Major Risk Factor For Atherosclerosis Research Articles

Polymorphisms of human platelet alloantigens HPA-1 and HPA-2 associated with severe coronary artery disease

Insofar as platelet membrane glycoprotein (GP) polymorphisms were identified as potential risk factors for coronary artery disease (CAD), we investigated the contribution of human platelet antigen (HPA)-1 (GPIIb/IIIa) and HPA-2 (GPIb/IX) alleles and haplotypes to CAD pathogenesis. Study subjects comprised 247 middle-age CAD patients and 316 age-, gender-, and race-matched controls; HPA genotyping was performed by polymerase chain reaction with sequence specific primers. The frequencies of HPA-1b (P<.001) and HPA-2b (P<.001) alleles and HPA-1a/1b (P<.001), HPA-1b/1b (P<.001), and HPA-2a/2b (P<.001) genotypes were higher in patients than control subjects. Select HPA haplotypes comprising the HPA-1b/2a (Pc=2.2 × 10(-4)) and HPA-1b/2b (Pc=.001) haplotypes which were positively associated, and the HPA-1a/2a (Pc=3.2 × 10(-5)) which was negatively associated with CAD, confer a disease susceptibility and protective nature to these haplotypes. Multivariate analysis confirmed the positive association of HPA-1b/2a [adjusted odds ratio (aOR)=3.63; 95% CI=2.42-5.43] and HPA-1b/2b (aOR=2.92; 95% CI=1.43-5.94) haplotypes with CAD, after adjustment for a number of covariates. Our results suggest that HPA-1/HPA-2 haplotypes may be considered to be a major risk factor for CAD in middle-aged Tunisians.

Protein kinase C activation stabilizes LDL receptor mRNA via the JNK pathway in HepG2 cells

LDL is the most abundant cholesterol transport vehicle in plasma and a major prognostic indicator of atherosclerosis. Hepatic LDL receptors limit circulating LDL levels, since cholesterol internalized by the liver can be excreted. As such, mechanisms regulating LDL receptor expression in liver cells are appealing targets for cholesterol-lowering therapeutic strategies. Activation of HepG2 cells with phorbol esters enhances LDL receptor mRNA levels through transcriptional and posttranscriptional mechanisms. Here, we show that 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced stabilization of receptor mRNA requires the activity of protein kinase C and is accompanied by activation of the major mitogen activated protein kinase pathways. Inhibitor studies demonstrated that receptor mRNA stabilization is independent of the extracellular signal-regulated kinase or p38(MAPK), but requires activation of the c-Jun N-terminal kinase (JNK). An essential role for JNK in stabilizing receptor mRNA was further confirmed through small interfering RNA (siRNA) experiments and by activating JNK through two protein kinase C-independent mechanisms. Finally, prolonged JNK activation increased steady-state levels of receptor mRNA and protein, and significantly enhanced cellular LDL-binding activity. These data suggest that JNK may play an important role in posttranscriptional control of LDL receptor expression, thus constituting a novel mechanism to enhance plasma LDL clearance by liver cells.

Low-density lipoprotein clearance in patients with chronic renal failure

Chronic renal failure increases the risk of atherosclerosis. The clearance of low-density lipoprotein (LDL), a major risk factor for atherosclerosis, has been reported as being disturbed in dialysis patients. We studied LDL metabolism in non-dialyzed patients with chronic kidney disease (CKD). LDL clearance was studied with a radiotracer method in 57 CKD patients and 10 healthy controls. In the CKD patients, the fractional catabolic rate of LDL apo B (LDL FCR), an indicator of LDL clearance from plasma, ranged from 0.13 to 0.56 pools/day with a mean value of 0.34 pools/day being comparable to that of the control subjects. In the renal patients, LDL FCR correlated significantly with estimated glomerular filtration rate (eGFR) (r = 0.340, P = 0.010) and this association remained significant after the adjustment with age, body mass index, gender, presence of diabetes and LDL cholesterol concentration (P = 0.004). In CKD patients with eGFR <15 mL/min/1.73 m(2) the mean LDL FCR was significantly reduced when compared to that of CKD patients with eGFR >30 mL/min/1.73 m(2) (P = 0.005). LDL apo B production rate was not associated with renal function or different between renal patients and control subjects. The clearance of LDL seems to be related to the severity of renal impairment, but a remarkable reduction in LDL catabolism can be observed only in patients with advanced renal failure.

