Exploring the association of fibrinogen and CRP with the clinical spectrum of CAD and periprocedural outcomes in patients undergoing percutaneous coronary interventions.

BACKGROUND: The pathophysiology of an atherosclerotic plaque is mediated by the mechanisms involving thrombus formation and systemic inflammation. While C-reactive protein (CRP) levels are useful in predicting a cardiovascular event in intermediate risk population, the usefulness of routinely measuring fibrinogen in patients with acute coronary syndrome (ACS) is debatable. Also, data on the association of these markers with periprocedural outcomes in patients undergoing percutaneous coronary interventions (PCI) is scarce. AIMS: The study aimed to determine whether the levels of fibrinogen and CRP vary across the different spectra of CAD and whether they have any correlation with cardiac Troponin I levels. MATERIALS AND METHODS: A total of 284 patients with coronary artery disease undergoing percutaneous coronary intervention were included in the study. Complete blood count, serum lipid profile, serum CRP, fibrinogen, and troponin I were measured for all patients. RESULTS: Patients with STEMI had significantly higher levels of CRP as compared to those with unstable angina (USA) and chronic stable angina (CSA). Patients presenting with ACS had significantly higher baseline fibrinogen as compared to those with CSA. A significant positive correlation between CRP and admission Troponin I (r = 0.50; P < 0.05) as well as fibrinogen and admission troponin I (r = 0.30; P < 0.05) was observed. The CRP levels were significantly higher in 15 patients with periprocedural MI as compared to those who did not develop periprocedural MI. CONCLUSIONS: : The levels of the markers of inflammation and atherothrombosis vary with presentation across varied spectra of CAD with generally higher levels in acute presentation and in those who develop periprocedural MI.

HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy.

People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs.

Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation.

Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.

Effect of statin on perioperative myocardial injury in isolated valve surgery.

BACKGROUND: Statins have known pleiotropic effects that confer protection from ischemia-reperfusion injury. Because cardiopulmonary bypass is a potentially reversible ischemia-reperfusion sequence, we aimed to assess whether statin loading could help to limit myocardial injury in patients undergoing isolated heart valve replacement under cardiopulmonary bypass. METHODS: One hundred patients with rheumatic valvular heart disease undergoing valve replacement received either a loading dose of rosuvastatin (40 mg initiated 7 days before surgery; loaded group) or no statins (non-loaded group). Cardiac troponin I, creatine kinase MB, and brain natriuretic peptide were measured at 8, 24, and 48 hours postoperatively. The primary endpoint was the extent of perioperative myocardial injury measured by the area under the curve for each biomarker. RESULTS: Despite similar baseline levels, all biomarkers at 8, 24, and 48 h were significantly lower in the loaded group. The area under the curve of each biomarker was significantly lower in the loaded group than in the non-loaded group (troponin I: 31.43 vs. 77.21 ng·h·mL-1, creatine kinase MB 309.31 vs. 429.12 ng·h·mL-1, brain natriuretic peptide 5176.11 vs. 16119.31 pg·h·mL-1, all p < 0.001). The mean changes from baseline to peak levels were also significantly lower in the loaded group. The loaded group had a shorter hospital stay but no significant difference was seen in ventilator time, inotrope time, aortic crossclamp time, cardiopulmonary bypass time, or intensive care unit stay. CONCLUSION: In patients undergoing valve replacement, high-dose statin loading before surgery had a favorable impact on the release kinetics of various cardiac biomarkers.

Statin reload before off-pump coronary artery bypass graft: Effect on biomarker release kinetics.

Objectives: Statins confer protection from ischemia/reperfusion through various pathways including pleiotropic mechanisms. Following chronic administration, activation of intrinsic cellular mechanisms causes attenuation of these pleiotropic effects. Methods: Since coronary artery bypass surgery (CABG) represents a reversible ischemia-reperfusion sequence, we assessed if statin reload is effective in patients undergoing off-pump CABG (n = 100) in limiting myocardial injury. Patients received loading dose of rosuvastatin (40 mg initiated 7 days before surgery) while nonloaded patients continued whatever statin dose they were receiving and served as controls. Cardiac biomarkers (Troponin-I, creatine kinase muscle/brain [CK-MB], and B-type natriuretic peptide [BNP]) were measured at 8, 24, and 48 h postoperatively. The primary end-point was the extent of perioperative myocardial injury (area under the curve [AUC]: AUC of each biomarker). Results: Despite similar baseline levels, all biomarkers at 8, 24, and 48 h were significantly lower in the loaded group. The AUC for each biomarker was also significantly lower in the loaded group (cTnI 37.96 vs. 70.12 ng. hr/ml, CK-MB 229.64 vs. 347.04 ng. hr/ml, and BNP 5257.56 vs. 15606.68 pg. hr/ml, all P < 0.001). Delta cTnI (change from baseline to peak level) (1.00 ± 1.34 vs. 2.25 ± 2.59), delta CK-MB (4.54 ± 5.89 vs. 10.68 ± 9.95), and delta BNP (120.41 ± 172.48 vs. 449.23 ± 790.95) all P < 0.001 were also significantly lower in the loaded group. Those loaded with rosuvastatin had lower inotrope duration (22.9 ± 23.33 vs. 31.26 ± 25.39 h, P = 0.04) and ventilator support time (16.94 ± 6.78 vs. 23.8 ± 20.53 h, P = 0.03). Conclusion: In patients undergoing off-pump CABG, statin reload can "recapture" cardioprotection in patients already on statins with favorable effect on release kinetics of biomarkers and postoperative outcomes.

