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1.  Usefulness of C-Reactive Protein as a Marker for Prediction of Future Coronary Events in the Asian Indian Population: Indian Atherosclerosis Research Study 
Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.
PMCID: PMC2989863  PMID: 21152190
2.  Chronic infections & coronary artery disease with special reference to Chalmydia pneumoniae 
Background & objectives:
Studies on cardiovascular diseases (CVD) in India have shown about 10-20 per cent of cases with no obvious risk factors, raising a suspicion of infections as a cause. There is a paucity of data on this possible role of infections. This study was, therefore, undertaken to find out the association between infection due to Chlamydia pneumoniae and other organisms and coronary artery disease (CAD).
Patients with CAD were selected in group I (acute myocardial infarction, AMI) and group III (patients undergoing coronary artery bypass graft (CABG) surgery), and normal controls in group II. Routine biochemical, haematological and inflammatory tests [C-reactive protein (CRP), total leucocyte count (TLC), fibrinogen, ESR], serodiagnostic tests for IgA and IgG antibodies to C. pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), Mycoplasma pneumoniae and Parvovirus B-19 by ELISA kits, C. pneumoniae antigen by microimmunofluorescence and PCR from endothelial tissue obtained at CABG were carried out. Aortic punch biopsies were done in patients who underwent CABG.
Acute MI patients had a significantly higher association with accepted cardiac risk factors, lipid profile, inflammatory and thrombogenic tests. IgG and IgA antibodies levels against C. pneumoniae were not significantly different in the controls as against the AMI group. However, C. pneumoniae antigen seropositive group had significant association with HDL cholesterol, lipid tetrad index (P<0.001) and with triglycerides. Parvovirus B antigen was detected in 8.3 per cent of tissue specimens by PCR and of 44 patients with AMI (6.8%) were also positive for parvovirus B-19 IgG antibodies.
Interpretation & conclusions:
There was no direct evidence of the involvement of C. pneumoniae and other infective agents and viruses in CAD. It is possible that such infections produce an indirect adverse effect on the lipid profile.
PMCID: PMC3336855  PMID: 22446866
Chlamydia pneumoniae; chronic infections; coronary artery disease
3.  Elevated plasma platelet-activating factor acetylhydrolase activity and its relationship to the presence of coronary artery disease* 
Platelet-activating factor acetylhydrolase (PAF-AH) is a circulating enzyme that has an important role in the development of coronary artery disease (CAD). The correlations between PAF-AH and CAD are controversial. Furthermore, the differences of the enzyme levels between patients with stable and unstable CAD are not fully determined. The purpose of this study was to evaluate plasma PAF-AH levels and its association with the presence of CAD and some clinical risk factors in the patients.
This case-control study included 50 control subjects without CAD, 50 stable CAD patients and 50 unstable CAD patients with angiographically documented CAD. Plasma PAF-AH activity was determined by a commercial kit. The inflammatory markers, high sensitivity C-reactive protein (hsCRP) and oxidized low density lipoprotein (ox-LDL), and lipid profile were also measured. Comparisons of biochemical risk factors among all groups were performed by one way ANOVA. The association of PAF-AH activity with the presence of CAD was analyzed by multiple logistic regression.
Plasma PAF-AH activity levels were higher in unstable CAD patients (0.040 ± 0.012 μmol/min/ml) than in stable CAD patients (0.032 ± 0.010 μmol/min/ml) and control subjects (0.026 ± 0.009 μmol/min/ml) (p < 0.01). Plasma PAF-AH activity was also independently associated with the presence of CAD (p< 0.01).
Plasma PAF-AH activity levels were highly increased in unstable and stable CAD patients as compared to control subjects and may be a useful biomarker for CAD prediction.
PMCID: PMC3214380  PMID: 22091291
Platelet-Activating Factor Acetylhydrolase; Stable Coronary Artery Disease; Unstable Coronary Artery Disease
4.  A preliminary study of inflammatory markers in non-alcoholic steatohepatitis patients 
The Libyan Journal of Medicine  2010;5:10.3402/ljm.v5i0.5071.
It was reported that C-reactive protein (CRP) levels increase in parallel with the progression of chronic liver diseases, such as chronic hepatitis and liver cirrhosis. Inflammatory markers, such as high sensitive C-reactive protein (hsCRP), ferritin, transferrin, albumin, alpha-1 acid glycoprotein (AAG), alpha-2 macroglobulin (AMG), alpha-1 anti-trypsin (AAT) and lipoprotein a [Lp(a)] were measured in coronary artery disease patients (CAD) and CAD patients with non-alcoholic steatohepatitis (NASH). In the present preliminary study an attempt was made to study whether there is an increase in the levels of CRP in CAD patients associated with NASH. CAD patients showed an increase in CRP and serum ferritin levels. In CAD patients with NASH along with an increase in the levels of serum ferittin (p<0.001), the levels of serum AMG and ceruloplasmin (CP) were also increased (p<0.01). The CAD patients with NASH had a higher proportion of diabetes, hypertension and dyslipidaemia compared to CAD patients. But how this difference contributes to the elevation in acute inflammatory markers particularly AMG and CP levels in CAD patients with NASH cannot be explained. This study shows that a substantial number of CAD patients may be associated with NASH. Non-invasive simple parameters that reflect the degree of inflammation and fibrosis of the liver in patients with NASH would facilitate improved understanding and treatment of the disease. Further studies may be necessary to evaluate the percentage of NASH patients progressing to CAD.
