% of patients who were troponin negative. 1–3 Although there already exists an association, 75% to 80% of patients with increased troponin levels had no evidence of intracoronary thrombus. It has been previously shown that the angiographic morphology of the culprit lesion in unstable angina pectoris (UAP) or non–Q-wave acute myocardial infarction (AMI) is characteristic, with 50% to 70% of patients having an acute coronary or complex lesion, which is the angiographic correlate of a disrupted or fi ssured atherosclerotic plaque and/or the presence or intracoronary thrombus. 4,5 This lesion is uncommon in culprit lesions from patients presenting with symptoms of stable angina. Therefore, it was hypothesized that this lesion classifi cation system might represent a more sensitive method for examining the association between elevated troponin and the presence of intracoronary thrombus.

Elevated C-reactive protein levels are associated with myocardial ischemia early in the course of non-ST elevation coronary syndromes

Background High plasma levels of C-reactive protein (CRP) are associated with shortor long-term ischemic complications in patients with unstable coronary artery disease. However, a possible direct relationship of plasma CRP with spontaneous myocardial &hernia early I” the course of non ST elevation acute coronary syndromes (NSTACS) was not thoroughly investigated. MethodsTo evaluate this issue 172 consecutive patients with NSTACS with no elevated plasma cardiac troponin T levels upon admission (cTnT-zO.1 yojdl) who underwent a 24 hour continuous IBlead electrocardiographic (ECG) monitoring were studied. The associatlon of plasma CRP levels upon admission with either the incidence or duration of the recorded myocardial ischemla (ST-segment shifts) was evaluated. Patients divided into three groups according to the tertiles of CRP values upon admission. Results During 3,696 hours of contmuous 12.lead ECG monitoring, 169 ST-segment shifts were recorded in 48 patients with a mean number of 3.5k2.0 shifts per patient and a mean duration of 29.6i23.6 min per episode, corresponding to a total duration of 124.4k143.6 mm per patlent. There was a significant gradual increased risk for either the incidence (p<O.OOl) or the total duration of ST-segment shifts with increasing of CRP tertiles (p=O.Ol). MultivarIate analysis showed that CRP tertiles were independently and positively related to the occurrence of ST-segment shifts. Conclusions High plasma levels of CRP may be associated with a higher incidence of myocardial tschemia early III the tours.? of NSTACS, suggesting a direct relationship of inflammation in this process.

Peripheral conduction disease in left ventricular dysfunction.

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