High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction.

We sought to evaluate the safety and efficacy of N-acetylcysteine (NAC) on ischemia and reperfusion in a pig model focusing on cardio-renal protection. High doses of NAC may provide protection from contrast induced nephropathy (CIN). NAC has also been demonstrated to reduce myocardial infarction size and improve left ventricular function after ischemia in both humans and animals studies. In this study we tested the safety and cardiorenal protective efficacy of intracoronary NAC delivered in the radiographic contrast agent in a pig model that simulates the catheter based reperfusion therapy of ST elevation myocardial infarctions. 27 pigs underwent 45 min of ischemia after surgical ligation of distal left descending coronary artery. With coronary reperfusion the animals received at total of 200 mL of the contrast agent Iopamidol with and without NAC to mimic radiographic contrast use during invasive reperfusion therapy. At 24 h the following endpoints were compared: LV function (MRI, echocardiography), myocardial injury (infarct size, area-at-risk, troponin, creatinine kinase) and CIN (creatinine, BUN and renal histology). The effects of NAC on platelet reactivity were also evaluated. Intracoronary administration of NAC administered in the contrast agent is safe. NAC reduces platelet reactivity and there was a trend towards a better cardiac function at 24 h. There was no significant difference in the size of the myocardial infarction. In this model of ischemia-reperfusion high dose NAC did not protect from CIN. High dose intracoronary NAC administered with the radiographic contrast is safe but does not provide significant cardio-renal protection.

Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform.

It has been reported previously that diabetic cardiomyopathy can be inhibited or reverted with chronic zinc supplementation. In the current study, we hypothesized that total cardiac calcium and zinc content is altered in early onset diabetes mellitus characterized in part as hyperglycemia (HG) and that exposure of zinc ion (Zn2+) to isolated cardiomyocytes would enhance contraction-relaxation function in HG more so than in nonHG controls. To better control for differential cardiac myosin isoform expression as occurs in rodents after ß-islet cell necrosis, hypothyroidism was induced in 16 rats resulting in 100% ß-myosin heavy chain expression in the heart. ß-Islet cell necrosis was induced in half of the rats by streptozocin administration. After 6 wks of HG, both HG and nonHG controls rats demonstrated similar myofilament performance measured as thin filament calcium sensitivity, native thin filament velocity in the myosin motility assay and contractile velocity and power. Extracellular Zn2+ reduced cardiomyocyte contractile function in both groups, but enhanced relaxation function significantly in the HG group compared to controls. Most notably, a reduction in diastolic sarcomere length with increasing pacing frequencies, i.e., incomplete relaxation, was more pronounced in the HG compared to controls, but was normalized with extracellular Zn2+ application. This is a novel finding implicating that the detrimental effect of HG on cardiomyocyte Ca2+ regulation can be amelioration by Zn2+. Among the many post-translational modifications examined, only phosphorylation of ryanodine receptor (RyR) at S-2808 was significantly higher in HG compared to nonHG. We did not find in our hypothyroid rats any differentiating effects of HG on myofibrillar protein phosphorylation, lysine acetylation, O-linked N-acetylglucosamine and advanced glycated end-products, which are often implicated as complicating factors in cardiac performance due to HG. Our results suggest that the relaxing effects of Zn2+ on cardiomyocyte function are more pronounced in the HG state due an insulin-dependent effect of enhancing removal of cytosolic Ca2+ via SERCA2a or NCX or by reducing Ca2+ influx via L-type channel or Ca2+ leak through the RyR. Investigations into the effects of Zn2+ on these mechanisms are now underway.

N-acetylcysteine-enhanced contrast provides cardiorenal protection.

OBJECTIVES: We sought to evaluate the cardiac and renal effects of an N-acetylcysteine (NAC)-enhanced intracoronary radiographic contrast agent. BACKGROUND: Recent studies suggest that high-dose NAC provides better protection from contrast-induced nephropathy, and the antioxidant properties of NAC may also provide cardiac protection. The use of angiographic contrast agents as a drug delivery vehicle for cardiorenal protection effects has not been investigated. METHODS: In a pig model of prolonged cardiac ischemia-reperfusion, NAC-enhanced contrast medium was tested and compared with iopamidol contrast only. Myocardium and renal function were assessed after 24 h. RESULTS: There was no significant difference in the area-at-risk for myocardial infarction (MI) between contrast only and NAC-enhanced contrast medium. In contrast, MI size was about 40% smaller in NAC-enhanced contrast medium-treated animals. These findings were associated with a significant difference in MI morphology. MIs in the NAC-enhanced contrast medium group had a mottled appearance, whereas in the contrast only group they were homogeneous and had a discrete border zone. These differences could explain a higher incidence of periprocedural ventricular arrhythmias in the NAC-enhanced contrast medium group. Histopathological analysis of the myocardium revealed a reduction in programmed cell death by NAC-enhanced contrast medium that may explain the increase in ischemia tolerance. Last, NAC-enhanced contrast medium administration blunted the rise in serum creatinine levels by about 60% and protected from renotubular apotosis. CONCLUSIONS: NAC-enhanced contrast medium reduces MI size and protects renal function in a pig model of ischemia and reperfusion.