PMCID: PMC3071177  PMID: 21483580
C-reactive protein; alpha-1 acid glycoprotein; alpha 2 macroglobulin; alpha 1 anti trypsin; lipoprotein a; coronary artery disease; non-alcoholic steatohepatitis
Atherosclerosis  2012;223(1):230-234.
Apolipoprotein E (apoE) has been implicated as conveying increased risk for coronary artery disease (CAD). Previous studies suggest a role of apoE as a modulator of immune response and inflammatory properties. We hypothesized that the presence of apo E4 is associated with an increased inflammatory burden in subjects with CAD as compared to subjects without CAD.
ApoE genotypes, systemic (C-reactive protein [CRP], fibrinogen, serum amyloid-A [SAA]) and vascular inflammatory markers (Lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) were assessed in 324 Caucasians and 208 African Americans, undergoing coronary angiography.
For both ethnic groups, Lp-PLA2 index, an integrated measure of Lp-PLA2 mass and activity, increased significantly and stepwise across apoE isoforms (P=0.009 and P=0.026 for African Americans and Caucasians respectively). No differences were found for other inflammatory markers tested (CRP, fibrinogen, SAA and PTX-3). For the top cardiovascular score tertile, apo E4 carriers had a significantly higher level of Lp-PLA2 index in both ethnic groups (P=0.027 and P=0.010, respectively).
The presence of the apo E4 isoform was associated with a higher level of Lp-PLA2 index, a marker of vascular inflammation. Our results suggest that genetic variation at the apoE locus may impact cardiovascular disease risk through enhanced vascular inflammation.
PMCID: PMC3389284  PMID: 22632920
ApoE genotype; inflammation; coronary artery disease; ethnicity
6.  A retrospective case-control study of modifiable risk factors and cutaneous markers in Indian patients with young coronary artery disease 
JRSM Cardiovascular Disease  2012;1(3):cvd.2012.012010.
Indians have the highest risk rates for coronary artery disease (CAD) among all ethnic groups. There is a paucity of data on the risk factors and clinical markers associated with premature CAD. We aimed to determine whether young CAD is due to preventable lifestyle-related factors and cutaneous clinical markers are useful in identifying at-risk patients.
Single-centre retrospective study.
Tertiary care center.
A total of 292 patients (age ≤40 years) who presented with acute CAD between January 2005 and June 2009 and 92 age, and gender-matched controls.
Major outcome measures
Details of smoking, family history of premature CAD, waist size, blood sugar and lipid profile. Clinical evidence of arcus juvenilis, premature greying of hair and premature baldness sought.
Dyslipidaemia (91%), smoking (74.3%), low high-density lipoprotein cholesterol (HDL-C) (68.9%), central obesity (47.7%) and greying of hair (34.9%) were the most commonly associated factors. Compared with male patients, females had greater prevalence of dyslipidaemia, low HDL-C, central obesity, hypertension, diabetes and family history of premature CAD. The presence of cutaneous markers was significantly associated with premature CAD.
CAD in young Indian people is multifactorial; dyslipidaemia, low HDL-C, smoking, hypertension, central obesity and family history of premature CAD are the most common risk factors. Smoking in men and central obesity in women are the most prevalent factors. Clinicians should be highly suspicious of patients with presence of cutaneous markers, and they should be followed intensively for lifestyle modifications.
PMCID: PMC3738325  PMID: 24175065
7.  Relationship of high sensitivity C-reactive protein with presence and severity of coronary artery disease  
Pakistan Journal of Medical Sciences  2013;29(6):1425-1429.
Objective: Inflammation plays a key role in the pathogenesis of atherosclerosis. This study aimed to assess the relationship of serum inflammatory marker high sensitivity C Reactive protein (hsCRP), with the presence and severity of angiographically evaluated coronary artery disease (CAD).
Methods: This study was conducted at departments of physiology and cardiology, College of Medicine & King Khalid University Hospital, King Saud University, Riyadh from August 2009 to March 2012. Eighty seven patients (57 males and 30 females) with angiographically evaluated CAD were studied. In all these patients CAD severity was assessed by Gensini scoring and vessel scoring. Control group consisted of 29 healthy subjects (17 males and 12 females). Fasting venous blood samples were analyzed for lipid profile and high sensitivity C-reactive protein (hsCRP).