Weight Loss and Blood Pressure Reduction in Obese Subjects in Response to Nutritional Guidance Using Information Communication Technology

The metabolic syndrome caused by visceral-fat obesity is a major risk factor for atherosclerosis. This study used a new information communication technology (ICT) to investigate body weight (BW) and blood pressure (BP) changes in response to nutritional guidance. Obese subjects with hypertension, hyperlipidemia, or impaired glucose tolerance received guidance with the ICT method (n = 13) or face-to-face according to conventional methods (n = 39). The effects of the methods were compared. After 12 weeks, significant weight loss and BP reduction were observed in the ICT group. Also, significant higher improvements were observed in total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and HbA1c in the ICT-group compared with those groups using the conventional method. The effectiveness of the ICT method in reducing BW, BP, total and LDL cholesterol, and HbA1c was demonstrated.

Radiation effects on the intima–media thickness of the common carotid artery in post-radiotherapy patients with head and neck malignancy

Background:Post-radiation large vessel injury has not received as much attention as microvascular irradiation injury. A few studies have shown that common carotid intima–media thickness (IMT) is increased after radiotherapy to...

Differences in DBA/1J and DBA/2J reveal lipid QTL genes

Recent advances in mouse genomics have revealed considerable variation in the form of single-nucleotide polymorphisms (SNPs) among common inbred strains. This has made it possible to characterize closely related strains and to identify genes that differ; such genes may be causal for quantitative phenotypes. The mouse strains DBA/1J and DBA/2J differ by just 5.6% at the SNP level. These strains exhibit differences in a number of metabolic and lipid phenotypes, such as plasma levels of triglycerides (TGs) and HDL. A cross between these strains revealed multiple quantitative trait loci (QTLs) in 294 progeny. We identified significant TG QTLs on chromosomes (Chrs) 1, 2, 3, 4, 8, 9, 10, 11, 12, 13, 14, 16, and 19, and significant HDL QTLs on Chrs 3, 9, and 16. Some QTLs mapped to chromosomes with limited variability between the two strains, thus facilitating the identification of candidate genes. We suggest that Tshr is the QTL gene for Chr 12 TG and HDL levels and that Ihh may account for the TG QTL on Chr 1. This cross highlights the advantage of crossing closely related strains for subsequent identification of QTL genes.

Pulsatile Mechanical Pressure Promotes Angiotensin-Converting Enzyme Expression in Aortic Smooth Muscle Cells

Hypertension is a major risk factor for atherosclerosis, and elevated pressure (i.e., mechanical pressure stresses) has been known to modulate vascular remodeling, possibly by affecting the tissue renin-angiotensin system. In the present study we applied pulsatile pressure to human aortic smooth muscle cells (HASMCs) and investigated whether mechanical pressure stress affects cell proliferation and/or the angiotensin-converting enzyme (ACE), and we tested whether the administration of an angiotensin II (AII) receptor blocker has a favorable effect. Three hours of pulsatile atmospheric pressure resulted in an approximately 8% increase in cell proliferation of human aortic smooth muscle cells. The cell surface ACE level, enzyme activity and mRNA expression were all elevated (37%, 110% and 17%, respectively) under pressurized conditions, and co-administration of AII reduced all these values. The reductions in these three parameters resulting from the administration of AII were all abolished by AII receptor blocker co-administration and values were increased (11%, 62% and 12%, respectively) under pressurized conditions. Pulsatile atmospheric pressure increased the amount of phosphorylated extracellular signal-regulated kinase (ERK) by approximately 54% in HASMCs. The administration of PD98059 (10 microM) resulted in a decrease in phosphorylated ERK and ACE activity in HASMCs compared to those of the pressurized control. From these observations, we conclude that pulsatile mechanical pressure is one of the mediators of ACE production in vascular smooth muscle cells and that AII receptor blocking may prevent negative feedback. The present findings may provide a potential therapeutical target beyond lowering blood pressure in hypertensive patients.

