Maziar Rahmani

Cardiovascular risk factors in an Iranian urban population: Tehran Lipid and Glucose Study (Phase 1)

Summary.Objectives: Coronary artery disease is becoming more prevalent in developing countries, particularly in urban areas. This study was conducted to determine the prevalence of cardiovascular risk factors among Tehran urban population. Methods: The prevalence and distribution of high blood pressure, cigarette smoking, dyslipoproteinemia, diabetes mellitus, and obesity was determined in 15005 subjects, aged three years and over, selected by cluster random sampling in Tehran urban district-13 between February 1999 to August 2001. Total energy intake, percent of energy derived from protein, carbohydrate, and fat were assessed in a subsidiary of 1474 persons by means of two 24-hour dietary recalls. Results: In adults, 78% of men and 80% of women presented at least one CVD risk factor. The percentage of adult women with two or more risk factors was significantly greater than the one for men. Prevalence of DM, hypertension, obesity, high TC, low HDL, high TGs, and smoking was 9.8, 20.4, 14.4, 19.3, 32, 5.3, and 22.3%, respectively. In children and adolescents, two or more CVD risk factors were found in 9% of boys and 7% of girls. Prevalence of hypertension, obesity, high TC, low HDL, and high TGs, was 12.7, 5.2, 5.1, 10.2, and 5%, respectively. The mean percentage values of energy intake derived from carbohydrate, protein, and fat were 57.8±6.9, 11.1±1.8, and 30.9±7.2, respectively. Conclusion: The prevalence of cardiovascular risk factors among Tehran urban population is high; particularly of high total cholesterol, low HDL cholesterol levels, and high waist to hip ratio. An effective strategy for life style modification is a cornerstone of a population approach to the cardiovascular risk factors. Moreover, these results will serve as a baseline for assessment of future trends in the risk factors studied.

Allograft Vasculopathy Versus Atherosclerosis

Over the last 4 decades, heart transplantation (HTx) has evolved as a mainstream therapy for heart failure. Approximately half of patients needing HTx have organ failure consequent to atherosclerosis. Despite advances in immunosuppressive drugs, long-term success of HTx is limited by the development of a particular type of coronary atherosclerosis, referred to as cardiac allograft vasculopathy (CAV). Although the exact pathogenesis of CAV remains to be established, there is strong evidence that CAV involves immunologic mechanisms operating in a milieu of nonimmunologic risk factors. The immunologic events constitute the principal initiating stimuli, resulting in endothelial injury and dysfunction, altered endothelial permeability, with consequent myointimal hyperplasia and extracellular matrix synthesis. Lipid accumulation in allograft arteries is prominent, with lipoprotein entrapment in the subendothelial tissue, through interactions with proteoglycans. The apparent endothelial “intactness” in human coronary arteries of the transplanted heart suggest that permeability and function of the endothelial barrier altered. Various insults to the vascular bed result in vascular smooth muscle cell (SMC) activation. Activated SMCs migrate from the media into the intima, proliferate, and elaborate cytokines and extracellular matrix proteins, resulting in luminal narrowing and impaired vascular function. Arteriosclerosis is a broad term that is used to encompass all diseases that lead to arterial hardening, including native atherosclerosis, postangioplasty restenosis, vein bypass graft occlusion, and CAV. These diseases exhibit many similarities; however, they are distinct from one another in numerous ways as well. The present review summarizes the current understanding of the risk factors and the pathophysiological similarities and differences between CAV and atherosclerosis.

Serum lipid levels in an Iranian adults population: Tehran lipid and glucose study

Data from 6246 participants aged 20–64 years (2339 males and 3907 females) in the cross-sectional phase of Tehran Lipid and Glucose Study (February 1999–May 2000) were used to determine distribution of serum lipid levels after 12–14 hour overnight fast. Mean total cholesterol (TC) concentration was 210 mg/dl. TC was significantly greater in females than males, 213 and 206 mg/dl, respectively (p < 0.0001). Thirty-one percent of population had TC values between 200 and 239 and 24% had values of 240 mg/dl or greater. Mean low-density lipoprotein cholesterol (LDL-C) was 129 and 135 mg/dl in males and females, respectively (p < 0.0001). Twenty-seven percent had LDL-C values between 130 and 159 and 23% had values 160 mg/dl or greater. The mean triglycerides (TGs) values were 190 and 162 mg/dl for males and females, respectively (p < 0.0001). The mean high-density lipoprotein cholesterol (HDL-C) was 39 in males and 45 mg/dl in females (p < 0.0001). The results showed higher levels of TC, LDL-C and TGs and slightly lower HDL-C in Tehranian adults than other studies in the industrialized countries.