Results: There were non-significant differences in age, weight and BMI among healthy subjects and CAD patients. Comparison of lipid profile between control and CAD patients showed that CAD patients had significantly higher TG and significantly lower HDL levels compared to control subjects. CAD patients presented with significantly higherhsCRP levels than controls. Linear regression analysis between hsCRP and CAD severity determined by Gensini scores showed a significant positive correlation (r=0.423, p=0.018). Triple vessel disease patients had significantly higher hsCRP levels than one vessel and two vessel disease, while the difference was non significant between one and two vessel disease groups.
Conclusions: These results suggest that patients with angiographically evaluated CAD have significantly higher levels of hsCRP levels compared to healthy individuals and are correlated with the presence & severity of CAD.
PMCID: PMC3905368  PMID: 24550967
High sensitivity C-reactive protein; Coronary artery disease; Gensiniscore; Vessel scores; Angiography
8.  Emerging relations between infectious diseases and coronary artery disease and atherosclerosis 
Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.
PMCID: PMC1232552  PMID: 10920732
9.  Normal levels of inflammatory markers in treated patients with familial hypercholesterolaemia: a cross-sectional study 
JRSM Cardiovascular Disease  2012;1(3):cvd.2012.012011.
To assess the relationship of levels of inflammatory risk markers to presence of clinical coronary artery disease (CAD) in patients with treated heterozygous familial hypercholesterolaemia.
A cross-sectional study of patients on the Simon Broome Familial Hyperlipidaemia Register.
Six hospital outpatient clinics in the UK.
A total of 211 men and 199 women with heterozygous familial hypercholesterolaemia.
Main outcome measures
Analysis of conventional risk factors and concentrations of high-sensitivity C-reactive protein (hsCRP), lipoprotein(a), serum intercellular adhesion molecule (sICAM), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (LpPLA2) mass.
CAD was present in 104 men and in 55 women; the mean ages of onset were 43.1 and 46.5 years, respectively. On univariate analysis there was a positive relationship of CAD with age, male sex, smoking, IL-6 and sICAM, and an inverse relationship with low-density lipoprotein (LDL) and LpPLA2. On multivariate analysis, age, smoking, low LDL and low LpPLA2 were associated with CAD. When LpPLA2 values were adjusted for apoB and aspirin usage, there was no significant difference between those with and without CAD. Only age and smoking were independently associated with CAD in men, and IL-6 and lipoprotein(a) in women.
Although on univariate analysis inflammatory marker levels were associated with CAD in these patients, the majority of the associations, including that for hsCRP, disappeared when corrected for smoking and apoB. This may be because atherosclerotic plaques in these statin-treated patients were quiescent or an effect of aspirin usage. In this observational study newer risk markers were not usefully associated with the presence or absence of symptomatic CAD.
PMCID: PMC3738326  PMID: 24175066
10.  Lipoprotein-Associated Phospholipase A2, C-Reactive Protein, and Coronary Artery Disease in Individuals with Type 1 Diabetes and Macroalbuminuria 
Given the paucity of data in type 1 diabetes concerning lipoprotein-associated phospholipase A2 (Lp-PLA2), we examined its prospective relationship with coronary artery disease (CAD), as well as effect modification by C-reactive protein (CRP) and haptoglobin genotype, in individuals with type 1 diabetes who are at an increased risk for CAD due to also having macroalbuminuria (n=96).
Although Lp-PLA2 activity was univariately predictive of CAD (HR=1.54 per sd, p=0.009), this relationship was not significant after covariate adjustment (p=0.59). There was a significant interaction between Lp-PLA2 and CRP (p=0.02), ie. those with both markers greater than median level were more likely to have a CAD event than those persons with low levels of both (HR=2.89, p=0.06). When stratified by haptoglobin genotype, Lp-PLA2 was predictive of CAD in persons with the 2/1 (HR=2.40, p=0.05), but not 2/2 (HR=0.66, p=0.27), genotype.
The association between Lp-PLA2 activity and CAD differs by CRP and haptoglobin genotype in this group of persons with type 1 diabetes and macroalbuminuria.
PMCID: PMC2858394  PMID: 20368232
Lp-PLA2; Type 1 Diabetes; Macroalbuminuria; Coronary Artery Disease; C-Reactive Protein; Haptoglobin Genotype
11.  Premature Coronary Artery Disease in Indians and its Associated Risk Factors 
Of particular concern to India is not only the high burden of cardiovascular diseases (CVDs), but also the effects of these diseases on the productive workforce aged 35–65 years. Heart diseases are rising in Asian Indians 5–10 years earlier than in other populations around the world. The mean age for first presentation of acute myocardial infarction in Indians is 53 years. Coronary artery disease (CAD) that manifests at a younger age can have devastating consequences for an individual, the family, and society. Prevention of these deaths in young people is a nation's moral responsibility. A strategy involving prevention of CVDs long before their onset will be more cost-effective than providing interventions at a stage when the disease is well established. We review the rising trends in CAD with particular emphasis on prevalence of premature CAD and the associated risk factors in young Indian CAD patients. Action strategies to reduce the risk are suggested.