Lipopolysaccharide associates with pro-atherogenic lipoproteins in periodontitis patients

Periodontitis patients are known to suffer from endotoxemia, which may be among the major risk factors for atherosclerosis. In health, lipopolysaccharide (LPS) is mainly carried with high density lipoprotein (HDL) particles. Shift of LPS toward lipoproteins with lower densities may result in less effective endotoxin scavenging. Our aim was to determine plasma LPS activity and lipoprotein-distribution before and after treatment in periodontitis patients. Very low and intermediate density (VLDL-IDL), low density (LDL), HDL 2, HDL3, and lipoprotein-deficient plasma (LPDP) were isolated by sequential ultracentrifugation. Patients included 34 subjects aged 53.5 +/- 8.3 years, before and 6 months after periodontal treatment. The mean LPS distribution decreased among lipoprotein classes as follows: VLDL-IDL 41.3 +/- 12.1%, LPDP 25.0 +/- 7.0%, HDL3 13.1 +/- 5.2%, LDL 11.5 +/- 3.7%, and HDL2 9.2 +/- 2.8%. Plasma and VLDL-IDL-associated LPS correlated positively, and LDL- and HDL-associated LPS negatively with clinical periodontal parameters and plasma cytokine concentrations. Mean plasma LPS activity increased after periodontal treatment from 44.0 +/- 17.0 to 55.7 +/- 24.2 EU/ml (P = 0.006). No significant changes were found in LPS lipoprotein distribution and lipoprotein compositions after the treatment. Endotoxemia increases with severity of periodontitis. In periodontitis, LPS associates preferentially with the pro-atherogenic VLDL-IDL fraction. Periodontal treatment has only minor effects on plasma LPS activity or distribution, which reflects persistence of the disease.

Computational Biological Analysis Reveals a Role for Nitric Oxide Synthase and Adiponectin in the Pathobiology of Insulin Resistance Syndrome and Coronary Artery Disease

Insulin resistance syndrome is a major risk factor for atherosclerosis and coronary heart disease (CAD). Endothelial dysfunction due to reduced nitric oxide generation is seen in both insulin resistance syndrome and CAD. Endothelial dysfunction also occurs in obesity, diabetes mellitus, and other cardiovascular diseases. In the present study, we employed multiple sequence alignment using Clustal W tool and constructed a phylogenetic tree using functional protein sequences extracted from NCBI and Gene cards. These studies showed that nitric oxide synthase and adiponectin play a major role in insulin resistance and coronary artery disease. This and other studies suggest that endothelial dysfunction is an early event in insulin resistance syndrome.

Age‐related differences in insulin‐like growth factor‐1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells

Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin-like growth factor-1 receptor (IGF-1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF-1R signaling changes with age in VSMC is not known. We previously found age-related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age-related vascular pathology similar to humans, we compared IGF-1R expression in early passages of VSMC and found a constitutive activation of IGF-1R in VSMC from old compared to young rats, including IGF-1R expression and its tyrosine kinase activity. The link between IGF-1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF-1R with IGF-1 in young cells and attenuation of IGF-1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF-1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip-1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a-targets based on FOXO3a-siRNA treatment. Furthermore, IGF-1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF-1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis.