Distribution of blood pressure and prevalence of hypertension in Tehran adult population: Tehran Lipid and Glucose Study (TLGS), 1999–2000

The purpose of this study was to estimate the current prevalence and distribution of hypertension in an adult Tehranian population. Data were collected for 3343 men and 5148 women aged 20–69 years in the Tehran Lipid and Glucose Study (TLGS), which is a cross-sectional phase of a large epidemiologic study, first established in 1999. The study used the mean of two separate blood pressure (BP) measurements in each individual. Twenty-two percent (23% of women vs 20% of men, P = 0.01) had hypertension according to ‘JNC-VI’ and ‘WHO-ISH’ criteria. The average systolic BP (SBP), diastolic BP (DBP) and pulse pressure of hypertensive participants were 31, 16, and 15 mm Hg higher than the corresponding value for normotensives, respectively. Thirty-six percent of participants with JNCVI-based hypertension were using antihypertensive medication (23% of men and 43% of women). Of these, 40% (45% of men and 39% of women) had normal BP. Hypertension awareness was 50% in these participants (57% in men vs 37% in women, P < 0.001). Data for 3179 men and 4646 women aged 20–69 years with no antihypertensive treatment were used for analysis of BP measures. Of these, 15% (16% of men and 14% of women, P = 0.006) had high and 85% (84% of men and 86% of women) normal or high-normal BP levels according to JNC-VI. Prevalence of optimal BP was 49% (47% of men and 51% of women). Mean SBP was 117.8 ± 16.6 and 116.4 ± 16.4 mm Hg in men and women, respectively (P < 0.001). The equivalent values were 77.4 ± 10.7 and 77.3 ± 9.9 mm Hg for DBP (P = 0.5) and 40.4 ± 12 and 39.1 ± 11.7 mm Hg for pulse pressure (P < 0.001). A relatively high prevalence of JNC-VI/WHO-ISH defined hypertension was found in the TLGS adult population with 50% undiagnosed and 60% uncontrolled hypertension. These findings emphasise further considerations for detection and better management of hypertension in the urban population of Tehran.

Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice

Background— Coxsackievirus B3 (CVB3) causes human myocarditis, which can result in cardiac damage, maladaptive remodeling, and heart failure. Matrix metalloproteinases (MMP)-8 and -9 have been identified in virus-infected myocardium, but their particular roles and underlying mechanisms of effect are unknown. For the first time, we examine the severity of CVB3-induced myocarditis in MMP-8–and MMP-9–deficient mice. Methods and Results— CVB3-infected MMP-8 and MMP-9 knockout (KO) mice and corresponding wild-type (WT) mice were euthanized and harvested at 9 days after infection. Expression of MMP-2, -8, -12, and -13 and tissue inhibitors of MMPs was assessed by zymography or immunoblotting on harvested hearts, and in situ hybridization was performed to detect active infection. Infected MMP-9 KO mice had greater myocardial injury and foci of infection than WT mice despite similar pancreatic infection. Increased fibrosis (10.6±2.7% versus 7.1±2.6%, P=0.04), viral titer, as well as decreased cardiac output, were evident in MMP-9 KO compared with WT mice as assessed by picrosirius red staining, plaque assay, and echocardiography, respectively. Immune infiltration was also greatly increased in MMP-9 KO compared with WT mice (15.2±12.6% versus 2.0±3.0%, P<0.002). Myocardial interferon-&bgr;1, interferon-&ggr;, interleukin-6, interleukin-10, and macrophage inflammatory protein-1&agr; expression was elevated in MMP-9 KO mice as measured by quantitative real-time polymerase chain reaction and ELISA. In contrast, MMP-8 KO mice had the same degree of cardiac injury, fibrosis, and viral infection as their WT counterparts. Conclusions— During acute CVB3 infection, MMP-9 appears necessary to halt virus propagation in the heart, promote proper immune infiltration and remodeling, and preserve cardiac output.

