Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries

Background. Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10⁻⁶ mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10⁻⁹ to 10⁻⁵ mol/L) after contraction by 3×10⁻⁸ mol/L of endothelin-1.

Results. Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% ± 10.2% and 65.9% ± 10.1% at 2 hours and 39.4% ± 4.7% and 68.4% ± 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% ± 8.2% and 45.0% ± 5.5% at 2 hours and 38.1% ± 8.2% and 56.5% ± 8.8% at 24 hours, respectively (NS).

Conclusions. In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.     

Prevention of radial artery graft vasospasm after coronary bypass

Background. Pharmacologic prophylaxis for prevention of notorious radial artery (RA) spasm is critical because of the increasingly routine use of the RA conduit during coronary bypass. Therefore, we investigated the vasodilatory effect of calcium antagonist in combination with nitroglycerin (NTG) RA segments.

Methods. We evaluated the vasodilatory effect of nifedipine alone, verapamil alone, diltiazem alone, NTG alone, and calcium antagonist in combination with in endothelin-1 (ET-1)-, angiotensin II (AII)-, 5-hydroxytryptamine (5-HT)-, and norepinephrine (NE)-precontracted human RA rings mounted in organ baths.

Results. Nifedipine (10⁻⁵ M) alone, diltiazem (10⁻⁵ M) alone, verapamil (10⁻⁵ M) alone, and NTG (10⁻⁵ M) alone showed maximum vasodilatory effect in either 10⁻⁷ M ET-1-, 10⁻⁷ M AII-, 10⁻⁵ M NE-, or 10⁻⁴ M 5-HT-precontracted RA segments. The 10⁻⁵ M NTG alone-induced vasodilation (88.5% ± 7.7%) in ET-1-precontracted segments was the highest vasodilation (ANOVA, p = 0.0008) among NTG alone-induced vasodilatory effects in RA. The relaxing effect of any of the calcium antagonists alone varied from 32.7% ± 13.2% to 76.5% ± 20.5% in RA precontracted with different vasoconstrictors. Nearly 200% vasodilation was observed with calcium antagonist in combination with NTG in AII-precontracted vessels. Nonetheless, the vasodilatory effect of calcium antagonist in combination with NTG in RA segments precontracted with different vasoconstrictors other than AII was nearly 100%.

Conclusions. A calcium antagonist in combination with NTG is more potent than calcium antagonist alone or NTG alone in prevention of human RA vasospasm after coronary bypass.     

Impaired distensibility of neoaorta after arterial switch procedure

Background. Although the arterial switch operation has become the standard surgical procedure for treatment of complete transposition, postoperative problems have not been fully appreciated. One such problem may be the postoperative function of great arteries that are manipulated radically.

Methods. The diameters at four levels of the aorta were measured in 36 patients who had undergone arterial switch operation and the distensibilities were calculated. The data were compared with that of age-matched controls.

Results. At the level of the Valsalva sinus, aortic diameters after one-staged and two-staged operations were 137.0% ± 21.3%N and 152.4% ± 17.7%N of the normal aorta, respectively. The distensibilities at the Valsalva sinus in patients after one-staged and two-staged operations were 1.2 ± 0.7 and 1.5 ± 0.8 cm² · dyn⁻¹ · 10⁻⁶, and at the supraaortic ridge were 2.5 ± 1.5 and 1.9 ± 1.5 cm² · dyn⁻¹ · 10⁻⁶, respectively.

Conclusions. In patients after arterial switch procedure, the distensibility of the base of aorta is decreased. Long-term follow-up is necessary to clarify the influence of the “stiffness” of the base of aorta.     

Epoxyeicosatrienoic acids (EET(11,12)) may partially restore endothelium-derived hyperpolarizing factor-mediated function in coronary microarteries.

Background. Endothelial cells derive nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The cytochrome P-450–monooxygenase metabolites of arachidonic acid (epoxyeicosatrienoic acids [EETs]) have been suggested to be EDHF. This study was designed to examine the effect of EET_11,12 with regard to the possibility of restoring EDHF function when added into hyperkalemic cardioplegic solution.

