As originally published in 1991: Triiodothyronine-enhanced left ventricular function after ischemic injury. Updated in 1998.
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Animals↗
Biomedical subjects
A Abd-Elfattah
Publications and source records attributed to A Abd-Elfattah.
Future cardioprotective considerations.
Remarkable strides have been made in perioperative myocardial protection for heart operations. Recent advances in understanding the physiology of myocardial ischemia and its protective responses suggest that there is a possibility for further improvement. Some of these strategies are discussed in this article, which updates current thinking in regard to operative developments contributing to myocardial protection, preconditioning, inhibition of adenosine triphosphate catabolism, the critical role of adenosine, management of myocardial edema, antioxidant therapy, endothelial cell injury, and the interaction between activated leukocytes and the endothelium. Some potential new directions for cardioprotection are identified.
Cardiac Surgical Procedures↗
Effects of triiodothyronine on stunned myocardium.
Administration of thyroid hormone, triiodothyronine (T3), causes numerous cardiovascular effects such as increases in stroke volume, cardiac output, heart rate, and myocardial contractility, and decreases in systemic vascular resistance. Along with other stressors, cardiopulmonary bypass (CPB) has been associated with reduced levels of T3. We examined the effects of T3 on early postischemic myocardial recovery in rabbit hearts subjected to crystalloid perfusion to simulate a low T3 state, and in pig hearts following global ischemia due to CPB. Studies using the former system showed that T3 administration results in significantly improved developed pressure after reperfusion of mildly ischemic hearts compared to controls, without producing inotropic effects. In more severely stunned rabbit hearts, physiologic and 10 times physiologic doses of T3 produced significantly improved (p < 0.05) stroke work end-diastolic length compared to placebo treatment. T3 treated pigs undergoing CPB and subjected to 30 minutes of global normothermic ischemia experienced significantly enhanced recovery of left ventricular contractility compared to controls at 90 and 120 minutes post reperfusion. Neither placebo nor T3 affected myocardial adenosine triphosphate levels. These data show that T3 enhances recovery from myocardial stunning without producing acute inotropic effects.
Animals↗
Interleukin-1 receptor antagonist improves survival and preserves organ adenosine-5'-triphosphate after hemorrhagic shock.
BACKGROUND: This study was designed to determine the role of interleukin-1 (IL-1) in hemorrhagic shock death. METHODS: Pentobarbital anesthetized C3H/HeN mice (n = 59) were prepared with a femoral arterial catheter and were randomized to treatment with an IL-1 receptor antagonist (IL-1ra, 10 mg/kg, n = 29) or an equal volume of phosphate-buffered saline solution (vehicle, n = 30) by subcutaneous bolus injection at 15 minutes before hemorrhage and again at 120 minutes. Continuous posthemorrhage delivery of IL-1ra or vehicle was performed in each group (1.5 mg IL-1ra in 30 microliters/day) through a subcutaneous osmotic pump. Rapid hemorrhage of 4 ml/100 gm weight was followed by normal saline resuscitation of 12 ml/100 gm 60 minutes later. RESULTS: Survival analysis by Wilcoxon rank sum analysis revealed a significantly improved 5-day survival in IL-1ra-treated mice (n = 15, 20%) as compared with vehicle-treated mice (n = 14, 6%, p < 0.001). To determine a possible mechanism of this survival advantage, the remaining mice in each treatment group were killed at 30 minutes to obtain blood and tissue samples from the heart, liver, and kidney for measurement of adenosine-5'-triphosphate (ATP). No difference in hematocrit, circulating neutrophils, or levels of glucose, lactate, or tumor necrosis factor was identified between groups to explain the improved outcome. IL-1ra prevented hemorrhage-induced ATP depletion observed in vital organs of vehicle-treated mice. CONCLUSIONS: The data implicate IL-1 in shock-induced ATP depletion and suggest IL-1ra may improve hemorrhagic shock survival by preventing ATP depletion in vital organs.
Adenosine Triphosphate↗
Polyethylene glycol-conjugated superoxide dismutase attenuates reperfusion injury when administered twenty-four hours before ischemia.