Gene expression profiling of coronary artery disease and its relation with different severities.

Global gene expression profiling is a powerful tool enabling the understanding of pathophysiology and subsequent management of diseases. This study aims to explore functionally annotated differentially expressed genes (DEGs); their biological processes for coronary artery disease (CAD) and its different severities of atherosclerotic lesions. This study also aims to identify the change in expression patterns of DEGs in atherosclerotic lesions of single-vessel disease (SVD) and triple-vessel disease (TVD). The weight of different severities of lesion was estimated using a modified Gensini score. The gene expression profiling was performed using the Affymetrix microarray platform. The functional annotation for CAD was performed using DAVID v6.8. The biological network gene ontology tool (BiNGO) and ClueGO were used to explore the biological processes of functionally annotated genes of CAD. The changes in gene expression from SVD to TVD were determined by evaluating the fold change. Functionally annotated genes were found in an unique set and could be distinguishing two distinct severities of CAD. The biological processes such as cellular migration, locomotion, cell adhesion, cytokine production, positive regulation of cell death etc. enriched the functionally annotated genes in SVD, whereas, wound healing, negative regulation of cell death, blood coagulation, angiogenesis and fibrinolysis were enriched significantly in TVD patients. The genes THBS1 and CAPN10 were functionally annotated for CAD in both SVD and TVD. The 61 DEGs were identified, those have changes their expression with different severities of atherosclerotic lesions, in which 13 genes had more than two-fold change in expression between SVD and TVD. The consistent findings were obtained on validation of microarray gene expression of selected 10 genes in a separate cohort using real-time PCR. This study identified putative candidate genes and their biological processes predisposing toward and affecting the severity of CAD.

Heart rate manipulation in dilated cardiomyopathy: Assessing the role of Ivabradine.

BACKGROUND: Heart rate (HR) reduction is of benefit in chronic heart failure (HF). The effect of heart rate reduction using Ivabradine on various echocardiographic parameters in dilated cardiomyopathy has been less investigated. METHODS: Of 187 patients with HF (DCM, NYHA II-IV, baseline HR>70/min), 125 patients were randomized to standard therapy (beta blockers, ACEI, diuretics, n=62) or add-on Ivabradine (titrated to maximum 7.5mg BD, n=63). Beta-blockers were titrated in both the groups. RESULTS: At 3 months both groups had improvement in NYHA class, 6min walk test, Minnesota Living With Heart Failure (MLWHF) scores and fall in BNP, however the magnitude of change was greater in Ivabradine group. Those on Ivabradine also had lower LV volumes, higher LVEF (28.8±3.6 vs 27.2±0.5, p=0.01) and more favorable LV global strain (11±1.7vs 12.2±1.1, p=<0.001), MPI (0.72±0.1 vs 0.6±0.1, p=<0.001), LV mass (115.2±30 vs 131.4±35, p=0.007), LV wall stress (219.8±46 vs 238±54) and calculated LV work (366±101 vs 401±102, p=0.05). The benefit of Ivabradine was sustained at 6 months follow up. The % change in HR was significantly higher in Ivabradine group (-32.2% vs -19.3%, p=0.001) with no difference in blood pressure. Resting HR<70/min was achieved in 96.8% vs 27.9%, respectively in the two groups. CONCLUSION: Addition of Ivabradine to standard therapy in patients with DCM and symptomatic HF and targeting a heart rate<70/min improves symptoms, quality of life and various echocardiographic parameters.

The association of polymorphic variants, rs2267788, rs1333049 and rs2383207 with coronary artery disease, its severity and presentation in North Indian population.

