Cardioprotection by Hypothyroidism Is Not Mediated by Favorable Hemodynamics-Role of Canonical Thyroid Hormone Receptor Alpha Signaling.

Hypothyroidism has been shown to reduce infarct size in rats, but the underlying mechanisms are unclear. We used isolated pressure-constant perfused hearts of control, hypothyroid and hyperthyroid mice and measured infarct size, functional parameters and phosphorylation of key molecules in cardioprotective signaling with matched heart rate. Compared with controls, hypothyroidism was cardioprotective, while hyperthyroidism was detrimental with enlarged infarct size. Next, we asked how thyroid hormone receptor α (TRα) affects ischemia/reperfusion (IR) injury. Thus, canonical and noncanonical TRα signaling was investigated in the hearts of (i) mice lacking TRα (TRα0), (ii) with a mutation in TRα DNA-binding domain (TRαGS) and (iii) in hyperthyroid TRα0 (TRα0hyper) and TRαGS mice (TRαGShyper). TRα0 mouse hearts were protected against IR injury. Furthermore, infarct size was reduced in the hearts of TRαGS mice that lack canonical TRα signaling but maintain noncanonical TRα action. Hyperthyroidism did not increase infarct size in TRα0 and TRαGS mouse hearts. These cardioprotective effects were not associated with increased phosphorylation of key proteins of RISK, SAFE and eNOS pathways. In summary, chronic hypothyroidism and the lack of canonical TRα signaling are cardioprotective in IR injury and protection is not due to favorable changes in hemodynamics.

Sex is no determinant of cardioprotection by ischemic preconditioning in rats, but ischemic/reperfused tissue mass is for remote ischemic preconditioning.

We determined the impact of sex on the magnitude of cardioprotection by local and remote ischemic preconditioning (IPC and RIPC) and of ischemic/reperfused peripheral tissue mass on protection by RIPC. Hearts of female and male Lewis rats were excised, perfused with buffer, and underwent either IPC by 3 × 5/5 min global zero-flow ischemia/reperfusion (GI/R) or time-matched perfusion (TP) before 30/120 min GI/R. In a second approach, anesthetized female and male Lewis rats underwent RIPC, 3 × 5/5 min ischemia/reperfusion of one or both hindlimbs (1-RIPC or 2-RIPC), or placebo. Thirty minutes after the RIPC/placebo protocol, hearts were excised and subjected to GI/R. In female and male hearts, infarct size was less with IPC than with TP before GI/R (IPC+GI/Rfemale : 12 ± 5%; IPC+GI/Rmale : 12 ± 7% vs. TP+GI/Rfemale : 33 ± 5%; TP+GI/Rmale : 37 ± 7%, P < 0.001). With 2-RIPC, infarct size was less than with 1-RIPC in female and male rat hearts, respectively (2-RIPC+GI/Rfemale : 15 ± 5% vs. 1-RIPC+GI/Rfemale : 22 ± 7%, P = 0.026 and 2-RIPC+GI/Rmale : 16 ± 5% vs. 1-RIPC+GI/Rmale : 22 ± 8%, P = 0.016). Infarct size after the placebo protocol and GI/R was not different between female and male hearts (36 ± 8% vs. 34 ± 5%). Sex is no determinant of IPC- and RIPC-induced cardioprotection in isolated Lewis rat hearts. RIPC-induced cardioprotection is greater with greater mass of ischemic/reperfused peripheral tissue.

Aspirate from human stented saphenous vein grafts induces epicardial coronary vasoconstriction and impairs perfusion and left ventricular function in rat bioassay hearts with pharmacologically induced endothelial dysfunction.

Stent implantation into aortocoronary saphenous vein grafts (SVG) releases particulate debris and soluble vasoactive mediators, for example, serotonin. We now analyzed effects of the soluble mediators released into the coronary arterial blood during stent implantation on vasomotion of isolated rat epicardial coronary artery segments and on coronary flow and left ventricular developed pressure in isolated perfused rat hearts. Coronary blood was retrieved during percutaneous SVG intervention using a distal occlusion/aspiration protection device in nine symptomatic patients with stable angina pectoris and a flow-limiting SVG stenosis. The blood was separated into particulate debris and plasma. Responses to coronary plasma were determined in isolated rat epicardial coronary arteries and in isolated, constant pressure-perfused rat hearts (±nitric oxide synthase [NOS] inhibition and ±serotonin receptor blockade, respectively). Coronary aspirate plasma taken after stent implantation induced a stronger vasoconstriction of rat epicardial coronary arteries (52 ± 8% of maximal potassium chloride induced vasoconstriction [% KClmax = 100%]) than plasma taken before stent implantation (12 ± 8% of KClmax); NOS inhibition augmented this vasoconstrictor response (to 110 ± 15% and 24 ± 9% of KClmax). Coronary aspirate plasma taken after stent implantation reduced in isolated perfused rat hearts only under NOS inhibition coronary flow by 17 ± 3% and left ventricular developed pressure by 25 ± 4%. Blockade of serotonin receptors abrogated these effects. Coronary aspirate plasma taken after stent implantation induces vasoconstriction in isolated rat epicardial coronary arteries and reduces coronary flow and left ventricular developed pressure in isolated perfused rat hearts with pharmacologically induced endothelial dysfunction.