Stephanie Aker

Glucocorticoid Treatment Prevents Progressive Myocardial Dysfunction Resulting From Experimental Coronary Microembolization

Background—The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction. Methods and Results—Microembolization was induced by injecting microspheres (42-μm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n = 7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n = 7) or 30 minutes after (n = 5) microembolization. In addition, chronically instrumented dogs received either placebo (n = 4) or methylprednisolone (n = 4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0±2.1% (mean±SEM) at baseline to 5.8±0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0±0.7% at 4 to 6 hours after microembolization back to baseline (19.1±1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction. Conclusions—Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.

TNFα in ischemia/reperfusion injury and heart failure

Abstract.During myocardial ischemia, both the myocardial and serum TNFα concentrations are rapidly increased within the area at risk. With prolongation of ischemia and development of cardiomyocyte necrosis, the TNFα concentration increases also in the surrounding viable portions of the myocardium. Indeed, in the scenario of myocardial ischemia/reperfusion, treatment with TNFα antibodies reduced the extent of myocardial infarction in rabbits and attenuated the contractile dysfunction following microembolization in dogs. In the latter studies, the serum TNFα concentration remained unaltered thereby supporting the notion of a direct action of TNFα at the level of cardiomyocytes during ischemia/reperfusion.In heart failure, the serum TNFα concentration is also increased, and in patients with advanced heart failure the serum TNFα concentration is an independent predictor of mortality. The origin of the increased serum TNFα concentration is not clearly identified yet, but TNFα derived from the heart and peripheral organs contributes to the increased serum TNFα concentration. Treatment with TNFα antibodies in the clinical scenario, however, did not improve the prognosis of heart failure patients.

The contribution of reactive oxygen species and p38 mitogen-activated protein kinase to myofilament oxidation and progression of heart failure in rabbits.

Background and purpose:  The formation of reactive oxygen species (ROS) is increased in heart failure (HF). However, the causal and mechanistic relationship of ROS formation with contractile dysfunction is not clear in detail. Therefore, ROS formation, myofibrillar protein oxidation and p38 MAP kinase activation were related to contractile function in failing rabbit hearts.

Increased inducible nitric oxide synthase and arginase II expression in heart failure: no net nitrite/nitrate production and protein S-nitrosylation.

Our objective was to address the balance of inducible nitric oxide (NO) synthase (iNOS) and arginase and their contribution to contractile dysfunction in heart failure (HF). Excessive NO formation is thought to contribute to contractile dysfunction; in macrophages, increased iNOS expression is associated with increased arginase expression, which competes with iNOS for arginine. With substrate limitation, iNOS may become uncoupled and produce reactive oxygen species (ROS). In rabbits, HF was induced by left ventricular (LV) pacing (400 beats/min) for 3 wk. iNOS mRNA [quantitative real-time PCR (qRT-PCR)] and protein expression (confocal microscopy) were detected, and arginase II expression was quantified with Western blot; serum arginine and myocardial nitrite and nitrate concentrations were determined by chemiluminescence, and protein S-nitrosylation with Western blot. Superoxide anions were quantified with dihydroethidine staining. HF rabbits had increased LV end-diastolic diameter [20.0 + or - 0.5 (SE) vs. 17.2 + or - 0.3 mm in sham] and decreased systolic fractional shortening (11.1 + or - 1.4 vs. 30.6 + or - 0.7% in sham; both P < 0.05). Myocardial iNOS mRNA and protein expression were increased, however, not associated with increased myocardial nitrite or nitrate concentrations or protein S-nitrosylation. The serum arginine concentration was decreased (124.3 + or - 5.6 vs. 155.4 + or - 12.0 micromol/l in sham; P < 0.05) at a time when cardiac arginase II expression was increased (0.06 + or - 0.01 vs. 0.02 + or - 0.01 arbitrary units in sham; P < 0.05). Inhibition of iNOS with 1400W attenuated superoxide anion formation and contractile dysfunction in failing hearts. Concomitant increases in iNOS and arginase expression result in unchanged NO species and protein S-nitrosylation; with substrate limitation, uncoupled iNOS produces superoxide anions and contributes to contractile dysfunction.

Inhibition of Na+/H+ -exchanger with sabiporide attenuates the downregulation and uncoupling of the myocardial β-adrenoceptor system in failing rabbit hearts

1 Chronic heart failure (HF) is characterized by left ventricular (LV) structural remodeling, impaired function, increased circulating noradrenaline (NA) levels and impaired responsiveness of the myocardial β‐adrenoceptor (βAR)‐adenylyl cyclase (AC) system. In failing hearts, inhibition of the sodium/proton‐exchanger (NHE)‐1 attenuates LV remodeling and improves LV function. The mechanism(s) involved in these cardioprotective effects remain(s) unclear, but might involve effects on the impaired βAR‐AC system. 2 Therefore, we investigated whether NHE‐1 inhibition with sabiporide (SABI; 30 mg kg−1 day−1 p.o.) might affect myocardial βAR density and AC activity in relation to changes in LV end‐diastolic diameter (LVEDD) and LV systolic fractional shortening (LVS‐FS) after 3 weeks of rapid LV pacing in rabbits. 3 After 3 weeks of rapid LV pacing LVEDD was significantly increased (Shams 17±0.2 mm, n=9 vs 3wksHF 20±0.5 mm, n=8; P<0.05) and LVS‐FS decreased (Shams 31±1%, n=9 vs 3wksHF 10±1%, n=8; P<0.05). SABI treatment significantly improved LV function independent of whether rabbits were treated after 1 week of pacing (3wksHF+2wksSABI (n=7): LVEDD 18±1 mm; LVS‐FS 16±4%) or before pacing (3wksHF+3wksSABI (n=9): LVEDD 18±1 mm; LVS‐FS 18±6%). After 3 weeks of rapid LV pacing, SABI treatment significantly attenuated increases in serum NA content (Shams 0.83±0.19, 3wksHF 2.68±0.38, 3wksHF+2wksSABI 1.22±0.32, 3wksHF+3wksSABI 1.38±0.33 ng ml−1). Moreover, βAR density (Shams 64±5, 3wksHF 38±3, 3wksHF+2wksSABI 48±4, 3wksHF+3wksSABI 55±3 fmol mg−1 protein) and responsiveness (isoprenaline‐stimulated AC activity. (Shams 57.6±4.9, 3wksHF 36.3±6.0, 3wksHF+2wksSABI 56.9±6.0, 3wksHF+3wksSABI 54.5±4.8 pmol cyclic AMP mg−1 protein−1 min−1) were significantly improved in SABI‐treated rabbits. 4 From the present data we cannot address whether the improved βAR‐AC system permitted improved LV function and/or whether the improved LV function resulted in less activation of the sympathetic nervous system and by this in a reduced stimulation of the βAR‐AC system. Accordingly, additional studies are needed to fully establish the cause‐and‐effect relationship between NHE‐1 inhibition and the restoration of the myocardial βAR system.

Identification of necrotic tissue by phase-contrast microscopy at an early stage of acute myocardial infarction.

Identification of Necrotic Tissue by Phase–Contrast Microscopy at an Early Stage of Acute Myocardial Infarction