Vinod K Shah

The clinical effectiveness of Warfarin is established. Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability of Warfarin dosage is largely genetically determined, and it can be partly explained by the C1173T and G-1639A polymorphisms of vitamin K epoxide reductase complex subunit 1 (VKORC1) which is its target and *2 and *3 allele of Cytochrome P-450 (CYP) 2C9 [CYP2C9] enzyme which metabolizes to its inactive form. Aim of the present study was to determine the prevalence of these variant alleles known to influence the warfarin dose and correlate genotypes with the average INR as well as mean dose of Warfarin required to maintain INR, in the Indian population. Study population included 100 healthy individuals and 83 patients operated for Aortic or Mitral Valve replacement and prescribed warfarin thereafter. Of these 83 patients records of INR for the period of six months and mean maintenance dose (stable therapeutic dose) of warfarin required to maintain INR were available for 26 patients. For the remaining patients, apart from their demographic data only maintenance dose was available. Genotyping of above mentioned polymorphisms was carried out by using PCR-based restriction digestion method. Although less as compared to wild type alleles, the variant alleles of CYP2C9*2 and *3 as well as of VKORC1 polymorphisms (C1173T and G-1639A) were observed in our study population. Mean maintenance dose (mg/day) of Warfarin was in the decreasing order of patients as compared to the wild type genotypes for all above mentioned polymorphisms. The decrease in the dose was in the order of heterozygotes for CYP2C9*2 to CYP2C9*3 to C1173T and G-1639A of VKORC1 (P<0.001). There was significant correlation (r=0.51, P<0.001) observed between the dose estimated by pharmacogenetic algorithm of Sconce et al (2005) and actual stable therapeutic dose. INR was high for mutant variants (3.8 to 4) after first dose suggesting that they require decreased mean daily dose of Warfarin. In the present study the effect of CYP2C9*2, *3, and VKORC1 (C1173T and G-1639A) genotypes on warfarin dose was observed. However, the genotyping has not been incorporated into daily practice. Perhaps more practical approach would be for clinicians to take genotype information into consideration along with other factors when dosing warfarin.

Prerequisites for a biomarker to enter clinical routine in acute coronary syndrome (ACS) are several folds. The most important features are that the biomarker can be offered on a routine platform to diagnose and identify high-risk individuals of ACS, provide higher sensitivity and specificity than the ECG in predicting outcome, and should have impact on therapeutic decision making. In recent years, a deeper understanding of the pathobiology of the atherothrombosis as the underlying mechanism of ACS has directed scientific studies towards the evaluation of certain pathogenic components involved in the process as potential biomarkers for the clinical settings of ACS. Under investigations are markers to identify early injury/ischemia, markers for detection of vulnerable plaque, its disruption, of thrombosis and markers for inflammation. The aim of this paper is to review the current contribution of biochemical markers to clinical cardiology and also to discuss some important developments in this field.

Stem cell therapy for conditions characterized by myocyte loss in myocardial infarction and heart failure is intuitively appealing. Stem cells from various sources, including heart itself in preclinical and animal studies, have shown the potential to improve the function of ventricular muscle after ischaemic injury. The clinical experience from worldwide studies have indicated the safety profile but with modest benefits. The predominant mechanisms of transplanted cells for improving cardiac function have pointed towards paracrine effects rather than transdifferentiation into cardiomyocytes. Thus, further investigations should be encouraged towards bench side and bedside to resolve various issues for ensuring the correct type and dosing of cells, time, and method of delivery and identify correct mechanism of functional improvement. An interdisciplinary effort at the scientific, clinical, and the government front will bring successful realization of this therapy for healing the heart and may convert what seems now a Pandora's Box into a Pot of Gold.

