Unveiling gender differences in demand ischemia: a study in a rat model of genetic hypertension

Objective: Female gender is associated with reduced tolerance against acute ischemic events and a higher degree of left ventricular hypertrophy under chronic pressure overload. We tested whether female and male rats with left ventricular hypertrophy present the same susceptibility to demand ischemia. Methods: Hearts from hypertrophied female and male salt-resistant and salt-sensitive Dahl rats (n=8 per group) underwent 30min of demand ischemia induced by rapid pacing (7Hz) and an 85% reduction of basal coronary blood flow, followed by 30min of reperfusion on an isovolumic red cell perfused Langendorff model. Results: In female hearts, high-salt diet induced a pronounced hypertrophy of the septum (2.38±0.09 vs 2.17±0.08mm; p≪0.01), whereas male hearts showed the greatest increase in the anterior/posterior wall of the left ventricle (LV) (3.19±0.22 vs 2.01±0.16mm; p≪0.05) compared with salt-resistant controls. At baseline, LV-developed pressure/g LV was significantly higher in female than male hearts (200±13 and 196±14 vs 161±10 and 152±15mmHgg−1; p≪0.01), independent of hypertrophy, indicating greater contractility in females. During ischemia, LV-developed pressure decreased in all groups; at the end of reperfusion, hypertrophied female and male hearts showed higher developed pressures independent of gender (148±3 and 130±8 vs 100±7 and 85±6mmHg; p≪0.01). In contrast, diastolic pressure was more pronounced in female than in male hypertrophied hearts during ischemia and reperfusion (24±3 vs 12±2mmHg; p≪0.01). Conlusions: In the pressure overload model of the Dahl salt-sensitive rat, female gender is associated with a more pronounced concentric hypertrophy, whereas male hearts develop a more eccentric type of remodeling. Although present at baseline, after ischemia/reperfusion systolic function is gender-independent but more determined by hypertrophy. In contrast, diastolic function is gender-dependent and aggravated by hypertrophy, leading to pronounced diastolic dysfunction. We can conclude that in the malignant setting of demand ischemia/reperfusion gender differences in hypertrophied hearts are unmasked: female hypertrophied hearts are more susceptible to ischemia/reperfusion than males. To determine whether in female hypertensive patients with acute coronary syndromes, diastolic dysfunction could contribute to the worse clinical course, further experimental and clinical studies are neede

Quinaprilat during cardioplegic arrest in the rabbit to prevent ischemia-reperfusion injury

AbstractObjectives: This study evaluated intracardiac angiotensin-converting enzyme inhibition as an adjuvant to cardioplegia and examined its effects on hemodynamic, metabolic, and ultrastructural postischemic outcomes. Methods: The experiments were performed with an isolated, erythrocyte-perfused, rabbit working-heart model. The hearts excised from 29 adult New Zealand White rabbits (2950 ± 200 g) were randomly assigned to four groups. Two groups received quinaprilat (1 μg/mL), initiated either with cardioplegia (n = 7) or during reperfusion (n = 7). The third group received l-arginine (2 mmol/L) initiated with cardioplegia (n = 7). Eight hearts served as a control group. Forty minutes of preischemic perfusion were followed by 60 minutes of hypothermic arrest and 40 minutes of reperfusion. Results: All treatments substantially improved postischemic recovery of external heart work (62% ± 6%, 69% ± 3%, and 64% ± 5% in quinaprilat during cardioplegia, quinaprilat during reperfusion, and l-arginine groups, respectively, vs 35% ± 5% in control group, P <.001) with similarly increased external stroke work and cardiac output. When administered during ischemia, quinaprilat significantly improved recovery of coronary flow (70% ± 8%, P =.028 vs quinaprilat during reperfusion [49% ± 5%] and P =.023 vs control [48% ± 6%]). l-Arginine (55% ± 7%) showed no significant effect. Postischemic myocardial oxygen consumption remained low in treatment groups (4.6 ± 1.2 mL · min−1 · 100 g−1, 6.0 ± 2.2 mL · min−1 · 100 g−1, and 4.7 ± 1.6 mL · min−1 · 100 g−1 in quinaprilat during cardioplegia, quinaprilat during reperfusion, and l-arginine groups, respectively, vs 4.2 ± 0.8 mL · min−1 · 100 g−1 in control group), even though cardiac work was markedly increased. High-energy phosphates, which were consistently elevated in all treatment groups, showed a significant increase in adenosine triphosphate with quinaprilat during ischemia (2.24 ± 0.14 μmol/g vs 1.81 ± 0.12 μmol/g in control group, P =.040). Ultrastructural grading of mitochondrial damage revealed best preservation with quinaprilat during ischemia (100% [no damage], P =.001 vs control). Conclusion: These experimental findings have clinical relevance regarding prevention of postoperative myocardial stunning and low coronary reflow in patients undergoing heart surgery.J Thorac Cardiovasc Surg 2002;124:352-6

