Risk Of Adverse Coronary Events Research Articles

Spontaneously diabetic Ins2(+/Akita):apoE-deficient mice exhibit exaggerated hypercholesterolemia and atherosclerosis.

Type 1 diabetes (T1D) increases the risk of adverse coronary events. Among risk factors, dyslipidemia due to altered hepatic lipoprotein metabolism plays a central role in diabetic atherosclerosis. Nevertheless, the likely alterations in plasma lipid/lipoprotein profile remain unclear, especially in the context of spontaneously developed T1D and atherosclerosis. To address this question, we generated Ins2(+/Akita):apoE(-/-) mouse by cross-breeding Ins2(+/Akita) mouse (which has Ins2 gene mutation, causing pancreatic β-cell apoptosis and insulin deficiency) with apoE(-/-) mouse. Ins2(+/Akita):apoE(-/-) mice developed T1D spontaneously at 4-5 wk of age. At 25 wk of age and while on a standard chow diet, diabetic Ins2(+/Akita):apoE(-/-) mice exhibited an approximately threefold increase in atherosclerotic plaque in association with an approximatelty twofold increase in plasma non-HDL cholesterol, predominantly in the LDL fraction, compared with nondiabetic controls. To determine factors contributing to the exaggerated hypercholesterolemia, we assessed hepatic VLDL secretion and triglyceride content, expression of hepatic lipoprotein receptors, and plasma apolipoprotein composition. Diabetic Ins2(+/Akita):apoE(-/-) mice exhibited diminished VLDL secretion by ~50%, which was accompanied by blunted Akt phosphorylation in response to insulin infusion and decreased triglyceride content in the liver. Although the expression of hepatic LDL receptor was not affected, there was a significant reduction in the expression of lipolysis-stimulated lipoprotein receptor (LSR) by ~28%. Moreover, there was a marked decrease in plasma apoB-100 with a significant increase in apoB-48 and apoC-III levels. In conclusion, exaggerated hypercholesterolemia and atherosclerosis in spontaneously diabetic Ins2(+/Akita):apoE(-/-) mice may be attributable to impaired lipoprotein clearance in the setting of diminished expression of LSR and altered apolipoprotein composition of lipoproteins.

In vivo mapping of vascular inflammation using multimodal imaging.

BackgroundPlaque vulnerability to rupture has emerged as a critical correlate to risk of adverse coronary events but there is as yet no clinical method to assess plaque stability in vivo. In the search to identify biomarkers of vulnerable plaques an association has been found between macrophages and plaque stability—the density and pattern of macrophage localization in lesions is indicative of probability to rupture. In very unstable plaques, macrophages are found in high densities and concentrated in the plaque shoulders. Therefore, the ability to map macrophages in plaques could allow noninvasive assessment of plaque stability. We use a multimodality imaging approach to noninvasively map the distribution of macrophages in vivo. The use of multiple modalities allows us to combine the complementary strengths of each modality to better visualize features of interest. Our combined use of Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) allows high sensitivity PET screening to identify putative lesions in a whole body view, and high resolution MRI for detailed mapping of biomarker expression in the lesions.Methodology/Principal FindingsMacromolecular and nanoparticle contrast agents targeted to macrophages were developed and tested in three different mouse and rat models of atherosclerosis in which inflamed vascular plaques form spontaneously and/or are induced by injury. For multimodal detection, the probes were designed to contain gadolinium (T1 MRI) or iron oxide (T2 MRI), and Cu-64 (PET). PET imaging was utilized to identify regions of macrophage accumulation; these regions were further probed by MRI to visualize macrophage distribution at high resolution. In both PET and MR images the probes enhanced contrast at sites of vascular inflammation, but not in normal vessel walls. MRI was able to identify discrete sites of inflammation that were blurred together at the low resolution of PET. Macrophage content in the lesions was confirmed by histology.Conclusions/SignificanceThe multimodal imaging approach allowed high-sensitivity and high-resolution mapping of biomarker distribution and may lead to a clinical method to predict plaque probability to rupture.

The interaction between clopidogrel and proton pump inhibitors (PPI): is there any clinical relevance?