Covalent linkage of polyethylene glycol to superoxide dismutase prolongs the serum half-life of the enzyme and may facilitate intracellular access. We tested the myocardial protective effect of polyethylene glycol superoxide dismutase administered once, 24 hours before ischemia. Because hearts were studied ex vivo in a crystalloid perfused system, cardioprotection could be ascribed to intramyocardial or membrane-bound polyethylene glycol superoxide dismutase accumulation. Thirty isolated rabbit hearts from the four following groups were studied: (1) control: untreated rabbits (n = 7); (2) PEG-control: 24-hour intravenous preinfusion of methoxypolyethylene glycol 5000 (5 mg/kg) to examine the effect of polyethylene glycol alone, without conjugation to superoxide dismutase (n = 8); (3) PEG-SOD 10,000: 24-hour preinfusion of polyethylene glycol superoxide dismutase (10,000 U/kg) (n = 8); (4) PEG-SOD 30,000: 24-hour preinfusion of polyethylene glycol superoxide dismutase (30,000 U/kg) (n = 7). After measurement of baseline function with use of an intraventricular balloon, hearts were subjected to normothermic ischemia until a 4 mm Hg rise in intracavitary pressure was observed. Function was assessed at 15-minute intervals throughout reperfusion and expressed as percent return of developed pressure. After 60 minutes of reperfusion, recovery of function was greater for the PEG-SOD 30,000 group (85.6% +/- 2.6%) when compared with either the untreated or PEG-control group (68.9% +/- 2.3% and 71.4% +/- 2.0%, respectively). A similar difference was seen throughout reperfusion. Although an improved return of function was shown in the lower dose PEG-SOD 10,000 group, the margin of difference when compared with any of the control groups was determined to be insignificant at all times of reperfusion and at 60 minutes (75.9% +/- 3.2%). These data demonstrate that high, but not low, doses of polyethylene glycol superoxide dismutase significantly reduce reperfusion injury when administered 24 hours before initiation of global ischemia. Moreover, since the perfusate was superoxide dismutase free, this effect was most likely intramyocardial or membrane bound and therefore might be added to protection afforded by circulating superoxide dismutase.
Animals↗
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.
Adenine Nucleotides↗
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.
Animals↗
Myocardial protection: what the surgeon does.
With changing patient demographics resulting in greater risk of myocardial ischemia, avoidance of low-output states must begin with patient selection. From that point, a variety of well-established surgical techniques can be used to provide myocardial protection. Hypothermia and cardioplegia are fundamental among these; however, it should be recognized that alternate approaches must be considered. The well-documented deleterious effects of overdistension and hypoperfusion must be borne in mind. To this is added the complex formulation of contemporary cardioplegic solutions based on thorough understanding of the pathophysiology of ischemic injury. Specific deleterious consequences of ischemia and/or hypothermia are abnormalities of tissue volume regulation, lack of high-energy substrate availability, reduced capacity for postischemic oxidative metabolism, depressed availability of high-energy phosphate precursors, and the potential damage done by oxygen-induced free-radical-mediated oxidant injury.
Cardiac Surgical Procedures↗
Differential ventricular ischemic injury: an experimental model of right ventricular failure with a variable degree of left ventricular dysfunction.
The hemodynamic manifestations of right ventricular dysfunction after ischemic injury depend not only on the severity of injury but also on the degree of coexistent left ventricular dysfunction. A better understanding of right ventricular failure and of optimal therapies has been hindered in part by lack of suitable experimental models of selective and differential ventricular injury. Therefore, we developed a technique of differential ventricular myocardial protection during a period of global cardiac ischemia and examined the effect of such an injury on intrinsic right and left ventricular myocardial function, metabolism, and regional blood flow. Twenty-six dogs were subjected to 30 minutes of ischemia while being supported by cardiopulmonary bypass. During ischemia, right and left ventricular myocardial temperatures were independently varied by selective ventricular endomyocardial thermal regulation. Nine dogs underwent right and left ventricular normothermic ischemia, eight underwent right and left ventricular hypothermic ischemia, and nine underwent right ventricular normothermic and left ventricular hypothermic ischemia. In both ventricles, normothermic ischemia resulted in greater depression of ventricular ability to generate stroke work as a function of end-diastolic dimension (p less than 0.05), greater depletion of myocardial adenine nucleotide content (p less than 0.05), and greater subendocardial reperfusion hyperemia (p less than 0.05). Myocardial temperature of the contralateral ventricle during ischemia had no effect (p = not significant) on intrinsic ventricular functional, metabolic, or regional blood flow response to injury. For a given degree of right ventricular injury assessed by these parameters, the degree of left ventricular injury could be independently varied by as much as 50%. This is a particularly suitable model for the investigation of acute right ventricular failure.