PMCID: PMC1993956  PMID: 17319107
premature CAD; prevalence; risk factors
12.  Inflammation but Not Endothelial Dysfunction Is Associated with the Severity of Coronary Artery Disease in Dyslipidemic Subjects 
Mediators of Inflammation  2009;2009:469169.
Introduction. Endothelial dysfunction and inflammation play a key role in the development of atherosclerosis. The present study evaluated endothelial function, inflammatory parameters, and carotid intima-media thickness (IMT) in dyslipidemic patients with or without coronary artery disease (CAD). Methods. Metabolic profile and inflammatory parameters were determined in dyslipidemic patients with (+CAD, n = 33) and without (−CAD, n = 69) symptomatic CAD. Endothelial function was evaluated by flow mediated dilatation (FMD) and plasma concentration of nitrites and nitrates. Carotid IMT was measured by ultrasound. Results. No significant differences were observed in anthropometric hemodynamic or metabolic parameters between the groups. After adjusting by age and medication usage, some inflammatory markers were significantly higher in +CAD; however no significant differences in FMD or plasma levels of nitrites were observed. Conclusions. In subjects with dyslipidemia, the presence of CAD is associated with an elevation of certain inflammatory markers and carotid IMT but not with further endothelial dysfunction.
PMCID: PMC2702507  PMID: 19584917
13.  Increased serum myeloid-related protein 8/14 level is associated with atherosclerosis in type 2 diabetic patients 
Myeloid-related protein 8/14 (MRP8/14) is a stable heterodimer formed by two different calcium-binding proteins (MRP8 and MRP14). Studies have identified that MRP8/14 regulates vascular inflammation and serves as a novel marker of acute coronary syndrome. In this study, we evaluated the correlation between serum levels of MRP8/14, hsCRP, endogenous secretory receptor for advanced glycation end-products (esRAGE) and the occurrence of coronary artery disease (CAD), or carotid intima-media thickness (IMT) when CAD was not yet developed in diabetic patients.
Serum levels of MRP8/14, esRAGE and hsCRP were measured in 375 diabetic patients. Then the results of those who had CAD were compared against who had not. Also, we investigated the associations between above-mentioned indicators and IMT of subjects without CAD in both diabetic group and non-diabetic one.
Serum MRP8/14 was significantly higher in CAD than in non-CAD group (9.7 ± 3.6 ug/ml vs. 8.2 ± 3.0 ug/ml, P < 0.001). It was associated with severity of CAD (r = 0.16, P = 0.026). In non-CAD group, MRP8/14 was associated with IMT in patients with (r = 0.30, P < 0.001) or without diabetes (r = 0.26, P = 0.015). The areas under the curves of receiver operating characteristic for CAD were 0.63 (95% CI 0.57-0.68) for MRP8/14, 0.76 (95% CI 0.71-0.81) for hsCRP and 0.62 (95% CI 0.56 -0.67) for esRAGE.
In summary, we report that diabetic patients with CAD had elevated plasma MRP8/14 levels which were also positively correlated with the severity of CAD and carotid IMT in patients without clinically overt CAD.
PMCID: PMC3120649  PMID: 21592353
MRP8/14; Diabetes mellitus; Coronary artery disease; Intima media thickness
14.  Interleukin 6 and Atrial Fibrillation in Patients with Coronary Artery Disease: Data from the Heart and Soul Study 
American heart journal  2007;155(2):303-309.
Previous studies suggest that markers of inflammation are elevated in patients with atrial fibrillation (AF). However, because inflammation has been implicated in contributing to risk of both AF and coronary artery disease (CAD), which are often present in the same populations, it is important to control for confounding by the presence of CAD. We therefore examined several biomarkers of inflammation and ultimately genotyped IL-6 polymorphisms in AF patients in a cohort of subjects with known CAD.
We performed a cross-sectional analysis of 971 participants in the Heart and Soul Study, 46 of whom had AF. IL-6, CRP, tumor necrosis factor-α, CD-40 ligand, monocyte chemoattractant protein-1, and fibrinogen levels were measured.
In both unadjusted and adjusted analyses, IL-06 was the only biomarker significantly associated with AF (median IL-6 3.76 pg/ml and 2.52 pg/ml in those with and without AF, respectively, p=0.0005; adjusted odds ratio [OR] 1.77 p=0.032). The IL-6 –174CC genotype was significantly associated with the presence of AF in the adjusted analysis (OR 2.34, p=0.04) and with higher IL-6 levels (p=0.002).
In this cohort of subjects with CAD, AF was significantly associated with elevated IL-6 levels and the IL-6 –174CC genotype. No associations were found with other biomarkers, including CRP. This suggests that IL-6 is a uniquely important mediator in the pathophysiology of AF.
PMCID: PMC2247366  PMID: 18215601
15.  Silent myocardial ischaemia and long-term coronary artery disease outcomes in apparently healthy people from families with early-onset ischaemic heart disease 
European Heart Journal  2011;32(22):2766-2772.
