Sameer Raina

Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiac fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22(phox), p47(phox), p67(phox), NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H2O2. Since SA had similar effect as ASA on AT1R expression, we suggest that ASAs effect is mediated by its SA moiety.

Regulation of MSR-1 and CD36 in macrophages by LOX-1 mediated through PPAR-γ.

We observed uniform sustained Dil-ox-LDL uptake in macrophages in the presence or absence of ox-LDL receptor-1 (LOX-1). We wondered if the deficiency of LOX-1 modulates the expression of two other scavenger receptors, macrophage scavenger receptor-1 (MSR1) and CD36, on macrophages to account for the unaltered ox-LDL uptake. Macrophages were isolated from wild-type (WT) and LOX-1 knockout (KO) mice and stimulated with ox-LDL. Dil-ox-LDL uptake and expression of MSR1 and CD36 examined. Abrogation of LOX-1 did not significantly change Dil-ox-LDL uptake by macrophages. LOX-1 KO macrophages showed a significant decrease in CD36 at baseline as well as after ox-LDL stimulation and a marked almost 100% increase in the expression of MSR1, both at mRNA and protein levels (all p<0.05 vs. WT macrophages). Further, we observed a reduction in the expression of PPAR-γ in LOX-1 KO macrophages. To ascertain the role of PPAR-γ in the altered expression of MSR1 and CD36, LOX-1 KO macrophages were treated with troglitazone, a PPAR-γ agonist. Activation of PPAR-γ by troglitazone reversed the increased expression of MSR1 as well as the decreased expression of CD36 in LOX-1 KO macrophages. LOX-1 abrogation induces MSR1 and inhibits CD36 expression. The increase in MSR1 most likely accounts for sustained Dil-ox-LDL uptake despite LOX-1 abrogation. The alterations in CD36 and MSR1 occur through a decrease in PPAR-γ.

U.S. Trends in Inpatient Utilization of Fractional Flow Reserve and Percutaneous Coronary Intervention.

Fractional flow reserve (FFR) of intermediate coronary stenosis is a highly accurate, reproducible, and cost-effective modality with powerful prognostic value. Results of the FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) [(1)][1] and FAME-2 trials [(2)][2] have shown a

Meta-analysis of clopidogrel pretreatment in acute coronary syndrome patients undergoing invasive strategy

BACKGROUND It is unknown whether pretreatment with clopidogrel in acute coronary syndrome (ACS) managed invasively, is superior to a strategy of administering clopidogrel in the cardiac catheterization laboratory at the time of percutaneous coronary intervention (PCI). Current practice guidelines do not endorse one strategy over the other. METHODS A comprehensive literature search was done to identify all relevant studies comparing pretreatment with clopidogrel to administration in the cardiac catheterization laboratory at the time of PCI (no pretreatment). A meta-analysis using a random effects model was used to calculate outcomes of interest. RESULTS Our search identified 16 studies including 61,517 ACS patients undergoing cardiac catheterization. At 30days, clopidogrel pretreatment was associated with lower MACE 7.67% vs 9.46% (odds ratio (OR) 0.77, 95% confidence interval (CI) [0.68, 0.86]; P<0.0001) and all-cause mortality 2.8% vs 4.1% (OR 0.70, 95% CI [0.58, 0.85]; P=0.0003). Mortality according to the longest follow up available was also significantly lower with pretreatment. No difference in major bleeding events was observed. These results were not significantly different between randomized vs observational studies or STEMI vs NSTEACS patients. Sensitivity analysis showed significantly lower MACE 7.98% vs 9.6% (OR 0.83, 95% CI [0.71, 0.96]; P=0.01) without increased major bleeding in NSTEACS patients undergoing PCI within 48h from pretreatment. CONCLUSION In ACS patients undergoing PCI, clopidogrel pretreatment was associated with significantly lower 30day all-cause mortality and major adverse cardiovascular events without increased major bleeding events.

Methadone induced Torsades de Pointes mimicking seizures in clinical presentation

Torsades de Pointes (TdP) has been associated with high dose methadone use. This usually presents clinically with palpitations, dizziness and syncope. We report a case of methadoneinduced TdP with an unusual clinical presentation mimicking convulsive seizures. This case highlights the importance of being aware of methadone-induced TdP and the possible atypical clinical manifestations of this condition.

PREDICTIVE ACCURACY OF RESTING GRADIENT (PD/PA) FOR IDENTIFYING ISCHEMIC CORONARY LESIONS

Adenosine is used to induce maximal hyperemia during fractional flow reserve (FFR) measurement. Adenosine administration can be time consuming, with added cost and sometimes may have undesirable side effects. We evaluated the predictive accuracy of resting trans-lesional gradient (distal coronary

CLINICAL DECISION MAKING FOR THE HEMODYNAMIC GRAY ZONE (FFR 0.75-0.80) AND IMPACT ON LONG TERM OUTCOMES

A fractional flow reserve (FFR) value between 0.75 and 0.80 is considered the “gray zone” and outcomes data are limited in this group. We sought to evaluate the impact of revascularization vs. medical therapy alone (deferral) on long term outcomes for patients in the gray zone. Consecutive

Prognostic utility of late gadolinium enhancement on cardiac magnetic resonance in cardiac amyloidosis: a meta-analysis

Background Cardiac Amyloidosis (CA) is an important prognostic indicator in patients with systemic amyloidosis. Cardiac MRI has emerged as imaging modality of choice to evaluate patients with CA. Delayed hyper-enhancement cardiac magnetic resonance (DHE-CMR) provides incremental diagnostic and prognostic utility in suspected CA. We performed a meta-analysis to evaluate the prognostic role of LGE by CMR (LGE-CMR) imaging in patients with CA.