Adenine Nucleotides↗
Preload dependence of right ventricular blood flow: I. The normal right ventricle.
Right ventricular (RV) failure is commonly treated with intravascular volume expansion to increase the RV-left atrial pressure gradient and improve left-sided filling. As RV pressure rises, chamber distention occurs and wall tension increases. These studies were designed to determine if increased wall tension might impede RV myocardial blood flow in the normal canine right ventricle and thus contribute to RV failure. Hemodynamic data, the septal-RV free wall dimension, and RV myocardial blood flow were obtained at low and high levels of preload and in both the autoregulated and vasodilated (adenosine, 2 mg per kilogram of body weight per minute) states. Elevated filling pressure decreased RV myocardial blood flow in both the autoregulated (0.85 +/- 0.18 to 0.67 +/- 0.15 ml/min/gm; p less than .05) and vasodilated (2.25 +/- 0.50 to 0.85 +/- 0.25 ml/min/gm; p less than .05) states but did not change the transmural distribution of blood flow to the right ventricle. Vasodilator reserve was markedly impaired in the high-preload state. These observations suggest that preload is an important determinant of RV myocardial blood flow. Volume loading to treat RV dysfunction may be limited by impairment of RV myocardial blood flow.
Animals↗
Ventricular function after atrial cardioplegia.
Continuous retrograde coronary sinus cardioplegia (CSCP) has previously been carefully evaluated experimentally and shown to be efficacious during ischemia, even in the presence of coronary lesions and in the hypertrophied state. A new technique of retrograde cardioplegia delivery through the right atrium, using right ventricular distension and pressures of 60 mm Hg, has recently been described with excellent clinical results. This study was designed to specifically examine right ventricular function after atrial cardioplegia and acute passive right ventricular distension. CSCP (n = 10) was compared with cardioplegia delivered through the right atrium both continuously (n = 10) and intermittently (n = 8). When ventricular function was examined with the use of the load-independent relationship of stroke work vs end-diastolic length, there was a profound deterioration of right ventricular function in both atrial cardioplegia groups (44% and 37% of control values, respectively) after 1 hr of reperfusion. In contrast, biventricular function was fully preserved in the CSCP group 1 hr after reperfusion. Left ventricular function measured at the end of reperfusion was preserved in all three groups. Right ventricular ATP levels were slightly but significantly depressed in all groups and in the atrial cardioplegia groups, this metabolic change was also seen in the left ventricle. These metabolic and hemodynamic data may reflect the inability of atrial cardioplegia to cool the myocardium below 16 degrees C. Postoperative right ventricular dysfunction may be more common than has been previously thought when atrial cardioplegia is used, particularly in the absence of topical cooling.
Adenine Nucleotides↗
Right ventricular sensitivity to metabolic injury during cardiopulmonary bypass.
To determine intrinsic right ventricular susceptibility to metabolic injury, we examined the effect of ischemia and reperfusion during cardiopulmonary bypass on right and left ventricular myocardial adenine nucleotide metabolism in the absence of ventricular work load as a determinant of energy production and utilization. Dogs were subjected either to 30 minutes of normothermic or hypothermic myocardial ischemia and reperfusion or to 60 minutes of potassium-arrested normothermic ischemia; serial ventricular biopsy specimens were assayed for adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, nucleoside, and base content. In each group the depletion rates of right and left ventricular nucleotides with ischemia did not differ. Mitochondrial ability to rephosphorylate the nucleotide pool during and after ischemia also did not differ in the two ventricles, and there were no detectable differences in the catabolism of nucleotide precursors and loss of total purine content with reperfusion. These observations indicate that right ventricular myocardium is as equally sensitive to ischemic and reperfusion injury as left ventricular myocardium, and metabolic recovery from injury is equally prolonged.
Adenine Nucleotides↗