BACKGROUND: The polymorphic alleles of APOA5 (rs2266788 (C), rs3135506 (G)), LPA (rs10455872 (A), rs3798220 (G)) and 9p21.3 (rs1333049 (C), rs2383207(A)) have been reported in association with susceptibility of coronary artery disease (CAD) from genome wide association studies. We aimed to assess the association of genetic variants with coronary angiogram proven CAD, severity scored with modified Gensini score and association of risk for myocardial infraction (MI) in North Indian population. METHODS: We recruited 512 angiographic proven CAD patients (mean age 58.1±10.2years) and 272 controls (mean age 50.3±11.1years) with normal coronaries from North Indian population. The genotyping technique polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed for rs2266788, rs3135506 and rs10455872. Amplified refractory mutation system-PCR (ARMS-PCR) was used for genotyping of rs1333049, rs2383207 and rs3798220 genetic variants. RESULTS: The polymorphic risk allele of variants rs2266788 (C), rs1333049 (C), rs2383207 (A) and heterozygous polymorphic alleles of rs2266788 (TC) were significantly associated with CAD. The homozygous alleles of rs22667788 (CC) and rs1333049 (CC) had also been significantly associated with CAD. The significance of association of rs2266788 (C, CC, TC) and rs1333049 (C, CC) increases with severity of CAD. The presence of mutant allele of rs2266788 (C) was associated with risk of MI and unstable angina (UA). Also, homozygous risk allele of rs2266788 (CC) significantly associated with risk of MI and UA in patients of chronic stable angina (CSA) patients. Whereas, the risk allele of rs1333049 (C) have shown the association with MI and UA compared to controls. The genetic variants of rs3135506 (G), rs10455872 (A) and rs3798220 (G) have low frequency in our population and reflected no association with CAD. CONCLUSION: The polymorphic variants of Apo-A5; rs2266788 (C), 9p21.3; rs1333049 (C) rs2383207 (A) are associated with CAD, its severity and exerts the risk of MI in North Indian population.

Role of metabolic manipulator trimetazidine in limiting percutaneous coronary intervention-induced myocardial injury.

BACKGROUND: Trimetazidine (TMZ) is a metabolic modulator that shifts substrate utilization from fatty acid to carbohydrates, thereby, increasing myocardial glucose oxidation and improving myocardial ischemia. We evaluated whether TMZ is effective in reducing myocardial injury after percutaneous coronary intervention (PCI). METHODS: Patients with stable angina undergoing elective PCI were divided into two groups, one who received oral TMZ (35 mg BD) started 7 days before PCI (n = 48) and second who did not receive any TMZ (in addition to the standard therapy (n = 52)). Troponin-I (cTnI) and creatine kinase-MB (CK-MB) were measured before, 8, and 24 h after PCI. The primary end point was a difference in post-PCI cTnI and CK-MB levels (vs baseline). Frequency of cTnI release in the two groups, total amount of cTnI release, and difference in TIMI flow grade before and after the procedure were also assessed. RESULTS: Baseline demographics in the groups were comparable. Despite similar baseline levels, post-procedural cTnI was lower at 8 h (0.13 vs 0.56 ng/ml, p = 0.03) and 24 h (0.2 vs 1.13 ng/ml, p = 0.004) in the TMZ group. Decline or no change in cTnI was significantly more common in the TMZ group (26% vs 2%, p < 0.01). Total cTnI released after PCI, as assessed by area under curve was significantly lower in the TMZ group (15.84 vs 3.32 ng h/ml, p = 0.005). Although CK-MB levels were also lower in the TMZ group, the difference was not statistically significant. Incidence of post-PCI TIMI 1 or 2 flow was significantly lesser in the TMZ group. CONCLUSIONS: Oral TMZ started 7 days before PCI was effective in limiting PCI-induced myocardial injury with lower cTnI levels and higher prevalence of TIMI-3 flow.

Nuclear Magnetic Resonance-Based Metabolomics of Human Filtered Serum: A Great White Hope in Appraisal of Chronic Stable Angina and Myocardial Infarction.

BACKGROUND: Biochemical detection of chronic stable angina (CSA) and myocardial infarction (MI) are challenging. To address the shortcomings of the conventional biochemical approach for detection of MI, we applied serum lacking proteins and lipoprotein-based metabolomics in an approach using proton nuclear magnetic resonance (1H NMR) spectroscopy for screening of coronary artery disease (CAD) and especially MI. Our aim was to discover differential biomarkers among subjects with normal coronary (NC), CSA, and MI. METHODS: The study comprised serum samples from nondiabetic angiographically proven CAD [CSA (n = 88), MI (n = 90)] and NC (n = 55). 1H NMR spectroscopy was used to acquire metabolomics data. Clinical variables such as troponin I (TI), lactate dehydrogenase (LD), creatine kinase (CK, CK-MB, CK-MM), serum creatinine, and lipid profiles were also measured in all subjects. Metabolomic data and clinical measures were appraised separately using a chemometric approach and ROC analysis. RESULTS: The screening outcomes revealed that the pattern of methylguanidine, lactate, creatinine, threonine, aspartate, and trimethylamine (TMA), and TI, LD, CK, and serum creatinine were changed in CAD compared to NC. Statistical analysis demonstrated high precision (93.6% by NMR and 67.4% by clinical measures) to distinguish CAD from NC. Further analysis indicated that methylguanidine, arginine, and threonine, and TI, LD, and serum creatinine were significantly changed in CSA compared to MI. Statistical analysis demonstrated high accuracy (88.2% by NMR and 92.1% by clinical measures) to discriminate CSA from MI. CONCLUSIONS: In contrast to other laboratory methods, 1H NMR-based metabolomics of filtered sera appears to be a robust, rapid, and minimally invasive approach to probe CSA and MI.