Paul A. Rogers

Hydrogen Peroxide A Feed-Forward Dilator That Couples Myocardial Metabolism to Coronary Blood Flow

Objective—We tested the hypothesis that hydrogen peroxide (H2O2), the dismutated product of superoxide (O2·−), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O2·− and H2O2 production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H2O2. Methods and Results—The production of O2·− is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O2·− during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O2·− production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O2·− production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67±8% percent of maximal dilation) that was significantly reduced by catalase (5±0.5%, P<0.05) or the antagonist of Kv channels, 4-aminopyridine (18±4%, P<0.05). In intact animals, tissue concentrations of H2O2 are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H2O2 by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus po2. Conclusions—Taken together, our results demonstrate that O2·− is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H2O2. Our results further suggest that the production of H2O2 in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

We previously demonstrated a role for voltage-dependent K(+) (K(V)) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H(2)O(2), as responses were attenuated by the K(V) channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that K(V) channels participate in coronary reactive hyperemia and examined the role of K(V) channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 +/- 5% and inhibited hyperemic volume 32 +/- 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L-NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 +/- 6% block at 9 microg/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 microM correolide, a selective K(V)1 antagonist (76 +/- 7% and 47 +/- 2% block, respectively, at 1 microM). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 +/- 6% block at 10 microg/min) and by correolide in vitro (29 +/- 4% block at 1 microM). K(V) current in smooth muscle cells was inhibited by 4-AP (IC(50) 1.1 +/- 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for K(V)1 family members was detected in coronary arteries. Our data indicate that K(V) channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine- and NO-induced vasodilation.

Coronary Vasomotor Reactivity to Endothelin-1 in the Prediabetic Metabolic Syndrome

Objective:The purpose of the present investigation was to test the hypothesis that coronary vasoconstrictor responses to endothelin‐1 are augmented in the prediabetic metabolic syndrome.

Patients with severe chronic kidney disease benefit from early revascularization after acute coronary syndrome

BACKGROUND Early revascularization is associated with improved outcomes after non-ST-elevation acute coronary syndrome (ACS). It is unclear whether its benefits exist in patients with ACS and advanced chronic kidney disease (CKD), because these patients are often sub-optimally treated and excluded from clinical trials. METHODS We undertook meta-analyses of short- and long-term mortality outcomes in comparative studies examining the effectiveness of early revascularization in patients with ACS and CKD (as estimated by Glomerular Filtration Rate, eGFR). A literature search between 1995 and 2010 identified 7 published reports enrolling 23,234 patients with at least mild reduction in eGFR (<90 mL/min/1.73 m(2)), of whom 6276 and 16,958 patients received early revascularization versus initial medical therapy, respectively. Summary odds ratios (OR) and their 95% Confidence Intervals (CIs) were calculated using the random-effects models. Sensitivity analyses were performed by one-study removal, and publication bias was assessed by the funnel plot analysis. RESULTS Early revascularization was associated with a reduction in 1-year mortality compared to initial medical therapy (OR=0.46, 95% CI 0.26-0.82, P=0.008) among ACS patients with eGFR<60 mL/min/1.73 m(2). The mortality reduction with early revascularization occurred upfront (short term mortality OR=0.69, 95% CI 0.56-0.87, P=0.001), persisted at 3 years (OR=0.54, 95% CI 0.31-0.96, P=0.037), was evident across all CKD stages (including dialysis patients), and was independent of the influence of any single study. CONCLUSIONS Early revascularization after ACS is associated with reduced mortality in appropriately-selected patients with CKD, including those with severe CKD or receiving dialysis.

Revascularization improves mortality in elderly patients with acute myocardial infarction complicated by cardiogenic shock

implantation of a BVS, an emerging effective treatment for de-novo coronary artery disease [3] allowed for satisfactory treatment of both the ISR and the in-segment disease. Figure legend: Optical coherence tomography (OCT) appearance pre-implantation of a bioresorbable vascular scaffold (BVS) with significant neointimal proliferation over two layers of stent struts following pre-dilatation to facilitate adequate contrast flow for OCT (Panel A) with significant atheroma also seen at the proximal nonstented segment (Panel B) with balloon related dissection also present. Absorb 3.5 × 18 mm BVS with adequate BVS expansion and apposition over the two previously placed layers of metallic stent struts (Panels C, D and zoomed up image Panel E). Baseline angiographic image before any balloon dilatation (Panel F) shows severe in-stent and significant in-segment stenosis. Final angiographic appearance post BVS was satisfactory (Panel G).