A family history of premature coronary artery disease (CAD) in an apparently healthy individual conveys an increased risk of future CAD. The extent to which inducible myocardial ischaemia exists and is associated with long-term incident CAD in apparently healthy siblings of early-onset CAD patients is unknown.
Methods and results
Asymptomatic siblings (n = 1287, aged 30–59 years) of patients with onset of CAD <60 years of age underwent risk factor screening and maximal graded treadmill testing with nuclear perfusion imaging, and were followed for incident CAD events for up to 25 years. Incident CAD occurred in 15.2% of siblings (68% acute coronary syndromes); mean time to first CAD event was 8.2 ± 5.2 years. Inducible ischaemia was highly prevalent in male siblings (26.9%), and was independently associated with incident CAD. Male siblings ≥40 years of age who were low or intermediate risk by traditional risk assessment, had a prevalence of inducible ischaemia and a 10-year risk of incident CAD that were near or ≥20%. In female siblings ≥40 years of age, the presence of inducible ischaemia was also independently associated with incident CAD, but the prevalence of inducible ischaemia was markedly lower, as was the risk of incident CAD.
Inducible ischaemia is highly prevalent in male siblings, suggesting a previously unknown long quiescent period before the occurrence of a clinical event. While inducible ischaemia is associated with a worse prognosis, male siblings with negative tests still bear a high risk of incident disease, such that we propose that in male siblings over 40 years of age, aggressive primary prevention interventions be instituted without nuclear testing. For women, the prevalence of ischaemia was so low as to not warrant screening, but the incidence of CAD was high enough to at least warrant lifestyle interventions.
PMCID: PMC3214725  PMID: 21785111
Ischaemia; Coronary artery disease; Outcomes; Asymptomatic; Primary prevention; Risk assessment; Family; Sibling
16.  The (G>A) rs11573191 Polymorphism of PLA2G5 Gene Is Associated with Premature Coronary Artery Disease in the Mexican Mestizo Population: The Genetics of Atherosclerotic Disease Mexican Study 
BioMed Research International  2014;2014:931361.
Coronary artery disease (CAD) is a multifactorial disorder that results from an excessive inflammatory response. Secretory phospholipase A2-V (sPLA2-V) encoded by PLA2G5 gene promotes diverse proinflammatory processes. The aim of the present study was to analyze if PLA2G5 gene polymorphisms are associated with premature CAD. Three PLA2G5 polymorphisms (rs11573187, rs2148911, and rs11573191) were analyzed in 707 patients with premature CAD and 749 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis. Under dominant, recessive, and additive models, the rs11573191 polymorphism was associated with increased risk of premature CAD (OR = 1.51, Pdom = 3.5 × 10−3; OR = 2.95, Prec = 0.023; OR = 1.51, Padd = 1.2 × 10−3). According to the informatics software, this polymorphism had a functional effect modifying the affinity of the sequence by the MZF1 transcription factor. PLA2G5 polymorphisms were in linkage disequilibrium and the CGA haplotype was associated with increased risk of premature CAD (OR = 1.49, P = 0.0023) and with hypertension in these patients (OR = 1.75, P = 0.0072). Our results demonstrate the association of the PLA2G5 rs11573191 polymorphism with premature CAD. In our study, it was possible to distinguish one haplotype associated with increased risk of premature CAD and hypertension.
PMCID: PMC4052156  PMID: 24959594
17.  Altered fibrin clot structure/function and FXIII Leu34 genetic variant in patients with premature coronary artery disease 
Thrombosis and Haemostasis  2011;106(3):511-520.
Abnormal plasma fibrin architecture is a major determinant of both premature coronary artery disease (CAD) and hypofibrinolysis. The presence of the FXIIIVal34Leu genetic variant increases and accelerates fibrin stabilization. Its association with premature CAD remains controversial.
To evaluate fibrin clot structure/function in patients with premature CAD compared to healthy controls and whether the presence of the FXIII Val34Leu variant is an independent correlate of both impaired fibrinolysis and premature CAD.
Fibrin phenotype and FXIII Val34Leu genetic variant were determined in a cohort of 242 young patients (<45 years) who survived an MI and compared to 242 healthy controls matched for age and gender. Fibrin clot stiffness (elastic modulus) and response to rt-PA mediated fibrinolysis (clot lysis time and fibrinolysis rate) were measured using the Hemodyne analyser and by confocal microscopy. The effect of FXIII Val34Leu on long term survival was also evaluated.
CAD patients produced stiffer fibrin clots as compared to healthy controls (24.7±16 vs. 13.6±6 kdynes/cm2; p<0.0001) and displayed a reduced response to fibrinolysis with longer clot lysis time (16.5±12 vs. 10±7 min; p<0.0001) and lower fibrinolysis rate (8.3±7. vs. 14.7±19 sec−1×10−4; p<0.0001). Factor XIII Val34Leu presence led to a stepwise decrease in fibrinolysis rate with a gene dose effect in both patients (9.4±8 vs. 6.9±7 vs. 5.5±4 sec−1×10−4, for wildtype, heterozygous and homozygous, respectively, p value for all =0.02) and healthy controls, suggesting an effect independent from CAD. A similar impact of the Factor XIII Val34Leu substitution was observed on clot lysis time. Increased clot stiffness and hypofibrinolysis were both independent correlates of premature CAD. Factor XIII Val34Leu presence was neither protective of premature CAD (adjOR 0.83 [0.49–1.4] nor did it impact long term clinical outcome during a median follow-up of 6.3 years (±2.4).
