Michael P. Belanger

Gender-Differences in Myocardial Adaptation to Afterload in Normotensive and Hypertensive Rats

Echocardiographic studies suggest that women appear to exhibit a greater degree of myocardial hypertrophy in response to increased afterload than men. Therefore, gender differences and the role of estrogen and testosterone in the development of myocardial hypertrophy were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Male and female rats were either surgically neutered or underwent a sham operation at 21 days of age. A subgroup of neutered females of each strain received 17&bgr;-estradiol replacement. At 6 months, the heart weight–to–body weight ratio was assessed and correlated with systemic blood pressure. Compared with males, females had significantly smaller body and heart weights in both normotensive and hypertensive strains. Despite this, females consistently had significantly greater heart weight–to–body weight ratios. In females, neutering significantly lowered the heart weight–to–body weight ratio in WKY rats, which was returned to intact levels with estrogen replacement. Female SHR showed similar, but not statistically significant, responses. In males, neutering appeared to result in a higher heart weight–to–body weight ratio in WKY rats, but the opposite was seen in SHR. In addition, there was a significant correlation between arterial blood pressure and heart weight–to–body weight ratio (systolic r =0.45, P =0.0015: diastolic r =0.52, P =0.0002) in intact males and females of both strains, and for a given diastolic pressure, females always exhibited a greater heart weight–to–body weight ratio than males. Thus, a greater degree of myocardial hypertrophy in females appears to be related to the presence of estrogen in both normotensive and hypertensive rats. Females show a stronger relationship between heart/body weight and blood pressure than males, which occurred independent of the presence of estrogen.

Does the degree of cyanosis affect myocardial adenosine triphosphate levels and function in children undergoing surgical procedures for congenital heart disease

OBJECTIVE The outcome of children with cyanosis after cardiac surgical procedures is inferior to that of children who are acyanotic. Animal studies indicated detrimental effects of chronic hypoxia on myocardial metabolism and function. We studied whether the presence or the degree of cyanosis adversely affected myocardial adenosine triphosphate, ventricular function, and clinical outcome in children. METHODS Forty-eight children who underwent repair of tetralogy of Fallot were divided according to their preoperative saturation: group I, 90% to 100% (n = 14 patients); group II, 80% to 89% (n = 16 patients); and group III, 65% to 79% (n = 18 patients). Adenosine triphosphate was measured from right ventricular biopsy specimens taken before ischemia, at 15 minutes of ischemia, at end-ischemia, and at 15 minutes of reperfusion. Ejection fraction was measured by echocardiography. RESULTS Even before surgical ischemia, compared with groups I and II, group III had lower preoperative ejection fraction (59% +/- 2.9% vs 67% +/- 1.7% and 68% +/- 1.0%; P <.01) and lower preischemic adenosine triphosphate levels (15.1 +/- 2.1 vs 19.1 +/- 1.9 and 21.4 +/- 1.5 micromol/g dry weight; P <.01). After 15 minutes of ischemia, group III had lower adenosine triphosphate levels (11.2 +/- 1.8 vs 14.77 +/- 2.3 and 17. 6 +/- 3.1 micromol/g dry weight; P <.01). With reperfusion, both cyanotic groups lost further adenosine triphosphate compared with partial recovery in the acyanotic group (-22% +/- 3.8%, -20% +/- 3. 1% vs +18% +/- 1.8%; P <.01). Children in group III had a more complicated postoperative course as evidenced by longer ventilatory support (85 +/- 25 hours vs 31 +/- 15 and 40 +/- 21 hours; P =.07), inotropic support (86 +/- 23 hours vs 38 +/- 12 and 36 +/- 4 hours; P <.01), and intensive care unit stay (160 +/- 35 hours vs 60 +/- 10 and 82 +/- 18 hours; P =.02). CONCLUSIONS The degree of cyanosis adversely affects myocardial adenosine triphosphate, function, and clinical outcome of children who undergo cardiac operation. Children with cyanosis should be identified as a higher risk group that could be targeted for supportive interventions.

Sex differences in myocardial metabolism and cardiac function: an emerging concept

There is substantial evidence that there are dramatic sex-related differences in the incidence of cardiovascular disease, apparently related to the presence of steroid hormones. This is supported by the discovery of steroid hormone receptors in the heart and vasculature. More controversial is the area of sex-related differences in cardiac metabolism and function. A number of human and animal studies have demonstrated that estrogen and testosterone have cardiac metabolic effects. Additionally, research shows females have higher heart rates and various indices of function, including cardiac output and stroke volume, compared with males. However, some controversy exists, as other studies report that function in isolated muscle preparations is lower in females versus males. The reasons for these differences may reflect effects of sex hormones that are dependent on the conditions being studied. Cardiac function is reduced in postmenopausal females, suggesting that female sex hormones, specifically estrogen and progesterone, influence cardiac function. Apart from its well-documented vasodilatory effects, estrogen has also been shown to have negative inotropic effects and to reduce Ca2+ transients in cardiomyocytes. Similar results have been found for progesterone. Several studies show that testosterone administration appears to increase cardiac performance, while others show that it increases the stiffness of the ventricle due to increased collagen synthesis, thereby reducing diastolic performance. This review will discuss current evidence suggesting sex-related differences in cardiac metabolism and its energetics and function and will present the potential role of the principal sex steroid hormones.