Methods. Porcine coronary microartery rings were studied in a myograph. In groups 1 and 2, paired arteries were incubated in either hyperkalemic solution (K⁺ 20 mmol/L) or Krebs’ solution (control). In group 3, the paired arteries were incubated in hyperkalemia plus EET_11,12 (1 × 10^−6.5 mol/L) or hyperkalemia alone (control) at 37°C for 1 hour, followed by Krebs’ washout and then precontracted with 1 × 10^−8.5 mol/L U46619. The EDHF-mediated relaxation to EET_11,12 (group 1) or bradykinin (groups 2 and 3) was studied in the presence of N^G-nitro-l-arginine, indomethacin, and oxyhemoglobin.

Results. After exposure to hyperkalemia, the EDHF-mediated maximal relaxation by bradykinin (72.5% ± 7.8% versus 41.6% ± 10.6%; p < 0.05), but not by EET_11,12 (18.4% ± 3.3% versus 25.1% ± 4.9%; p > 0.05) was significantly reduced. Incubation with EET_11,12 partially restored EDHF function (33.3% ± 9.5% versus 62.0% ± 8.5%; p < 0.05).

Conclusions. In coronary microarteries, hyperkalemia impairs EDHF-mediated relaxation, and EET_11,12 may partially mimic the EDHF function. Addition of EET_11,12 into cardioplegic solution may partially restore EDHF-mediated function reduced by exposure to hyperkalemia.     

Sex and age distribution of 1,25(OH)2D3 receptors in peripheral blood mononuclear cells from normal human subjects

Specific receptors for 1,25 Dihydroxyvitamin D₃ have been described in human peripheral blood mononuclear cells (PBMC). We have tried to find out whether these receptors could show any difference in sex or age distribution. Twenty two healthy men aged 21–66 yr (mean ± SD 41.0 ± 13.6) and nineteen healthy women aged 22–60 yr (38.9 ± 13.9) have been studied. The mean dissociation constant (Kd) was similar in both sexes (1.35 ± 0.70 × 10⁻¹⁰M in males, 1.13 ± 0.66 × 10⁻¹⁰M in females), but the concentration of binding sites (Nmax) was significantly lower in females (2.32 ± 0.92 fmol/10⁷ PBMC vs 4.43 ± 1.38 fmol/10⁷ PBMC in males; p = 0.0001). Neither Kd nor Nmax were significantly correlated with age. No difference was found between pre and postmenopausal women. Further studies are needed to elucidate if this sex difference in PBMC receptors for 1,25 Dihydroxy vitamin D₃ is of any pathophysiological relevance.     

Right internal thoracic artery through the transverse sinus in myocardial revascularization

Background. A major concern in evaluating dynamic cardiomyoplasty has been whether the synchronous stimulation of latissimus dorsi muscle is essential for benefit or not. We studied 10 patients to determine the efficacy of the systolic augmentation generated by the synchronous electrical stimulation of the latissimus dorsi muscle.

Methods. Left ventricular ejection fraction, end-systolic and end-diastolic volume indexes, and stroke volume index obtained during resting, peak exercise, and recovery periods (“on” values) were compared with those obtained 1 week after cessation of electrical stimulus (“off” values). Double product and estimated total body oxygen consumption at peak exercise were also calculated and compared.

Results. Higher ejection fractions (0.36 ± 0.07 versus 0.33 ± 0.06 at rest, 0.40 ± 0.07 versus 0.33 ± 0.07 peak exercise, and 0.37 ± 0.06 versus 0.31 ± 0.06 at recovery) and lower end-systolic volume indexes with relatively constant end-diastolic volume indexes were observed with the cardiomyostimulator on. Further, exercise response was better with the cardiomyostimulator on. Double product indirectly reflected better myocardial oxygen supply/demand ratio when on at peak exercise (17 ± 2.2 mm Hg × beats/min × 10⁻³ for on versus 19 ± 2.6 mm Hg × beats/min × 10⁻³ for off). Estimated total body oxygen consumption was improved at peak exercise when the cardiomyostimulator was functional (12 ± 2.7 mL · kg⁻¹ · min⁻¹ versus 11 ± 2.6 mL · kg⁻¹ · min⁻¹).

Conclusions. Current data suggest a true systolic assist during synchronous contractions of the latissimus dorsi muscle. It is thought, therefore, that synchronous electrical stimulation is essential for maximum benefit and all the beneficial effect of cardiomyoplasty certainly cannot be attributed to simple wrapping itself.     