Stiff fibrin that is more resistant to fibrinolysis is a major determinant of premature CAD. Presence of the factor XIII Leu34 genetic variant provides a pharmacogenetic resistance to fibrinolysis ex-vivo but neither relates to premature CAD nor to recurrent acute coronary events.
PMCID: PMC3343691  PMID: 21800001
Atherothrombosis; Coronary Disease; Factor XIII Val34Leu; Fibrin structure; Fibrinogen; Hypofibrinolysis; Pharmacogenetic; Thrombosis
18.  Association of constitutional type of Ayurveda with cardiovascular risk factors, inflammatory markers and insulin resistance 
Ayurveda propounds that diseases manifest from imbalance of doshas. There, have been attempts to indicate biochemical basis of constitutional types described in Ayurveda.
The study was intended to assess the association of constitutional types (Prakriti) with cardiovascular risk factors, inflammatory markers and insulin resistance in subjects with coronary artery disease (CAD).
Settings and Design:
Hospital based cross sectional study.
Materials and Methods:
Three hundred patients with CAD >25 years were studied. Assessment of Prakriti was done by using Ayusoft software. Biochemical parameters, inflammatory markers (hsCRP, TNF-alpha and IL-6) and insulin resistance (HOMA-IR) were measured.
Statistical Analysis:
Was done using EPI INFO, version 3.5.3.
Mean age of patients was 60.97±12.5 years. Triglyceride, VLDL and LDL was significantly higher (P<0.0001, P<0.0001 and 0.0355, respectively) and HDL cholesterol (P<0.0001) significantly lower in vatta kapha (VK) Prakriti when compared with other constitution type. VK Prakriti was correlated with diabetes mellitus (r=0.169, P=0.003), hypertension (r=0.211, P≤0.0001) and dyslipidemia (r=0.541, P≤0.0001). Inflammatory markers; IL6, TNF alpha, hsCRP and HOMA IR was highest in VK Prakriti. Inflammatory markers were correlated positively with both VK and Kapha group.
There is strong relation of risk factors (diabetes, hypertension, dyslipidemia), insulin resistance, and inflammatory markers with Vata Kapha and Kapha Prakriti.
PMCID: PMC3487241  PMID: 23125512
Cardiovascular disease; HOMA IR; IL6; Vata Kapha
19.  The Level of hs-CRP in Coronary Artery Ectasia and Its Response to Statin and Angiotensin-Converting Enzyme Inhibitor Treatment 
Mediators of Inflammation  2006;2007:89649.
Background/Aim. Coronary artery ectasia (CAE) was thought of as a variant of atherosclerosis. C-reactive protein (CRP) which is among the most sensitive markers of systemic inflammation, and elevation of systemic and local levels of this inflammatory marker which has been associated with an increased risk for cardiovascular disease in the obstructive coronary artery disease (O-CAD) are well known, but little was known in CAE. The anti-inflammatory effects of statins and the effect of angiotensin-converting enzyme (ACE) inhibitors on endothelial dysfunction are well established in atherosclerosis. The aim of the present study was to investigate CRP level and its response to statin and ACE inhibitor treatment in CAE. Materials and method. We measured serum hs-CRP level in 40 CAE (26 males, mean age: 56.32 ± 9 years) and 41 O-CAD (34 males, mean age: 57.19 ± 10 years) patients referred for elective coronary angiography at baseline and after 3-month statin and ACE inhibitor treatment. Results. Plasma hs-CRP levels were significantly higher in CAE group than O-CAD group at baseline (2.68 ± 66 mg/L versus 1, 64 ± 64, resp., P < .0001). Plasma hs-CRP levels significantly decreased from baseline 3 months later in the CE (from 2.68±0.66 mg/L to 1.2±0.53 mg/L, P < .0001) as well as in the O-CAD group (from 1.64±0.64 mg/L to 1.01±0.56 mg/L, P < .001). Conclusion. We think that hs-CRP measurement may be a good prognostic value in CAE patients as in stenotic ones. Further placebo-controlled studies are needed to evaluate the clinical significance of this decrease in hs-CRP.