Serum lipid levels in an Iranian population of children and adolescents: Tehran lipid and glucose study.

Data from 3148 participants aged 3–19years (1447 males and 1701 females) in the cross-sectional phase of Tehran lipid and glucose study (February 1999–May 2000) were used to determine serum lipid levels [total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)] after 12–14 hours overnight fast. The values were analyzed by sex and age. Mean serum TC concentration was 170 mg/dl. TC was significantly greater in females than males (173 vs. 167 mg/dl, p < 0.05). The 90th and 95th percentiles for serum TC were 211 and 227 mg/dl, respectively. There was a significant decrease in mean TC in males during puberty. Thirty-one percent of population had TC values between 170 and 199 mg/dl and 16% had values of 200 mg/dl or greater. The mean TGs values were 103 for males and 108 mg/dl for females [non-significant (NS)]. The prevalence of high-risk values of TGs increased with age in males, reaching a peak at 17–19years. The mean HDL-C level was 45 mg/dl. Mean HDL-C was highest at 7–10years of age and decreased thereafter. The mean LDL-C was 102 in males and 107 mg/dl in females (NS). Twenty-two percent had LDL-C values between 110 and 129 mg/dl and 17% had values 130 mg/dl or greater. The results showed higher levels of TC, LDL-C and TGs and lower HDL-C in Tehranian children and adolescents than other studies. To design comprehensive public health programs to reduce serum lipid levels among Iranian children and adolescents, underlying factors for the high prevalence of dyslipoproteinemia should be sought.

Dietary Factors and Body Mass Index in a Group of Iranian Adolescents: Tehran Lipid and Glucose Study-2

OBJECTIVE To study the prevalence of overweight and obesity in an adolescent population in Tehran and to determine possible association with energy and nutrient intake and distribution of energy over the day. METHOD A cross-sectional study on 177 boys and 244 girls between 10-19 years old was performed. Overweight and obesity were defined by using recommended body mass index (BMI) cut-off values for adolescents. Total energy intake, percent of energy derived from protein, carbohydrate and fat and percent of energy supplied by each meal and snack were assessed by means of two 24-hour dietary recalls. RESULTS Prevalence of overweight and obesity was 10.7 and 5.1 in boys and 18.4 and 2.8 in girls, respectively. The composition of diet was not different between overweight/obese and normal weight subjects. BMI was related with breakfast energy percentage in girls (r = -0.18, p < 0.01), with total energy intake in boys (r = 0.23, p < 0.01), and with lunch energy percentage in both sexes. In boys (r = 0.16, p < 0.05) and in girls (r = 0.22, p < 0.01). CONCLUSION High prevalence of overweight and obesity among adolescents was seen. In boys some relationship between total energy intake, distribution of energy over the day and BMI was seen. In girls BMI was only related with distribution of energy over the day.

Novel Role for Integrin-Linked Kinase in Modulation of Coxsackievirus B3 Replication and Virus-Induced Cardiomyocyte Injury

Viral myocarditis is a major cause of sudden cardiac death in children and young adults. Among viruses, coxsackievirus B3 (CVB3) is the most common agent for myocarditis. Recently, more consideration has been given to the role of signaling pathways in pathogenesis of enteroviral myocarditis, providing new platform for identifying a new potential therapeutic target for this, so far, incurable disease. Previously, we reported on the role of the protein kinase-B/Akt in CVB3 replication and virus-induced cell injury. Here, we report on regulation of virus-induced Akt activation by the integrin-linked kinase in infected mouse cardiomyocytes and HeLa cells. This study also presents the first observation that inhibition of ILK in CVB3-infected cells significantly improves the viability of infected cells, while blocking viral replication and virus release. Complementary experiments using a constitutively active form of Akt1 revealed that the observed protective effect of ILK inhibition is dependent on the associated downregulation of virus-induced Akt activation. To our knowledge, this is the first report of such beneficial effects of ILK inhibition in a viral infection model and conveys new insights in our efforts to characterize a novel therapeutic target for treatment of enteroviral myocarditis.