Dental phenotype of the col1a2(oim) mutation: DI is present in both homozygotes and heterozygotes

Dentinogenesis imperfecta (DI) is a common but variable feature of osteogenesis imperfecta (OI). The Col1a2^oim mutation (oim) is a well-studied mouse model of chain deficiency OI. Heterozygous oim/+ mice have subtle skeletal fragility, while homozygous oim/oim mice have marked skeletal fragility. To further define the consequences of oim mutation, we examined teeth by light and scanning electron microscopy (SEM). The dental phenotype in Col1a2^oim (oim) mice is more severe in incisors than in molars and includes changes in pulp chamber size, tooth shape, and dentin ultrastructure. Teeth in oim/oim animals are clinically fragile, while oim/+ teeth are grossly normal. Incisor pulp chamber areas (in μm²) are: upper +/+ = 358 ± 75, lower +/+ = 671 ± 162, upper oim/+ = 161 ± 54, lower oim/+ = 156 ± 19, upper oim/oim = 6900 ± 1040, and lower oim/oim = 66 ± 62 (P < 10⁻⁵). Incisor non-pulp chamber cross-sectional areas (in μm²), reflecting dentin areas, are: upper +/+ = 39,000 ± 1670, lower +/+ = 35,600 ± 1980, upper oim/+ = 47,500 ± 2510, lower oim/+ = 26,000 ± 1830, upper oim/oim = 29,800 + 315, and lower oim/oim = 36,800 ± 3450 (P < 10⁻⁵). Ultrastructural abnormalities are more pronounced in incisors than in molars and depend on dosage of the mutant allele. These include reduction in the number and regularity of spacing of the dentinal tubules, lesser mineralization, and blurring of the boundary between peritubular and intertubular dentin. Our findings demonstrate that both oim/oim and oim/+ mice suffer from DI. The more severe incisor phenotype may reflect incisors' continuous growth.     

Effects of vitamin D3, 17β-estradiol, vasoactive intestinal peptide, and glutamate on electric coupling between rat osteoblast-like cells in vitro

Osteoblast-like cells express receptors for various hormones and neurotransmitters that induce widespread actions in the bone to which intercellular communication and its modulation may contribute. Therefore, we examined the effects of the osteotropic hormones vitamin D₃ (vitD₃) and 17β-estradiol (17β-E₂) as well as the neurotransmitter vasoactive intestinal peptide (VIP) and the excitatory amino acid glutamate (Glu) on gap junctions between rat osteoblast-like (ROB) cells in vitro. Electric coupling was measured by simultaneous intracellular recordings from neighboring cells. The coupling factor (c_f) was calculated from membrane potential changes induced by alternate current injections into both cells. In ROB cells c_f was increased by 5 × 10⁻⁸ mol/L vitD₃ to 130 ± 13% (mean ± SD; n = 6) of the initial value within 5–20 min. This effect was not reversible after washing with control saline for 10–15 min. In six cell pairs, c_f was not affected by vitD₃ (94 ± 5%). In three cell pairs superfusion of 10⁻⁸ mol/L E₂ reduced c_f to 80 ± 6% within 10 min, whereas, in two cell pairs, this hormone improved c_f to 140% within 20 min. Exposure of VIP (3 · 10⁻⁸ mol/L) did not alter c_f in the majority of cells (99 ± 3%; n = 11). In five cell pairs, c_f was improved within 5–15 min to 133 ± 12%, whereas, in one cell pair, c_f was reduced to 22% by VIP. In contrast, brief application of Glu (5 · 10⁻³ mol/L) decreased c_f to 75 ± 5% (n = 5), whereas, in nine other cell pairs, c_f was not affected (96 ± 5%). The findings indicate that cell-cell coupling of gap junctions between bone cells can be altered by actions of hormones and transmitters in a cell-pair-specific way, which may depend on their functional state.     

Pretreatment with phenoxybenzamine attenuates the radial artery's vasoconstrictor response to alpha-adrenergic stimuli

BACKGROUND: Although the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine. METHODS: Segments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 micromol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 micromol/L). RESULTS: Contractile responses to 15 micromol/L phenylephrine in control radial artery segments averaged 44.2% +/- 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 micromol/L phenylephrine (32.1% +/- 5.9%; P =.22), but 1000 micromol/L phenoxybenzamine completely abolished radial artery contraction (-7.2% +/- 4.4%; P <.001). The effect of 10 and 100 micromol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 micromol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 micromol/L norepinephrine in control radial artery segments averaged 54.7% +/- 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% +/- 5.1%; P =.04). In contrast, 1000 micromol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (-10.5% +/- 2.0%; P <.001). CONCLUSIONS: A brief pretreatment of the human radial artery bypass conduit with 1000 micromol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these alpha-adrenergic agonists.     

Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations

Fibroblast growth factor-23 (FGF23) is a circulating factor that plays critical roles in phosphate and vitamin D metabolism. The goal of our studies was to dissect the pathways directing the vitamin D–phosphate–FGF23 homeostatic axis. To test the role of diet in the regulation of Fgf23, wild-type (WT) mice were fed either a standard (0.44% phosphorus) or a low-phosphate (0.02%) diet. WT mice on standard diet had a serum phosphate of 9.5 ± 0.3 mg/dl and an Fgf23 concentration of 99.0 ± 10.6 pg/ml; mice on the low-phosphate diet had a phosphate of 5.0 ± 0.2 mg/dl (P < 0.01) and an Fgf23 of 10.6 ± 3.7 pg/ml (P < 0.01). To genetically separate the effects of phosphate and vitamin D on Fgf23, we examined vitamin D receptor null (VDR^−/−) mice, which are hypocalcemic and hypophosphatemic secondary to hyperparathyroidism. On standard diets, WT and VDR^+/− mice had Fgf23 levels of 106.0 ± 30.7 and 90.6 ± 17.3 pg/ml, respectively, whereas Fgf23 was undetectable in the VDR^−/−. Animals were then placed on a diet that normalizes serum calcium and phosphorus. This ‘rescue’ increased Fgf23 in WT to 192.3 ± 32.5 pg/ml and in VDR^+/− to 388.2 ± 89.6pg/ml, and importantly, in VDR^−/− to 476.9 ± 60.1 pg/ml (P < 0.01 vs. WT). In addition, renal vitamin D 1-alpha hydroxylase (1-OHase) mRNA levels were corrected to WT levels in the VDR^−/− mice. In summary, Fgf23 is suppressed in diet-induced hypophosphatemia and in hypophosphatemia associated with secondary hyperparathyroidism. Normalization of serum phosphate by diet in VDR^−/− mice increases Fgf23. Thus, our results demonstrate that Fgf23 is independently regulated by phosphate and by vitamin D.     

Prevention of Reperfusion Injury by Inhaled Nitric Oxide in Lungs Harvested From Non-Heart-Beating Donors

Background. In lung transplantation using non-heart-beating donors (NHBD), the postmortem period of warm ischemia exacerbates lung ischemia-reperfusion injury. We hypothesized that inhaled nitric oxide (NO) would reduce ischemia-reperfusion injury, and thus ameliorate the viability of the lung graft.

Methods. A blood-perfused, isolated rat lung model was used. Lungs were flushed and harvested from non-heart-beating donors after 30 minutes of in situ warm ischemia. The lung was then stored for 2 hours at 4°C. Inhaled NO at 30 ppm was given either during the period of warm ischemia, during reperfusion, or during both periods. Lung ischemia-reperfusion injury was assessed after 1 hour of reperfusion by measuring pulmonary vascular resistance, coefficient of filtration, wet-to-dry lung weight ratio, and myeloperoxidase activity.

Results. A severe IR injury occurred in lungs undergoing ischemia and reperfusion without NO as evidenced by high values of pulmonary vascular resistance (6.83 ± 0.36 mm Hg · mL⁻¹ · min⁻¹), coefficient of filtration (3.02 ± 0.35 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹), and wet-to-dry lung weight ratio (8.07 ± 0.45). Lower values (respectively, 3.31 ± 0.44 mm Hg · mL⁻¹ · min⁻¹, 1.49 ± 0.34 mL · min⁻¹ · cm H₂O⁻¹ · 100 g⁻¹, and 7.44 ± 0.43) were observed when lungs were ventilated with NO during ischemia. Lung function was further improved when NO was given during reperfusion only. All measured variables, including myeloperoxidase activity were significantly improved when NO was given during both ischemia and reperfusion. Myeloperoxidase activity was significantly correlated with coefficient of filtration (r = 0.465; p < 0.05).

Conclusions. These data suggest that inhaled NO significantly reduces ischemia-reperfusion injury in lungs harvested from non-heart-beating donors. This effect might be mediated by inhibition of neutrophil sequestration in the reperfused lung.     

Effects of intraoperative glucose administration on circulating metabolites and nitrogen balance during prolonged surgery

Study Objectives: To compare the effects of intraoperative administration of 2.5% glucose or Ringer’s solution on metabolism during prolonged surgery.

Design: Prospective, randomized study.

