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BackgroundTrimetazidine (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).MethodsPatients 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.ResultsBaseline 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.ConclusionsOral 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.

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.

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.

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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.

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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 (1 H 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). 1 H 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, 1 H NMR-based metabolomics of filtered sera appears to be a robust, rapid, and minimally invasive approach to probe CSA and MI. IMPACT STATEMENT This study was conducted on Indian populations comprising (a) patients with normal coronary, (b) patients with chronic stable angina, and (c) patients with myocardial infarction. The inference of this study is to not only develop biomarkers of these ailments, but to also find new mechanisms for the underlying pathology. In contrast to the conventional approach, the novel filtered-serum-based approach and application of advanced level statistical analysis provide the evidence that metabolomics may be a better choice for management of the underlying pathology. This study reveals profound information using a novel method, contributes to the advanced-level information that can be used for discovery of CSA and MI biomarkers, and may reveal the precise mechanism for underlying pathology.