Coxsackievirus B3 activates nuclear factor kappa B transcription factor via a phosphatidylinositol-3 kinase/protein kinase B-dependent pathway to improve host cell viability.

Coxsackievirus B3 (CVB3) is the most common viral infectant of heart muscle. CVB3 directly injures cardiomyocytes. We have previously reported on a regulatory role for the phosphatidylinositol‐3 kinase (PI3K)/protein kinase B (Akt) pathway during CVB3 infection. Yet, the mechanism underlying this regulatory role has not been elucidated. The PI3K/Akt pathway is involved in various cellular processes and exerts its function through the activation of several downstream effectors. Among them, nuclear factor kappa B (NFκB) transcription factor is involved in inflammation, survival and apoptosis. In this study, we investigated the role of NFκB as a potential downstream mediator of signals through the PI3K/Akt cascade, in regulating CVB3‐induced cellular injury. We report that CVB3 infection induces the translocation of NFκB into the nucleus of infected cells. Inhibition of the PI3K/Akt pathway markedly decreases virus‐induced NFκB activation. Further, NFκB inhibition significantly suppresses host viability, suggesting a pro‐survival role for NFκB. Short‐term treatment of cells with tumour necrosis factor‐α (TNF‐α), a potent activator of NFκB, promotes host cell viability without affecting virus replication. However, a prolonged treatment has a detrimental effect on cells, indicating the existence of a delicate balance between the anti‐ and pro‐apoptotic roles of TNF‐α in the setting of CVB3 infection.

Coronary artery disease is associated with the ratio of apolipoprotein A-I/B and serum concentration of apolipoprotein B, but not with paraoxonase enzyme activity in Iranian subjects

To determine the association of serum apolipoprotein (apo) A-I and B concentrations, and paraoxonase (PON) high-density lipoprotein (HDL) associated enzyme activity with angiographically determined coronary artery disease (CAD) in Iranian diabetic and non-diabetic CAD patients and non-diabetic control subjects, 251 subjects aged 30-70 years, who underwent their first coronary angiography were matched and randomly assigned into three groups: CAD(+)DM(+), CAD(+)DM(-), and CAD(-)DM(-) (control). Stenosis of > or =50% in one or more coronary arteries was classified as CAD(+). CAD(-) was defined as a maximum stenosis of 10% in any coronary artery. Fasting serum concentrations of cholesterol (TC), triglycerides (TGs), LDL-C, HDL-C, apo A-I/B and PON activity were determined. Apolipoprotein concentrations were measured in a fasting serum sample by immunoturbidometric assay and paraoxonase/arylesterase activities by spectrophotometric assay of p-nitrophenol/phenol production following addition of paraoxon/phenylacetate. Information concerning non-lipid risk factors were collected by questionnaires. No significant difference was observed in HDL-C, LDL-C, apo A-I, and PON/arylesterase activity between the study groups. The values of TC (213+/-38 vs 196+/-45, P<0.05), TGs (209+/-187 vs 151+/-113, P<0.01), apo B (99+/-22 vs 96+/-24, P<0.0001), TC/HDL-C (4.8+/-1.5 vs 4.0+/-1.3, P<0.001) and LDL-C/HDL-C (2.9+/-1.1 vs 2.4+/-1.1, P<0.05) were higher and apo A-I/B (1.7+/-0.4 vs 2.0+/-0.6, P<0.01) was lower in CAD(+)DM(+) patients than in control subjects. In CAD(+)DM(-) group, only the level of apo B (96+/-24 vs 85+/-18, P<0.01), and the ratio of apo A-I/B (1.8+/-0.4 vs 2.0+/-0.6, P<0.01), were significantly higher than those of control group. On multiple logistic regression analysis, the best markers for discrimination between CAD(+) groups and CAD(-) control subjects were the ratio of apo A-I/B in diabetic and apo B in non-diabetic patients. The results suggest that in Iranian diabetic and non-diabetic patients with CAD the concentration of apolipoproteins are better markers than traditional lipid parameters in discriminating between CAD(+) and CAD(-) subjects. Lack of significant difference in PON activity between CAD patients and CAD(-) controls supports the concept of interethnic variability in PON polymorphism and unimodal distribution of its activity in non-Europid populations observed in other studies.