The potential interaction between clopidogrel and proton pump inhibitors (PPI) in patients with acute coronary syndrome (ACS) raises serious concerns for cardiologists. However, in patients on this combination of drugs, there is no conclusive evidence of an increase in adverse cardiovascular events. From pharmacologic and pharmacodynamic perspectives, there is a real interaction between clopidogrel and PPIs because of the competitive inhibition of CYP2C19 isoenzyme which is required for biotransformation of clopidogrel to its active metabolite. The consequent decrease in the availability of this active metabolite leads to attenuation of antiplatelet efficacy of clopidogrel. In several observational trials, it was shown that decreased antiplatelet effect of clopidogrel due to PPIs may translate into poor cardiovascular outcomes. However, an incomplete RCT (COGENT) and a post hoc analysis of two large trials (PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trial) showed no significant adverse cardiovascular events with this combination. Caution is however needed in patients who are hypometabolizers of clopidogrel putting them at a higher risk of adverse coronary events. Since 3% of patients are likely to be hypometabolizers of clopidogrel, routine combination of clopidogrel and PPIs should be avoided. There is a heightened awareness of this interaction following multiple advisory warnings. At the same time, one should not withhold PPIs in patients who are at a high risk of developing gastrointestinal (GI) bleeding. In these patients, selected choices of PPI such as pantoprazole may be helpful and for low risk patients, serious consideration should be given to H2 receptor antagonists or antacids. Therefore, while not compromising the cardioprotective effect of antiplatelet agents, the gastroprotective benefit of PPI should be strongly considered in patients who need both. Health care providers should remain alert to more outcome data. Future researchers will need to demonstrate the safety of coadministration of PPIs and clopidogrel and trials should be powered to detect major adverse cardiovascular events and facilitate risk stratification based on genetic polymorphism.

Prognostic factors in patients who have survived myocardial infarction

Abstract Patients who have survived myocardial infarction (MI), compared to the general population, have an increased risk of reinfarction, myocardial revascularization, and death. In this study we investigated the prognostic significance of the predictors of the risk for adverse coronary events in 118 patients, both male and female, with a confirmed diagnosis of MI in the last 3 years. The predictors of reinfarction, revascularization and death in patients who survived MI were: poor adherence to hypolipemics (hazard ratio [HR] 3.06, p=0.006), physical inactivity (HR 2.22, p=0.056), the number of variable risk factors (HR 1.29, p=0.025), and age (HR 1.06, p=0.007). After the inclusion of the invariable risk factors in the model of multivariant analysis, the following factors were singled out as significant predictors of the risk: gender (HR 3.86, p=0.0015), physical inactivity (HR 2.38, p=0.007), change in the level of triglycerides (HR 1.49, p=0.040), change in the number of variable risk factors (HR 1.41, p=0.0007), and age (HR 1.05, p=0.009). A 3-year follow-up of the patients who survived the first MI and who were enrolled in this study of secondary prevention demonstrated that physical inactivity, the number of variable risk factors and age significantly contributed to an increased risk of reinfarction, revascularization, and death.

Platelet Function Tests and Outcomes in Patients with Coronary Stents

The efficacy of dual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention is well established. However, patient response varies widely, and insufficient platelet inhibition is associated with increased risk for adverse coronary events. Several platelet function assays are available, but no consensus exists on whether or how to use them to quantify on-treatment platelet reactivity in …

Clinical management of clopidogrel inefficiency by point of care platelet function testing and individual adjustment of anti-platelet therapy – initial experiences

Insufficient inhibition of ADP dependent platelet aggregation by clopidogrel is associated with an increased risk for adverse coronary events, such as stent thrombosis, after percutaneous coronary intervention. Here, we describe an approach to the clinical management of patients with insufficient inhibition of ADP dependent platelet aggregation by clopidogrel involving dose adjustment or switching of the thienoyridine. We put special emphasize on a patient who experienced recurrent acute myocardial infarction due to stent thrombosis associated with severe clopidogrel non response following elective coronary drug eluting stent implantation. In this patient, an inadequate clopidogrel effect at maintenance doses was confirmed by repeated platelet function assessment with a multiple electrode impedance point of care platelet function test. Subsequent dose adjustments still did not result in sufficient inhibition of ADP dependent platelet aggregation. Only after switching to the then shortly available new thienopyridine prasugrel could a sufficient platelet inhibition be obtained. However, our data from further patients show that although this may overcome inadequate clopidogrel efficiency in many cases, even under prasugrel suboptimal platelet inhibition may occur.

Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms

Long-term depression may increase the risk for adverse coronary events. Low levels of high-density lipoprotein cholesterol (HDL-C) have in particular been suggested to underlie this connection. A total of 124 participants with a recorded seven-year history of depressive symptoms (depressed, n = 63) or euthymic state (controls, n = 61) underwent a Structured Clinical Interview for DSM-IV to confirm their psychiatric diagnosis. Total cholesterol (TC), HDL-C and low-density lipoprotein cholesterol (LDL-C) levels, triglycerides, non-HDL-C and atherogenic indices (LDL-C/HDL-C and TC/HDL-C) were assessed. The HDL-C levels were lower and atherogenic indices higher in the depressed group compared with the controls. Furthermore, those with HDL-C level below the gender-adjusted median (< 1.54 mmol/l in women, < 1.16 mmol/l in men) were 2.4-fold more likely to be depressed in a model adjusting for age and non-HDL-C ( p = 0.019). After further adjustment for educational level, marital status, alcohol use, daily smoking and overweight this association remained significant ( p = 0.049). These findings suggest that compared with the healthy controls, those with long-term depression may have lower HDL-C values and higher atherogenic indices.

Platelet Polymorphisms Alter Risk for Adverse Coronary Events in Women Receiving HT

The platelet membrane glycoproteins Ibα (GP1Bα) and VI (GP6) participate in the adherence of platelets to injured vessel walls, which is the initial

Influence of Acute Renal Failure on Coronary Vasoregulation in Dogs

Impaired renal function is associated with an increased risk for cardiovascular events and death, but the pathophysiology is poorly defined. The hypothesis that coronary blood flow regulation and distribution of ventricular blood flow could be compromised during acute renal failure (ARF) was tested. In two separate groups (n = 14 each) of dogs with ARF, (1) coronary autoregulation (pressure-flow relations), vascular reserve (reactive hyperemia), and myocardial blood flow distribution (microspheres) and (2) coronary vessel responses to intracoronary infusion of select endothelium-dependent and -independent vasodilators were evaluated. In addition, coronary pressure-flow relations and vascular reserve after inhibition of nitric oxide and prostaglandin release were evaluated. Under resting conditions, myocardial oxygen consumption increased in dogs with ARF compared with no renal failure (NRF; 11.8 +/- 9.2 versus 5.0 +/- 1.5 ml O(2)/min per 100 g; P = 0.01), and the autoregulatory break point of the coronary pressure-flow relation was shifted to higher diastolic coronary pressures (60 +/- 17 versus 52 +/- 8 mmHg in NRF; P = 0.003); the latter was shifted further rightward after inhibition of both nitric oxide and prostaglandin release. The endocardial/epicardial blood flow ratio was comparable for both groups, suggesting preserved ventricular distribution of blood flow. In dogs with ARF, coronary vascular conductance also was reduced (P = 0.001 versus NRF), but coronary zero-flow pressure was unchanged. Vessel reactivity to each endothelium-dependent/independent compound also was blunted significantly. In conclusion, under resting conditions, coronary vascular tone, reserve, and vessel reactivity are markedly diminished with ARF, suggesting impaired vascular function. Consequently, during ARF, small increases in myocardial oxygen demand would induce subendocardial ischemia as a result of a limited capacity to increase oxygen supply and thereby contribute to higher risk for adverse coronary events and mortality.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Renovascular Disease and the Risk of Adverse Coronary Events in the Elderly

Renovascular disease is a cause of secondary hypertension and renal insufficiency and is suspected to contribute to morbidity and mortality of coronary heart disease. This investigation prospectively examined associations between renovascular disease and adverse coronary events among a population-based sample of elderly Americans. The Cardiovascular Health Study is a prospective, multicenter cohort study of cardiovascular disease risk factors, morbidity, and mortality among Americans older than 65 years. Renal duplex sonography was performed on 870 individuals between January 1995 and February 1997. Renovascular disease was defined as any focal peak systolic velocity of 1.8 m/s or greater (renal artery stenosis) or the absence of a Doppler-shifted signal from an imaged artery (renal artery occlusion). Adverse coronary events were defined as hospitalized angina, fatal or nonfatal myocardial infarction, and coronary revascularization. During a mean follow-up of 14 months, 68 participants experienced incident or recurrent adverse coronary events. The presence of renovascular disease demonstrated a significant relationship with adverse coronary events (hazard ratio, 1.96; 95% confidence interval, 1.00-3.83; P = .05) that remained after controlling for the effects of coexisting atherosclerotic risk factors and prevalent cardiovascular disease. The relationship between renovascular disease and adverse coronary events was not dependent on the effects of increased blood pressure. The presence of renovascular disease was associated with an increase in the risk of adverse coronary events in this sample. The increment in risk was not dependent on the effects of associated atherosclerotic risk factors, other prevalent cardiovascular disease, or increased blood pressure.