157 Changes in the Levels of Adiponectin and MCP-1 may be Responsible for Cigarette Smoke-Induced Atherosclerosis

Atherosclerotic plaque formation involves recruitment and adhesion of circulating monocytes to sites of blood vessel wall injury followed by their migration into the subendothelial space stimulated by MCP-1 (monocyte-chemoattractant-protein1). Monocytes differentiate into macrophages, cells that release a variety of factors and take up oxidized LDL, becoming foam cells. Smooth muscle cells of the vessel wall differentiate and migrate to the subendothelial space, interact with foam cells and components of the ECM to form a “fatty streak,” the precursor of plaque. Adiponectin, a protein secreted by adipocytes, circulates in the blood, maintains blood vessel wall stability and inhibits foam cell formation. Cigarette smoke is a major risk factor of atherosclerosis, although the mechanisms remain unknown. We showed previously that both firsthand and secondhand cigarette smoke stimulate MCP-1 in endothelial cells and others have shown that adiponectin levels in smokers with cardiovascular disease are reduced. We hypothesized that a localized increase in MCP-1 and a decrease in adiponectin are critical for cigarette smoke-induced plaque formation. To test this possibility, we used mice transgenic for human ApoB100, a model system that closely mimics human conditions that lead to atherosclerosis, and a smoking machine that closely simulates human smoking. We found that, in smoking mice, the micro vessels in the heart tissue are often filled with lipids, the areas surrounding the plaque-prone regions have numerous neutrophils, that these cells express high levels of MCP-1, and that the plaques are larger than in control mice. In addition, the level of the adiponectin monomer in the blood of smoking mice is lower and the presence of this protein in the heart tissue is also decreased. In conclusion, the decrease in adiponectin and the increase in MCP-1 levels may be responsible for cigarette smoke-induced atherogenesis.

Clinical and pathologic risk factors for atherosclerosis in cirrhosis: A comparison between NASH-related cirrhosis and cirrhosis due to other aetiologies

The precise prevalence of risk factors for atherosclerosis in NASH-related cirrhosis is unknown. The aims of this study were: (1) to compare the prevalence of major risk factors for atherosclerosis between subjects who underwent liver transplantation for NASH-related cirrhosis and those with cirrhosis of other aetiologies and (2) to compare pathologic changes of atherosclerosis within the explants hepatic hilar arteries between the groups. Sixty subjects with NASH-related cirrhosis and 60 subjects with cirrhosis of other aetiologies were reviewed retrospectively. Demographic and clinical characteristics related to atherosclerosis were analyzed and compared. The hepatic hilar arteries of the explanted livers were examined for pathologic changes. The prevalence of all coronary artery disease (CAD) risk factors and the metabolic syndrome was significantly higher in NASH-related cirrhosis group compared to cirrhosis of other aetiologies. The proportion of patients with a diagnosis of CAD was also significantly higher in the NASH-related cirrhosis group (21.6% vs. 5%, p=0.005). Pathological examination of hilar arteries showed possible atherosclerotic changes in only 4 cases (3 NASH-related cirrhosis; 1 HCV). Major risk factors for atherosclerosis are significantly more prevalent in subjects with NASH-related cirrhosis than in subjects with cirrhosis of other aetiologies and are predictive of an increased prevalence of CAD. This study suggests that NASH-related cirrhosis is not protective against atherosclerosis.

