Thomas Yeh

Triiodothyronine-enhanced left ventricular function after ischemic injury

Hypothyroidism is associated with profound left ventricular dysfunction. Brain-dead organ donors and patients undergoing cardiopulmonary bypass are chemically hypothyroid with significantly reduced circulating free triiodothyronine (T3). To test the hypothesis that T3 enhances left ventricular function in a hormonally deficient environment, a total of 36 healthy New Zealand White rabbit hearts were studied using a modified Langendorff preparation with Krebs-Henseleit perfusate and intra-ventricular balloon. In 9 normal rabbit hearts a cumulative dose-response curve with logarithmically increasing doses of T3 was obtained. The vehicle solution for T3 dissolution served as control (n = 9). Left ventricular function was assessed from peak developed pressure at baseline and after T3 administration. Triiodothyronine had no effect in normal hearts on peak developed pressure or end-diastolic pressure. In 18 rabbits, the acute effect of T3 administration after ischemia was investigated. Preischemic left ventricular function was measured to serve as baseline, and hearts were subjected to 37 degrees C global ischemia. Triiodothyronine (n = 9) or vehicle (n = 9) was infused during reperfusion, and left ventricular peak developed pressure was measured at 30 and 60 minutes of reperfusion. Recovery of function (expressed as percent return of left ventricular peak developed pressure) was significantly improved within 15 minutes of reperfusion (65.0% +/- 2.1% versus 80.2% +/- 4.1%) and remained significantly improved throughout the reperfusion period (p less than 0.05 by analysis of variance). These data suggest that although T3 possesses no inotropic properties, it significantly improves postischemic left ventricular function. The rapidity of the functional improvement suggests that these effects may be due to plasma membrane-mediated mechanisms.

Coronary artery endothelial cell and smooth muscle dysfunction after global myocardial ischemia

We hypothesized that coronary artery endothelial cell function and smooth muscle function are modified by global myocardial ischemia and used bradykinin-induced secretion of endothelium-derived relaxing factor as a marker of endothelial cell function. Bradykinin and sodium nitroprusside together determined maximum smooth muscle relaxation. Potassium chloride-induced contraction determined smooth muscle contractility. Endothelium-mediated smooth muscle relaxation expressed as a ratio of total coronary smooth muscle relaxation before and after ischemia quantified endothelial cell function. The effect of global normothermic ischemia on in situ coronary arteries from 7 swine hearts was studied. Coronary arterial rings taken from 0 to 220 minutes of ischemia at 20-minute intervals were studied in vitro. The data revealed unexpected tolerance of endothelium-mediated relaxation to ischemia. Endothelium-derived relaxing factor function was maintained to 160 minutes and smooth muscle function, to 120 minutes of ischemia. Coronary artery dysfunction seen in other studies after less ischemia may be the result of injury introduced during reperfusion, may be the consequence of myocardial injury, or may be due to events operative at the level of small arterioles.

Acute brain death alters left ventricular myocardial gene expression

OBJECTIVES The depressed myocardial function observed in brain dead organ donors has been attributed to massive sympathetic discharge and catecholamine cardiotoxicity. Because elevated catecholamines are associated with altered myocardial gene expression, we investigated whether acute brain death from increased intracranial pressure alters the expression of myocardial gene products important in contractility. METHODS A balloon expansion model was used to increase intracranial pressure in rabbits (n = 22). At timed intervals after brain death, mean arterial pressure, heart rate, electrocardiograms, histologic myocardial injury, and systemic catecholamines were assessed. Messenger RNA levels encoding myofilaments, adrenergic receptors, sarcoplasmic reticulum proteins, transcription factors, and stress-induced programs were measured with blot hybridization of total left ventricular RNA. RESULTS Increased intracranial pressure induced an immediate pressor response that temporally coincided with diffuse electrocardiographic ST segment changes. Systemic epinephrine and norepinephrine levels concurrently increased (5- to 8-fold within 1 minute), then fell below baseline within 2 hours, and remained depressed at 4 hours. By 1 hour, histologic injury was evident. Four hours after the induction of increased intracranial pressure, levels of messenger RNA-encoding skeletal and cardiac alpha-actins, egr-1, and heat shock protein 70 were significantly increased. Sham-operated animals did not exhibit these changes. CONCLUSIONS Select changes in myocardial gene expression occur in response to increased intracranial pressure and implicate ventricular remodeling in the myocardial dysfunction associated with acute brain death.