Setting: Teaching hospital.

Patients: 20 ASA physical status I and II adults patients scheduled for thoracic or abdominal surgery lasting at least 3 hours.

Interventions: Patients received Ringer’s solution (Group R) or 2.5% glucose solution (Group G) 10 ml · kg⁻¹ · h⁻¹ during surgery and 2 ml · kg.⁻¹ · h⁻¹ during the first two postoperative hours (Ringer’s or glucose), then 40 ml · kg.⁻¹ · day⁻¹ of 5% intravenous (IV) glucose postoperatively.

Measurements and Main Results: Plasma glucose, free fatty acids, ketone bodies, lactate, insulin, glucagon, cortisol, and growth hormone concentrations were determined after an overnight fast (T₀), on induction of anesthesia (T₁), at the end of surgery (T₂), 2 hours thereafter (T₃), and on the following morning (T₄). Capillary blood glucose was determined every 30 minutes from T₁ to T₂. Urinary nitrogen and 3-methylhistidine were measured every day for 5 days. There were no differences between groups in demographic data, anesthesia, or surgical procedures. All data were comparable at baseline and on the following morning. In Group R, no patient experienced hypoglycemia, but plasma fatty acids and ketone bodies increased during surgery. In Group G, glycemia rose to very high levels, with a significant increase in insulin during surgery. Other hormones were the same within the two groups. Urinary nitrogen and 3-methylhistidine were similar in both groups.

Conclusion: The absence of glucose infusion in prolonged surgery did not cause hypoglycemia, and no increase in protein catabolism was observed.     

Brain Damage and Myocardial Dysfunction: Protective Effects of Magnesium in the Newborn Pig

Background. Brain damage is associated with myocardial dysfunction resulting from excessive release of endogenous catecholamines and Ca²⁺ overload. Magnesium ion, a natural Ca²⁺ blocker, has recently been recognized as a myoprotective agent.

Methods. Myocardial function was assessed in 3- to 7-day-old piglets from pressure–volume data (obtained by the conductance catheter/micromanometer technique) before and for 4 hours after ligation of the aortic arch vessels and was correlated with ultrastructural changes. Group a (n = 6) received MgSO₄ immediately after induction of brain damage for 4 hours, whereas group b (n = 6) did not receive MgSO₄ and served as control.

Results. In both groups after induction of brain damage, there was a significant (p < 0.05) increase in end-systolic elastance and preload-recruitable stroke work that persisted for 1 hour. However, after 2 and 4 hours, there was a significant (p < 0.05) reduction in both variables in group b (end-systolic elastance, 74% ± 5% and 59% ± 6%, respectively, and preload-recruitable stroke work, 77% ± 4% and 64% ± 3%, respectively, compared with baseline), and in group a, the values returned to baseline. The chamber stiffness index rose significantly (p < 0.05) in group b 15 minutes after induction of brain damage and remained significantly (p < 0.05) higher for 4 hours versus no significant change in group a. Plasma levels of epinephrine and norepinephrine were similar in the groups before and after brain damage. Electron microscopic study showed severe ultrastructural changes in group b and significantly milder changes in group a.

Conclusions. We conclude that MgSO₄ may protect the neonatal myocardium when administered immediately after brain damage.     

Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation

Background. Blood cardioplegia (BCP) is widely used for myocardial protection during open heart operation. However, BCP may have a chance to induce neutrophil-mediated myocardial injury during aortic cross-clamping. We clinically evaluated the myocardial protective effect of leukocyte-depleted blood cardioplegia (LDBCP) for initial and intermittent BCP administration in pediatric patients.

Methods. Fifty patients undergoing open heart operation for congenital heart disease between January 1997 and March 1999 were reviewed. Twenty-five were administered LDBCP for myocardial protection during ischemic periods (LDBCP group), and the remaining 25 were given BCP without leukocyte depletion (BCP group).

Results. The difference in plasma concentrations of malondialdehyde between coronary sinus effluent blood and arterial blood just after reperfusion in the LDBCP group (1.68 ± 0.56 μmol/L) was significantly lower than that in the BCP group (2.35 ± 0.62 μmol/L; p < 0.01). The LDBCP group showed significantly lower plasma concentrations of human heart fatty acid-binding protein at 50 minutes after reperfusion (LDBCP group, 103.5 ± 38.7 IU/L; BCP group, 144.8 ± 48.8 IU/L; p < 0.01) and the peak value of creatine kinase-MB during the first 24 postoperative hours (LDBCP group, 17.0 ± 8.5 IU/L; BCP group, 26.0 ± 11.6 IU/L; p < 0.01) than did the BCP group. The maximum dose of catecholamine was significantly smaller in the LDBCP group (LDBCP group, 3.20 ± 2.18 μg · kg⁻¹ · min⁻¹; BCP group, 5.60 ± 2.83 μg · kg⁻¹· min⁻¹; p < 0.01).