The Role of the Endocannabinoid System in Atherosclerosis

Our current understanding of the pathophysiology of atherosclerosis suggests a prominent role for immune responses from its initiation through its complications. Given the increasing prevalence of cardiovascular risk factors worldwide, there is an urgent need to better understand the underlying mechanisms to improve current treatment protocols. A growing body of evidence suggests that endocannabinoid signalling plays a critical role in the pathogenesis of atherogenesis and its clinical manifestations. Blocking CB(1) receptors has been shown to mediate not only weight reduction, but also several cardiometabolic effects in rodents and humans, indicating a potential relevance for the process of atherosclerosis. Activation of CB(2) receptors with Delta(9)-tetrahydrocannabinol (THC) has been shown to inhibit atherosclerotic plaque progression in mice, mainly by inhibiting macrophage recruitment. Endocannabinoids released from endothelial cells, macrophages or platelets, reduce hypertension in rodents, a major risk factor for atherosclerosis. In addition, anandamide inhibits inflammatory gene expression in endothelial cells, and consequently monocyte adhesion. Conversely, endocannabinoids might also mediate pro-atherosclerotic effects by inducing platelet activation. In conclusion, the precise role of the endocannabinoid system during atherosclerosis is not yet understood. Whether increased endocannabinoid signalling is associated with disease progression and increased risk of acute thrombotic events remains to be determined.

Downregulation of hepatic lipoprotein assembly in rats by fermented products of Monascus pilosus

Objective Hypercholesterolemia is a major risk factor for atherosclerosis. The fermented products of Monascus sp. have been known for their antihypercholesterolemic effect; however, the studies mostly have focused on the inhibition of cholesterol biosynthesis in liver. In this study, we examined whether fermented products of Monascus pilosus have regulatory effects on the hepatic lipoprotein assembly. Methods Male Wistar rats were fed 1% cholesterol diet for 2 wk. After hypercholesterolemia was induced, the animals were maintained on this cholesterol diet supplemented with M. pilosus–fermented products grown in regular medium/garlic-containing medium or garlic powder for another 6 wk. The concentration of blood lipids and the expression of proteins involved in lipoprotein assembly and hepatic antioxidation were assayed. Results Maintenance on a 1% cholesterol diet for 2 wk significantly ( P < 0.05) raised animals' blood lipid levels and increased the expression of intestinal microsomal triacylglycerol transfer protein, hepatic apolipoprotein B-100, and acyl-coenzyme A:cholesterol acyltransferase. Supplementation of M. pilosus–fermented products or garlic powder significantly ( P < 0.05) lowered animals' blood lipid levels and inhibited the expression of intestinal microsomal triacylglycerol transfer protein and hepatic apolipoprotein B-100. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase was downregulated by the M. pilosus–fermented product grown in regular medium but not in garlic-containing medium. The expression of antioxidant enzymes was significantly upregulated by the M. pilosus–fermented product grown in garlic-containing medium. Conclusion Monascus sp.–fermented products exert the hypocholesterolemic effect by mechanisms other than the inhibition of cholesterol biosynthesis.

Breast arterial calcifications (BACs) found on screening mammography and their association with cardiovascular disease

Breast arterial calcifications (BACs) are common but unreported findings on screening mammograms. This study correlated mammographically detected BACs with coronary artery disease (CAD) risk factors and a history of atherosclerotic cardiovascular disease (ASCVD), estimating the relative risk of ASCVD in patients with BACs. Women arriving for breast cancer screening mammography gave their consent to complete a questionnaire and to allow their mammograms to be analyzed independently for the presence of BACs by certified radiologists, who were blinded to the results of the questionnaire. The questionnaire assessed major risk factors for CAD and gathered information on hormone therapy use. Of the 1,919 women with results, 268 were BAC positive, giving a BAC prevalence of 14%. Five cardiovascular risk factors (age, hypertension, hypercholesteremia, diabetes mellitus, and menopause) were significantly more prevalent in the BAC-positive population (P < 0.001). The BAC-positive group also had a significantly higher (P < 0.001) occurrence of ASCVD events (angina, previous myocardial infarction, previous abnormal angiography, previous stroke, and previous coronary artery bypass graft). Multiple logistic regression analysis found BACs to be strongly associated with ASCVD events (odds ratio = 2.29, 95% CI: 1.40-3.74) as compared with other CAD risk factors (including hypertension, cigarette smoking, diabetes mellitus, age, and family history of ASCVD). The association of BAC with ASCVD was present even after accounting for age. BACs are associated with an increased prevalence of both cardiovascular risk factors and cardiovascular morbidity. BACs may be a practical tool to use as a risk indicator for CAD in women.