The influence of age and sex on human internal mammary artery size and reactivity

Internal mammary arteries (IMAs) from women and the elderly have been postulated to be smaller and more reactive than IMAs from men and younger patients and, therefore, not as reliable for coronary artery bypass grafting in the short term. This study tests the physiologic basis for that hypothesis. Trimmed IMA segments were obtained from patients aged 50 to 76 years at coronary artery bypass grafting. Eighteen ring segments from 12 women and 35 ring segments from 17 men were mounted on a strain-gauge apparatus, and internal diameter at a transmural pressure of 100 mm Hg was determined from length-tension curves. Contractions to potassium chloride and a dose-response curve to norepinephrine or serotonin were obtained to simulate physiologic vasospasm. Sodium nitroprusside determined arterial relaxation. Linear regression was used to determine correlation of these parameters with age. Internal mammary arteries from women and men were of equal size. They had equal strength of contraction to potassium chloride and norepinephrine, but female IMAs had greater strength of contraction to serotonin. Female IMAs had weaker contraction to norepinephrine as a percent of maximum contraction to potassium chloride than IMAs from men. Internal mammary arteries from women had equal relaxation to sodium nitroprusside compared with IMAs from men. There was no correlation between age and arterial reactivity to vasoconstrictors, relaxation to sodium nitroprusside, or size. These data suggest that IMAs from women and the elderly are not more susceptible to reduction in flow due to smaller size. Postoperatively, it may be important that women be kept on platelet inhibitors because of their greater absolute contraction to serotonin and men on nitrovasodilators because of their greater relative contraction to norepinephrine.

Intractable bleeding from anorectal varices relieved by inferior mesenteric vein ligation

Intractable anorectal variceal bleeding is an uncommon manifestation of portal hypertension, distinct from simple hemorrhoids, that is managed with therapies as conservative as bedrest, stool softeners, and correction of coagulopathy and those as invasive as portosystemic shunt. In this case report, instant variceal decompression and cessation of bleeding followed a novel treatment: inferior mesenteric vein ligation.

Orotic acid improves left ventricular recovery four days after heterotopic transplantation

Orotic acid accelerates compensatory myocardial hypertrophy after regional ischemia and improves left ventricular function acutely after global ischemia. In this study, the effect of orotic acid on left ventricular function was investigated 4 days after global ischemia (75 minutes, 21 degrees C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily 100-mg/kg doses of intraperitoneally administered orotic acid, starting 1 day before transplantation, and showed a threefold increase in the serum level of orotic acid by 4 days. After 1 hour of reperfusion, the developed pressure was equally depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased by 3 +/- 3 mm Hg (versus the developed pressure measured at 1 hour) while the developed pressure in experimental animals was significantly increased by 25 +/- 8 mm Hg. Heterotopically transplanted hearts manifested diminished systolic function (stemming from ischemia and unloading) as well as decreased expression of adult myosin. Because orotic acid has been observed to produce an increase in protein synthesis in other models, we investigated whether this improvement in systolic function resulted from an orotic acid-mediated augmentation (or preservation) or normal adult myosin expression. Both orotic acid-treated and untreated hearts manifested decreased expression of the beta-myosin heavy chain protein and steady-state messenger RNA levels. Because function improved with decreased beta-myosin heavy chain expression, an alternate mechanism underlying orotic acid-mediated improvement in function is implicated. Nevertheless, orotic acid may be a therapeutic agent facilitating long-term recovery from global ischemia.

Absence of vasospasm in radial artery CABG on high-dose norepinephrine

One of the concerns in using radial artery as coronary artery bypass grafts centers around its unusual propensity for vasospasm when experimentally exposed to norepinephrine. This case report demonstrates an absence of vasospasm in a radial artery graft on high dose norepinephrine and may provide reassurance when alpha-agonists are required in this setting.

Inotropic stimulation and oxygen consumption in a canine model of dilated cardiomyopathy

Inotropic support for the dilated, failing ventricle results in complex hemodynamic changes affecting preload, afterload, contractility, and heart rate, each of which affects myocardial oxygen consumption. Appreciation of a hierarchy of hemodynamic determinants of myocardial oxygen consumption may be helpful to the clinician trying to balance oxygen demands and hemodynamic performance. We tested the hypothesis that epinephrine alters the hierarchy of hemodynamic determinants of myocardial oxygen consumption in a canine model of dilated cardiomyopathy created by rapid ventricular pacing. Dogs (n = 10) were instrumented to record left ventricular pressure and dimension, and a modified right heart bypass preparation was used to control left ventricular workload. Coronary sinus effluent was quantitatively collected and analyzed for oxygen content and used to calculate myocardial oxygen consumption. Epinephrine administration significantly increased myocardial oxygen consumption in the empty, beating heart; however, when the relationships of multiple determinants of left ventricular work and load were compared before and after epinephrine administration, no oxygen wasting effect was observed. Using multivariate linear regression analysis, a hierarchy of hemodynamic determinants of myocardial oxygen consumption was created. In the untreated heart, stroke work and cardiac output were the primary hemodynamic determinants of oxygen consumption; epinephrine significantly altered the determinants such that wall stress became the dominant hemodynamic determinant of myocardial oxygen consumption. Focused manipulation of wall stress in the treated, failing heart may limit the potentially deleterious effects of inotropic stimulation in this setting.