PMCID: PMC1804298  PMID: 17497040
20.  Atherothrombosis in South Asians: Implications of Atherosclerotic and Inflammatory Markers 
South Asian immigrants (SAIs) have a higher prevalence of cardiovascular (CV) morbidity and mortality compared with other populations. The major challenge associated with primary prevention of cardiovascular to coronary artery diseases (CAD) in SAIs involves early and accurate detection of CAD in asymptomatic individuals at high cardiovascular risk. Inflammatory processes are now recognized to play a central role in the pathogenesis of atherosclerosis and are found to be associated with future CV risk in a variety of clinical settings. Imaging measures, such as common carotid artery intima-media thickness (CCA-IMT), are being applied as surrogate markers for end-points, such as myocardial infarction (MI) and death in clinical trials. Considering high CAD risk in SAIs and knowing that conventional risk factors may not fully explain the excess CAD risk in this group, studies on the role of CCA-IMT in CAD prediction have been discussed. Also, C-reactive protein (CRP) validity in risk prediction, the role of dysfunctional high density lipoprotein (HDL) as a CAD risk marker in SAIs have been presented.
PMCID: PMC2840871  PMID: 21804640
Coronary artery disease; Cardiovascular disease; Dysfunctional HDL; South Asians; C-reactive protein.
21.  Personalized Medicine in Coronary Artery Disease: Insights From Genomic Research 
Korean Circulation Journal  2009;39(4):129-137.
Prior clinical studies have demonstrated that a family history of coronary artery disease (CAD) is associated with future cardiovascular events. Although there are several Mendelian disorders that are associated with CAD, most common forms of CAD are believed to be multifactorial and the result of many genes with small individual effects. The identification of these genes and their variation would be very helpful for the prediction, prevention, and management of CAD; linkage analysis or candidate gene case-control studies have been largely unsuccessful. On the contrary, recent advances in genomic techniques have generated a large amount of deoxyribonucleic acid (DNA)-based information. The link between CAD and inflammation and biological pathways has been highlighted. In particular, several genome-wide association studies have replicated a novel gene marker on chromosome 9p21. The information gained from genomic studies, in combination with clinical data, is expected to refine personalized approaches to assess risk and guide management for CAD. Genetic risk scores derived from several functional single nucleotide polymorphisms (SNPs) or haplotypes in multiple genes may improve the prediction of CAD. Despite the complexity of CAD genetics, steady progress is expected.
PMCID: PMC2771813  PMID: 19949601
Coronary artery disease; Genomics; Genes; Risk; Polymorphism, single nucleotide
22.  Differential regulation of functional gene clusters in overt coronary artery disease in a transgenic atherosclerosis-hypertensive rat model. 
Molecular Medicine  2002;8(7):367-375.
BACKGROUND: Human acute coronary syndrome refers to the spectrum of clinical manifestations of overt coronary artery (CAD) disease characterized by atherosclerotic plaque destabilization and resultant myocardial injury. Typically studied as distinct pathologies, emerging pathogenic paradigms implicate multiple processes beyond thrombosis and ischemic cell injury respectively, with significant pathway overlap involving inflammation, apoptosis, matrix degradation, and oxidative stress. However, all these pathways have also been implicated in still-quiescent coronary plaque progression, thus making it harder to pinpoint the turnkey events leading to overt-CAD. Analysis of transcription profiles could identify a working framework of pathogenesis distinguishing overt-CAD. MATERIALS AND METHODS: We investigated the transcription profile associated with overt-coronary artery disease (CAD), in contrast to quiescent-CAD and attenuated, quiescent-CAD using the Tg 53 transgenic atherosclerosis-hypertensive rat model, which exhibits end-stage coronary heart disease simulating human acute coronary syndromes. Using a rat-specific known-gene oligonucleotide array, twice corroborated transcription profiles from four individual Tg 53 rats exhibiting overt-CAD were analyzed and contrasted to transcription profiles of age-matched Tg 53 rats with quiescent-CAD (pooled n = 4) and attenuated, quiescent-CAD (pooled n = 4). RESULTS: Tg 53 male rats with overt-CAD exhibited distinct transcription profiles compared with both quiescent-CAD control groups. Functional gene cluster analysis detects upregulation of genes involved in inflammation (interleukin-1, interleukin-18, Fc gamma II receptor, thyrotropin releasing hormone), matrix balance (membrane type metalloproteinase, TIMP-1, lysyl oxidase), oxidized LDL entry (endothelial oxLDL receptor), which contrast deinduced gene clusters involved in angiogenesis, proliferation, metabolism, ion transport and adrenergic receptors. CONCLUSION: The data demonstrate that transcriptionally mediated events distinguish the onset of overt-CAD and identify a first list of putative "turnkey" genes. This altered molecular framework implies an altered "hardwiring" which a priori would require multifaceted, targeted intervention- currently not implemented to date. Although more studies are necessary, early concordance with current pathogenic paradigms of human coronary plaque destabilization and post-ischemic myocardial response provides translational significance to observations and hypotheses.
PMCID: PMC2040006  PMID: 12393934
23.  Comparison of anti-inflammatory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe 
Statins are frequently administered to reduce low-density lipoprotein cholesterol (LDL-C) and vascular inflammation, because LDL-C and high sensitive C-reactive protein (hs-CRP) are associated with high risk for cardiovascular events. When statins do not reduce LDL-C to desired levels in high-risk patients with coronary artery disease (CAD), ezetimibe can be added or the statin dose can be increased. However, which strategy is more effective for treating patients with CAD has not been established. The present study compares anti-inflammatory effects and lipid profiles in patients with CAD and similar LDL-C levels who were treated by increasing the statin dose or by adding ezetimibe to the original rosuvastatin dose to determine the optimal treatment for such patients.