Metabolic syndrome: A major risk factor for atherosclerosis in HIV-infected patients (SHIVA study)

Metabolic syndrome (MetS) is directly related to a high incidence of cardiovascular disease in the general population. The association is more doubtful among HIV-infected patients, although MetS has an elevated prevalence in this population. We explored the impact of MetS on early atherosclerosis markers. All HIV-infected outpatients followed at the Brest University Hospital were included in this cross-sectional hospital-based study (SHIVA study, France) (n=154). The MetS status (NCEP ATPIII definition, at least three of these five criteria: fasting glucose, triglycerides, HDL-C, waist circumference and hypertension.) of each patient was analyzed (Mann-Whitney test) according to carotid intima-media thickness, number of plaques, and a combined cardiovascular score. After exclusion of 6 patients treated with statins or insulin or both, MetS status was available for 140 (90.9%) patients and positive for 10 (7.1%). MetS status was due predominantly to blood glucose and triglyceride levels and was strongly correlated with all atherosclerosis markers (p < or = 0.01). The MetS prevalence in this population is low for a group with HIV infection, even after inclusion of the statin-treated patients (11.4%), but remains higher than among the general population. MetS in this population is probably a heterogeneous cluster of side effects of antiretroviral therapy (high triglycerides, lower HDL-C, and hypertension) and direct effects of HIV (glucose disturbances). Because it is strongly linked to the presence of plaque and intimal thickness, it is a pertinent criterion for deciding about cardiovascular prevention.

Blood Pressure Is the Main Determinant of the Reflection Wave in Patients with Type 2 Diabetes

Augmentation index (AI), the ratio of augmented pressure by the reflection pressure wave to the pulse pressure (PP), is an index of arterial stiffness and central blood pressure (BP). Although type 2 diabetes mellitus (DM) is a major risk factor for atherosclerosis, there is controversy with respect to how DM affects AI. In the present study, we investigated possible determinants of AI in 194 type 2 DM patients (mean age 67+/-9 years). AI was measured in the left radial artery using an automated tonometric method. In a simple correlation analysis, AI showed a positive association with age, and a negative association with body height, body weight, waist circumference, heart rate (HR), plasma glucose, and HbA1c. Women had significantly higher AI than men. Stepwise regression analysis revealed that mean BP (MBP) (beta=0.260, p<0.001), HR (beta=-0.550, p<0.001) and body height (beta=-0.217, p<0.001) were independent determinants of radial AI. Similarly, the second peak of systolic BP (SBP2), an index of central aortic systolic BP (SBP), showed a positive association with age, BMI, waist circumference, MBP and AI, and a negative association with body height. In a separate analysis performed in diabetic patients with treated hypertension (n=123), again, only MBP, HR and body height were significant determinants of radial AI. There was no difference in radial AI and SBP2 among the classes of antihypertensive drugs used. These findings indicate that tight BP control would be effective in reducing the reflection wave and aortic BP, which could independently relate to cardiovascular disease in type 2 diabetic patients.

Cholesterol: a century of research and debate.