To analyze soluble levels ofcell adhesion molecules (CAM) such as Intercellular CAM (ICAM), vascular CAM (VCAM-1), platelet endothelial CAM (PECAM-1), Endothelial (E)-selectin, and Platelet (P)-selectin in coronary artery disease patients and correlate with degree of severity of the disease. Study population included patients who suffered myocardial infarction at presentation (N=49) and those with unstable angina (N=79) and stable angina (N=14). Soluble levels of CAMs were measured by ELISA. At acute event in AMI patients, there was significant rise of soluble (s) E-selectin (4.5 fold, P = 0.001), sVCAM-1 (65.6%, p = 0.001), sPECAM-1 (46.2%, p = 0.02), sP-selectin (42.7%, p = 0.001) and sICAM-1 (20.1%, p = 0.003) as compared to controls. In unstable angina group as compared to AMI there was significant decrease in the levels observed in, sE-selectin (62.7%, p = 0.001), sPECAM-1 (47.5%, p = 0.001) as well as sVCAM-1 (17.9%, p = 0.04) and insignificant decrease with respect to sICAM-1 and no change with respect to sP-selectin levels. Stable angina group as compared to unstable angina group demonstrated no significant difference in sCAMs and the trend with AMI group was similar to that seen between unstable angina and AMI group. Significantly elevated levels of sE-selectin, sVCAM-1 and sPECAM-1 at acute event suggest them to be causal molecules as well as markers of plaque destabilization. Levels of sP-selectin in stable angina were similar to that observed in AMI and unstable angina groups suggesting elevated platelet activation in stable angina as well.

Matrix metalloproteinases (MMPs) contribute both in the formation as well as in the destabilization of atherosclerotic plaque. In the present study we analyzed circulating levels of MMP-7 that acts on chondroitin sulphate a proteoglycan that is particularly abundant in atherosclerotic plaque and MMP-8 which acts on Type I collagen, the synthesis and degradation of which is important for stability of the plaque and correlate with the degree of severity of coronary artery disease (CAD). Circulating levels of MMP-7 and MMP-8 and tissue inhibitors of MMP (TIMP) -1 and TIMP-2 were analysed by Enzyme Linked ImmunoSorbent Assay (ELISA7rpar;, in patients with acute myocardial infarction (AMI) at presentation (N=48), acute coronary syndrome (ACS) group (N=227rpar; (on treatment) and stable angina group (N=17) (on treatment). There was significant rise in MMP-8 (88.23%, P=0.001), in AMI group which decreased in ACS treated group 7lpar;15.9%, non-significant) as compared to controls. There was increasing trend of MMP-7 in AMI and ACS group and strong correlation with hsCRP. MMP-7 predominated in stable angina group. There was significant decrease in TIMP-2 in AMI group and TIMP-1 and TIMP-2 in ACS and stable angina group as compared to controls. Significant increase in MMP-8 and decrease in TIMP-2 during acute stage of AMI suggests MMP-8 and TIMP-2 are markers for vulnerable plaque independent of hsCRP for AMI. MMP-7 was found to be elevated in stable angina patients and was correlated with hsCRP at acute phase of AMI suggesting persistent at all stages of CAD.

To assess the safety and feasibility of transfusing autologous bone marrow stem cells (ABMSC) into the culprit coronary artery after an acute anterior wall myocardial infarction (MI) and further to see the ability of ABMSC to promote improvement in Left Ventricular lsqb;LV] function at follow-up. In an ongoing phase I clinical trial, twenty-seven patients of uncomplicated acute anterior wall MI treated as per the current practicing guidelines have been included. Among these, seventeen patients received intra-coronary unfractionated ABMSCs from 77ndash;15 days after acute MI (ABMSC group) and ten patients acted as controls. All the procedures carried out were without any complications. After 6 months, cardiac function analysis of ten patients from the ABMSC group by LV angiography and Cardiac Magnetic Resonance Imaging (MRI) demonstrated a significant rise of 12.74% (p = 0.001) and 7.1% (p = 0.001), respectively in the LV ejection fraction [LVEF]. There was an improvement in the LV systolic function wherein LV end systolic volume (LVESV) decreased significanty to 28.75% (p = 0.010) and 16.49% (p = 0.022) by LV angiography and cardiac MRI, respectively. LV end diastolic volume (LVEDV) decreased marginally by LV angiography (p = 0.548) and by cardiac MRI (p = 0.514). Five patients of the control group by LV angiography demonstrated non-significant rise of 1.0% (p = 0.706) in LVEF, 12.79% (p = 0.332) in LVEDV and 22.56% (p = 0.308) in LVESV. By cardiac MRI controls demonstrated significant rise in EF of 3.2% (p = 0.0367rpar; but non-significant fall of only 2.32% (p = 0.812) in LVEDV and 6.47% (p 7equals; 0.508) in LVESV. This study shows that intracoronary infusion of ABMSC is safe and feasible after acute MI and shows a favourable trend towards the improvement of LV function and prevention of ventricular remodeling which determines long-term survival.