46 patients with high-risk CAD and LDL-C and hs-CRP levels of >70 mg/dL and >1.0 mg/L, respectively, that were not improved by 4 weeks of rosuvastatin (2.5 mg/day) were randomly assigned to receive 10 mg (R10, n = 24) of rosuvastatin or 2.5 mg/day of rosuvastatin combined with 10 mg/day of ezetimibe (R2.5/E10, n = 22) for 12 weeks. The primary endpoint was a change in hs-CRP.
Baseline characteristics did not significantly differ between the groups. At 12 weeks, LDL-C and inflammatory markers (hs-CRP, interleukin-6, tumour necrosis factor-alpha and pentraxin 3) also did not significantly differ between the two groups (LDL-C: R10 vs. R2.5/E10: -19.4 ± 14.2 vs. -22.4 ± 14.3 mg/dL). However, high-density lipoprotein cholesterol (HDL-C) was significantly improved in the R10, compared with R2.5/E10 group (4.6 ± 5.9 vs. 0.0 ± 6.7 mg/dL; p < 0.05).
Both enhanced therapies exerted similar anti-inflammatory effects under an equal LDL-C reduction in patients with high-risk CAD despite 2.5 mg/day of rosuvastatin. However, R10 elevated HDL-C more effectively than R2.5/E10.
Trial registration
PMCID: PMC3598241  PMID: 23374898
Statin; Secondary prevention; Coronary artery disease
24.  Chlamydia Pneumoniae and Helicobacter Pylori Serology – Importance in Patients with Coronary Heart Disease 
Materia Socio-Medica  2012;24(3):151-156.
Chronic infections in CHD are due to one or both of the organisms Chlamydia pneumoniae and Helicobacter pylori.
To examine the association between serum markers of Chlamydia pneumoniae and Helicobacter pylori infection and markers of myocardial damage. in patients with acute coronary syndrome (ACS), with chronic coronary artery disease (CAD) and in–control group.
Material and methods:
Sera were taken from a total of 153 subjects. Subjects were divided in three groups: 64 patients with ACS; 53 patients with CAD and a group of 35 conditionally healthy individuals. Analysis of patients’ sera for IgG antibodies to H. pylori and markers for myocardial damage was done on the Immulite system. The presence of specific IgG and IgA antibodies to C. pneumoniae was determined with MIF, Sero FIA (Savyon Diagnostics, Israel). Statistical analysis of data was done using the statistical program SPSS (Statistical Package for Social Sciences), version 13.
Results and discussion:
There was a high significant difference in troponin levels between the three groups of subjects (p=0.0000). Levels of creatine kinase isoenzyme (CK-MB) were highest in the ACS group (500.0 ng/mL). There was a statistically significant difference between CG subjects and ACS patients due to more frequent detection of antichlamydial IgA antibodies in patients with acute coronary syndrome. Positive serum immune response for Helicobacter pylori was 17 (53.1%) and 29 (80.6%), respectively.
Increased IgA antibody titers for C. Pneumoniae, increased CRP values as well as classic markers of myocardial damage are risk factors for coronary events.
PMCID: PMC3732349  PMID: 23922522
markers of cardiac damage; chronic infections; Chlamydia pneumoniae and Helicobacter pylori.
25.  Epidemiology of Cardiovascular Disease in Type 2 Diabetes: The Indian Scenario 
Noncommunicable diseases, of which coronary artery disease (CAD) and diabetes top the list, have overtaken communicable diseases with respect to overall mortality, even in developing countries like India. High prevalence rates of diabetes and CAD are seen not only in affluent migrant Indians, but also in those living within the subcontinent. Indeed the epidemic of diabetes and CAD is now spreading to the middle- and lower-income groups in India. The risk for CAD is two to four times higher in diabetic subjects, and in Indians, CAD occurs prematurely, i.e., one to two decades earlier than in the West. Thus there is an urgent need for studies on CAD in diabetic and nondiabetic subjects in India.
The Chennai Urban Population Study, a population-based study in Chennai, in South India, showed a prevalence of CAD of 11%, which is 10 times more than what it was in 1970. Clustering of risk factors for CAD such as hyperglycemia, central body obesity, dyslipidemia, and hypertension tends to occur, and interplay of these risk factors could explain the enhanced CAD risk in Indians. Additionally, low-grade inflammation and a possible inherent genetic susceptibility are other contributing factors. Preventive measures such as lifestyle modification with healthy diet, adequate physical activity, and decrease in stress could help prevent the twin epidemics of diabetes and CAD.
PMCID: PMC2825638  PMID: 20167181
Asian Indians; cardiovascular risk factors; coronary artery disease; South Asians; type 2 diabetes

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