To The Editor: The excellent article by Dr Elmehdawi RR entitled “Hypolipidemia: A word of caution” has once again shown the multifaceted properties of cholesterol which is the most highly decorated molecule in biology [1]. Thirteen nobel prizes have been awarded to scientists who devoted major parts of their careers to cholesterol [2]. The word cholesterol is derived from the Greek words, chole= bile; steros= solid; ol= alcohol. Ever since it was first isolated from gallstones in 1784, cholesterol has exerted a hypnotic fascination for scientists from most diverse domains of science and medicine. Organic chemists have been fascinated with cholesterol because of its complex four ring structure with its steroid nucleus. Biochemists have also been interested because cholesterol is synthesized from a simple two-carbon substrate, acetate, through the action of at least 30 enzymes. Besides, cholesterol drew the attention of physiologists and cell biologists because of its essential function in animal cell membranes, where it modulates fluidity and maintains a barrier between cell and environment and being the raw material for the manufacture of steroid hormones and bile acids. Physicians started studying cholesterol after it has become evident that elevated levels of blood cholesterol accelerate the formation of atherosclerotic plaques leading to heart attack and stroke. Over the course of nearly a century of investigation, researchers have developed four lines of evidence: experimental, genetic, epidemiologic, and therapeutic - that irrefutably established the causal connection between cholesterol carrying low density lipoprotein (LDL) and atherosclerosis [3]. Few other major diseases have been subject to such intensive and ultimately fruitful research. Building on that knowledge scientists have been successful in developing an effective course of therapy – the statin drugs which are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting enzyme in cholesterol biosynthesis. High –density lipoprotein (HDL) cholesterol represent a strong inverse predicator of cardiovascular events. Recent studies have illustrated the clinical significance of high-density lipoprotein cholesterol in patients with low levels of low-density lipoprotein cholesterol [4, 5]. HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol below 70 mg per deciliter. As suggested by Dr Elmehdawi, caution needs to be asserted as we focus on aggressive management of hyperlipidemia due to the possible complications of drug induced hypolipidemia including intracerebral hemorrhage and sepsis [1]. There has been controversy in the literature concerning the contribution of hypercholesterolemia to subsequent development of dementia [6]. Longitudinal studies have established that midlife elevated serum cholesterol level is associated with an increased risk of subsequent Alzheimer's disease [7]. However, two large randomized controlled trials failed to show that statins (pravastatin and simvastatin) reduced dementia [8, 9]. Hypocholesterolemia is also a predisposing factor for infection in certain conditions as well as a prognostic indicator during sepsis [1]. But a recent systematic review, which analyzed studies of the literature comparing the outcome between statin and non- statin users among patients suffering from sepsis or other infections, reported a major consensus that statins may have a positive role in treatment of patients with sepsis and infection [10]. Heart failure (HF) is a common and a serious condition that is usually due to coronary artery disease (CAD). Hypercholesterolemia is a major risk factor for CAD but, paradoxically, patients with advanced HF often have low cholesterol, which is associated with poor prognosis [11]. Hence, even after 200 years of first being isolated, and nearly 100 years of fruitful research, this Janusfaced molecule continues to evoke controversy, and the debate on the role of cholesterol in biomedicine and the future direction of cholesterol-lowering therapy continues.