Does hyperoxia affect glucose regulation and transport in the newborn

OBJECTIVE Hyperglycemia has been found to occur in children placed on cardiopulmonary bypass. Our laboratory demonstrated that hyperoxia plays a role in this hyperglycemic response and also occurs in the absence of cardiopulmonary bypass. The purpose of this study was to elucidate potential mechanisms underlying the hyperoxic-induced hyperglycemia by examining glucagon, insulin, and epinephrine, which are important in glucose regulation and skeletal and cardiac glucose transporters (GLUT1 and GLUT4), which facilitate glucose entry. METHODS Three-day-old piglets were anesthetized, intubated, and ventilated to normoxia. Animals were then randomly allocated to either 5 hours of normoxia (n = 4) or hyperoxia (n = 6). Measurements of oxygen, blood glucose, plasma glucagon, insulin, and epinephrine levels were made. Total GLUT1 and GLUT4 content in cardiac and skeletal muscle was measured using Western blotting analysis. RESULTS A sustained hyperglycemic response (P <.001) was seen throughout the 5-hour ventilatory period. A significant twofold elevation in glucagon levels (P <.001) and a threefold elevation (P <.003) in plasma insulin levels occurred, despite no significant changes in plasma epinephrine. Total GLUT1 and GLUT4 content were significantly reduced in skeletal muscle by 66% and 59%, respectively, while no significant changes occurred in cardiac muscle. CONCLUSION This study demonstrates that significant elevations in glucagon and insulin and reductions in total skeletal muscle GLUT1 and GLUT4 content all contribute to hyperoxia-induced hyperglycemia seen in newborns. To optimize postoperative recovery of newborns, consideration should be given to the levels of oxygen used to avoid the potential development of insulin resistance and subsequent decrease in glucose entry.

Multiple In Vivo Liver Biopsies Using a Freeze-Clamping Technique

A multiple in vivo liver biopsy technique was developed to measure labile metabolites (creative phosphate [CP], ATP, lactate) without interfering with normal perfusion and metabolism. Anesthetized rats ( n = 7) had a midline abdominal incision done to expose the liver. Four biopsies were taken across 20 min. Bleeding was controlled by a small, nontraumatic clamp proximal to the biopsy. Prefrozen dressing forceps grasped the liver and scissors cut the biopsy, which was frozen in liquid nitrogen. Bleeding was minimal and hemodynamic stability was preserved. This technique has few complications, bleeding is easily controlled, and it allows for large multiple biopsies, which give reliable metabolic data and can be consistently taught.

Extracellular calcium concentration affects susceptibility to global ischemic injury in newborn but not adult hearts

BACKGROUND Whether immaturity in calcium handling, that persists for a time after birth, could increase sensitivity to extracellular calcium and affect the development of global ischemic injury in the newborn heart is unknown. To address this, the impact of alterations in extracellular calcium concentration on newborn vs. adult development of myocardial injury due to ischemia was studied. METHODS In Study 1, hearts of 3-day-old piglets and adult pigs were perfused with 1 of 3 different calcium concentrations: control (0.13 mmol/L); intermediate (2.23 mmol/L); high (4.44 mmol/L) before normothermic ischemia. In Study 2, newborn hearts were allocated to perfusion with or without the L-calcium channel antagonist verapamil before high (4.44 mmol/L) calcium exposure, followed by normothermic ischemia. Tolerance to ischemia was assessed by determining the time to irreversible injury in all hearts, and maximal intraventricular pressures at peak injury. RESULTS In adults, altering calcium did not significantly affect tolerance to ischemia. In newborns, increasing calcium exposure resulted in significantly greater intraventricular pressures at maximal injury when compared with the control (low) calcium group (p<.05). As well, newborns exposed to high calcium had a significantly shorter time to the development of ischemic injury compared with the other groups (p<.05). Those newborn hearts pretreated with an L-calcium channel antagonist before the high calcium exposure did not exhibit this increased susceptibility to ischemic injury (p<.05). CONCLUSIONS In contrast to adults, the development of ischemic injury in the newborn heart is affected by changes in extracellular calcium, that can be modified with an L-calcium channel antagonist. This information could be used to prolong the safe preservation time of newborn donor hearts harvested for transplantation, as well as to minimize postoperative ventricular dysfunction.