Preprocedural C-reactive protein levels and cardiovascular events after coronary stent implantation

OBJECTIVESThis study assessed the predictive value of preprocedural C-reactive protein (CRP) levels on six-month clinical and angiographic outcome in patients undergoing coronary stent implantation.BACKGROUNDRecent data indicate that low-grade inflammation as detected by elevated CRP serum levels predicts the risk of recurrent coronary events.METHODSWe prospectively investigated the predictive value of preprocedural CRP-levels on restenosis and six-month clinical outcome in 276 patients after coronary stent implantation. The primary combined end point was death due to cardiac causes, myocardial infarction related to the target vessel and repeat intervention of the stented vessel.RESULTSGrouping patients into tertiles according to preprocedural CRP-levels revealed that, despite identical angiographic and clinical characteristics at baseline and after stent implantation, a primary end point event occurred in 24 (26%) patients of the lowest tertile, in 42 (45.6%) of the middle tertile and in 38 (41.3%) of the highest CRP tertile, p = 0.01. On multivariate analysis, tertiles of CRP levels were independently associated with a higher risk of adverse coronary events (relative risk = 2.0 [1.1 to 3.5], tertile I vs. II and III, p = 0.01) in addition to the minimal lumen diameter after stent (p = 0.04). In addition, restenosis rates were significantly higher in the two upper tertiles compared with CRP levels in the lowest tertile (45.5% vs. 38.3% vs. 18.5%, respectively, p = 0.002).CONCLUSIONSLow-grade inflammation as evidenced by elevated preprocedural serum CRP-levels is an independent predictor of adverse outcome after coronary stent implantation, suggesting that a systemically detectable inflammatory activity is associated with proliferative responses within successfully implanted stents.

Should We Use CRP to Target Patients for Statin Therapy

Patients with elevated levels of the inflammatory marker C-reactive protein (CRP) are at higher risk for adverse coronary events than are patients whose CRP levels are not elevated. Recent data suggest that pravastatin reduces CRP levels independent of its effect on lipid levels. These researchers, one of whom holds a patent on the use of CRP in risk stratification, hypothesized that CRP levels could be effective …

Identification of patients at high risk for adverse coronary events while awaiting routine coronary angioplasty.

Identification of patients at risk for progression of coronary stenosis and adverse clinical events while awaiting coronary angioplasty is desirable. To determine the standard clinical or angiographic variables, or both, present at initial angiography associated with the development of adverse coronary events (unstable angina, myocardial infarction, and angiographic total coronary occlusion) in patients awaiting routine percutaneous transluminal coronary angioplasty (PTCA). Consecutive male patients on a waiting list for routine PTCA. Routine clinical details were obtained at initial angiography. Stenosis severity was measured using computerised angiography. Development of one or more of myocardial infarction, unstable angina, or angiographic total coronary occlusion while awaiting PTCA were recorded as an adverse event. Some 214 of 219 patients underwent a second angiogram. One had a fatal myocardial infarction and four (2%) were lost to follow up. Fifty patients (23%) developed one or more adverse events (myocardial infarction five, unstable angina 35, total coronary occlusion 23) at a median (range) interval of 8 (3-25) months. Twenty (57%) of the 35 patients with unstable angina developed adverse events compared with 30 (17%) of the 180 with stable angina (P = 0.0001). Plasma triglyceride concentration was 2.6 (1.2) mmol/l in patients with adverse coronary events compared with 2.2 (1.1) mmol/l in those without such events (P < 0.05). Patients with adverse events were younger than those without (54 (9) years v 58 (9) years, P < 0.01). The relative risk of an adverse event in patients with unstable angina and increased plasma triglyceride concentrations was 6.9 compared with those presenting with stable angina and a normal triglyceride concentration (P < 0.02). The study shows that adverse events are not uncommon in patients awaiting PTCA. Patients at high risk for adverse events may be predicted by the presence of acute coronary syndrome, increased concentration of plasma triglyceride, and younger age at the time of the first angiogram.

Current technology in assessing painless and painful ischemia

Recent technologic advances have yielded diverse techniques for studying myocardial ischemia, a useful functional expression of coronary artery disease. These techniques have revealed new characteristics and expanded our understanding of myocardial ischemia. In turn this has led to the establishment of more realistic and discriminating criteria on which to base diagnostic and management decisions. Many of the techniques are noninvasive and can be performed in the cardiologist's office. These include treadmill exercise testing; radioisotope techniques, including ejection fraction studies, stress thallium scintigraphy, and tomographic imaging; and ambulatory monitoring. Other, newer techniques include provocative tests that induce ischemia in patients who cannot exercise. These new noninvasive tests should be used to detect transient ischemia, estimate its severity, and thus record a measure of the patient's risk for adverse coronary events.