Cholesterol: a Century of Research and Debate

To The Editor: The excellent article by Dr Elmehdawi RR entitled “Hypolipidemia: A word of caution” has once again shown the multifaceted properties of cholesterol which is the most highly decorated molecule in biology [1]. Thirteen nobel prizes have been awarded to scientists who devoted major parts of their careers to cholesterol [2]. The word cholesterol is derived from the Greek words, chole= bile; steros= solid; ol= alcohol. Ever since it was first isolated from gallstones in 1784, cholesterol has exerted a hypnotic fascination for scientists from most diverse domains of science and medicine. Organic chemists have been fascinated with cholesterol because of its complex four ring structure with its steroid nucleus. Biochemists have also been interested because cholesterol is synthesized from a simple two-carbon substrate, acetate, through the action of at least 30 enzymes. Besides, cholesterol drew the attention of physiologists and cell biologists because of its essential function in animal cell membranes, where it modulates fluidity and maintains a barrier between cell and environment and being the raw material for the manufacture of steroid hormones and bile acids. Physicians started studying cholesterol after it has become evident that elevated levels of blood cholesterol accelerate the formation of atherosclerotic plaques leading to heart attack and stroke. Over the course of nearly a century of investigation, researchers have developed four lines of evidence: experimental, genetic, epidemiologic, and therapeutic - that irrefutably established the causal connection between cholesterol carrying low density lipoprotein (LDL) and atherosclerosis [3]. Few other major diseases have been subject to such intensive and ultimately fruitful research. Building on that knowledge scientists have been successful in developing an effective course of therapy – the statin drugs which are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting enzyme in cholesterol biosynthesis. High –density lipoprotein (HDL) cholesterol represent a strong inverse predicator of cardiovascular events. Recent studies have illustrated the clinical significance of high-density lipoprotein cholesterol in patients with low levels of low-density lipoprotein cholesterol [4, 5]. HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol below 70 mg per deciliter. As suggested by Dr Elmehdawi, caution needs to be asserted as we focus on aggressive management of hyperlipidemia due to the possible complications of drug induced hypolipidemia including intracerebral hemorrhage and sepsis [1]. There has been controversy in the literature concerning the contribution of hypercholesterolemia to subsequent development of dementia [6]. Longitudinal studies have established that midlife elevated serum cholesterol level is associated with an increased risk of subsequent Alzheimer's disease [7]. However, two large randomized controlled trials failed to show that statins (pravastatin and simvastatin) reduced dementia [8, 9]. Hypocholesterolemia is also a predisposing factor for infection in certain conditions as well as a prognostic indicator during sepsis [1]. But a recent systematic review, which analyzed studies of the literature comparing the outcome between statin and non- statin users among patients suffering from sepsis or other infections, reported a major consensus that statins may have a positive role in treatment of patients with sepsis and infection [10]. Heart failure (HF) is a common and a serious condition that is usually due to coronary artery disease (CAD). Hypercholesterolemia is a major risk factor for CAD but, paradoxically, patients with advanced HF often have low cholesterol, which is associated with poor prognosis [11]. Hence, even after 200 years of first being isolated, and nearly 100 years of fruitful research, this Janusfaced molecule continues to evoke controversy, and the debate on the role of cholesterol in biomedicine and the future direction of cholesterol-lowering therapy continues.

Diagnostic performance of plasma high sensitive C‐reactive protein in detecting three‐vessel coronary artery disease: modification by apolipoprotein E genotype

Objectives. Plasma high sensitive C‐reactive protein (hsCRP) concentration is an important clinical test of systemic inflammation and, like apoE ε4 allele, an important risk factor of coronary artery disease (CAD). We investigated whether the diagnostic performance of plasma hsCRP in detecting severe 3‐vessel CAD may be modified by apoE ε4 carrier status. Methods. The study population (Angiography and Genes Study) comprised 485 Finnish subjects (336 men and 149 women, mean age 64.0±1.0) undergoing coronary angiography. ApoE genotypes were determined by the PCR‐based method and by hsCRP using an automatic analyser. Results. The diagnostic performance of hsCRP concentration in distinguishing 3‐vessel CAD from its less widespread forms (non‐3‐vessel CAD) was assessed by receiver operating characteristic curve (ROC) analysis separately in apoE ε4 non‐carriers and ε4 carriers. ROC analysis showed that hsCRP predicted 3‐vessel CAD in apoE ε4 non‐carriers (AUC 0.646; SE 0.035; p = 0.0001; 95 % CI 0.578–0.714) but not in ε4 carriers (AUC 0.518; SE 0.049; p = 0.719; 95 % CI 0.422–0.615). Multinomial logistic regression analysis revealed a significant (p<0.05) apoE ε4 group versus hsCRP group (<1.0 mg/L/⩾1.0 mg/L) interaction in relation to incidence of 3‐vessel CAD. In apoE ε4 non‐carriers, high hsCRP (⩾1.0 mg/L) was significantly (OR 2.1; 95 % CI 1.233–3.562; p = 0.006) associated with high incidence of 3‐vessel CAD after adjustment for major CAD risk factors. Conclusion. The diagnostic performance of hsCRP in distinguishing 3‐vessel CAD from less extensive forms of coronary atherosclerosis is more accurate in a group of subjects without the apoE ε4 allele than in patients with it.