Myocardial energy metabolism and ultrastructure with polarizing and depolarizing cardioplegia in a porcine model

OBJECTIVES: This study investigated whether the novel St. Thomas’ Hospital polarizing cardioplegic solution (STH-POL) with esmolol/adenosine/magnesium offers improved myocardial protection by reducing demands for high-energy phosphates during cardiac arrest compared to the depolarizing St. Thomas’ Hospital cardioplegic solution No 2 (STH-2). METHODS: Twenty anaesthetised pigs on tepid cardiopulmonary bypass were randomized to cardiac arrest for 60 min with antegrade freshly mixed, repeated, cold, oxygenated STH-POL or STH-2 blood cardioplegia every 20 min. Haemodynamic variables were continuously recorded. Left ventricular biopsies, snap-frozen in liquid nitrogen or fixed in glutaraldehyde, were obtained at Baseline, 58 min after cross-clamp and 20 and 180 min after weaning from bypass. Adenine nucleotides were evaluated by high-performance liquid chromatography, myocardial ultrastructure with morphometry. RESULTS: With STH-POL myocardial creatine phosphate was increased compared to STH-2 at 58 min of cross-clamp [59.9 ± 6.4 (SEM) vs 44.5 ± 7.4 nmol/mg protein; P < 0.025], and at 20 min after reperfusion (61.0 ± 6.7 vs 49.0 ± 5.5 nmol/mg protein; P < 0.05), ATP levels were increased at 20 min of reperfusion with STH-POL (35.4 ± 1.1 vs 32.4 ± 1.2 nmol/mg protein; P < 0.05). Mitochondrial surface-to-volume ratio was decreased with polarizing compared to depolarizing cardioplegia 20 min after reperfusion (6.74 ± 0.14 vs 7.46 ± 0.13 µm2/µm3; P = 0.047). None of these differences were present at 180 min of reperfusion. From 150 min of reperfusion and onwards, cardiac index was increased with STH-POL; 4.8 ± 0.2 compared to 4.0 ± 0.2 l/min/m2 (P = 0.011) for STH-2 at 180 min. CONCLUSIONS: Polarizing STH-POL cardioplegia improved energy status compared to standard STH-2 depolarizing blood cardioplegia during cardioplegic arrest and early after reperfusion.publishedVersio

Simulating Surgical Skills in Animals: Systematic Review, Costs & Acceptance Analyses

Background:Modern surgery demands high-quality and reproducibility. Due to new working directives, resident duty hours have been restricted and evidence exists that pure on-the-job training provides insufficient exposure. We hypothesize that supplemental simulations in animal models provide a realistic training to augment clinical experiences. This study reviews surgical training models, their costs and survey results illustrating academic acceptance. Methods:Animal models were identified by literature research. Costs were analyzed from multiple German and Austrian training programs. A survey on their acceptance was conducted among faculty and medical students. Results:915 articles were analyzed, thereof 91 studies describedin-vivoanimal training models, predominantly for laparoscopy (30%) and microsurgery (24%). Cost-analysis revealed single-training costs between 307euro and 5,861euro depending on model and discipline. Survey results illustrated that 69% of the participants had no experience, but 66% would attend training under experienced supervision. Perceived public acceptance was rated intermediate by medical staff and students (4.26;1-low, 10 high). Conclusion:Training in animals is well-established and was rated worth attending in a majority of a representative cohort to acquire key surgical skills, in light of reduced clinical exposure. Animal models may therefore supplement the training of tomorrow's surgeons to overcome limited hands-on experience until virtual simulations can provide such educational tools