Conclusions. These results suggest the usefulness of LDBCP for protection from the myocardial injury that can be induced by BCP administration during aortic cross-clamping.     

Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative

Background. To evaluate the effects of colforsin daropate hydrochloride (colforsin), a water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass, we conducted a prospective randomized study.

Methods. Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; N = 14) or no colforsin treatment (control; N = 15). Administration of colforsin (0.5 μg · kg⁻¹ · min⁻¹) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cyclic adenosine monophosphate levels, hemodynamics, and respiratory function were measured serially.

Results. Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. Interleukin 1β, interleukin 6, and interleukin 8 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the colforsin group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) in the colforsin group, and the levels correlated inversely (r = −0.56, p = 0.002) with the respiratory index after cardiopulmonary bypass.

Conclusions. Intraoperative administration of colforsin daropate hydrochloride had potent inotropic and vasodilatory activity and attenuated cytokine production and respiratory dysfunction after cardiopulmonary bypass. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with cardiopulmonary bypass.     

Effect of hemofiltrated whole blood pump priming on hemodynamics and respiratory function after the arterial switch operation in neonates

Background. Primed blood might have some deleterious effects on neonates during cardiopulmonary bypass (CPB) due to unbalanced electrolytes and inflammatory mediators. We hemofiltrated pump-primed blood before CPB to reduce inflammatory mediators and to adjust pH and the concentrations of electrolytes. The current study investigated the effects of hemofiltrated whole blood priming on hemodynamics and respiratory function after CPB in neonates.

Methods. Patients who underwent the arterial switch operation in the neonatal period for transposition of the great arteries with intact ventricular septum were chosen for this study. Seventeen patients underwent CPB with hemofiltrated blood priming (group HF) and 23 patients underwent CPB with nonhemofiltrated blood priming (group N). The concentrations of electrolytes and bradykinin and high molecular weight kininogen of the primed blood before and after hemofiltration were measured. At 4 hours after completion of CPB, the left ventricular percent fractional shortening, and the relation between the mean velocity of shortening and the end-systolic wall stress (stress velocity index), were measured by echocardiogram in 7 patients in group HF and 6 patients in group N. Alveolar − arterial oxygen tension difference (AaDO₂) and respiratory index (AaDO₂ divided by arterial oxygen tension) were measured at several points for 48 hours after CPB in all patients.

Results. Hemofiltration of the primed blood maintained electrolytes within a physiologic level and significantly reduced the concentrations of bradykinin (5,649 ± 1,353 pg/mL versus 510 ± 35 pg/mL, p < 0.05) and high molecular weight kininogen (52.7% ± 3.2% versus 40.1% ± 3.0% of normal plasma value, p < 0.05). The percent of fractional shortening at 4 hours after completion of CPB was significantly higher in group HF (n = 7) than in group N (n = 6) (22.0% ± 0.7% versus 16.0% ± 0.4%, p < 0.01). There was also a trend toward better stress velocity index in group HF than in group N (0.81 ± 0.81 versus −2.17 ± 0.45, p = 0.09). AaDO₂ and respiratory index were significantly lower in group HF than in group N for 48 hours after CPB, respectively (p < 0.05).

Conclusions. Hemofiltrated fresh whole blood used for CPB priming attenuated cardiac impairment at early reperfusion periods and reduced pulmonary dysfunction in neonates with transposition of the great arteries with intact ventricular septum. This therapeutic strategy may have an advantage in preventing lung and heart dysfunction in pediatric patients who need CPB priming with blood.     

Effect of Low-Dose Positive Inotropic Drugs on Human Internal Mammary Artery Flow

Background. Dobutamine (a β-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an - and β-mimetic) frequently are used in the perioperative management of patients undergoing coronary artery bypass grafting.

Methods. We performed a double-blind clinical study to compare the effects on internal mammary artery free flow of low doses of these three positive inotropic drugs. Thirty patients in whom the left internal mammary artery was used for coronary artery bypass grafting were randomized into three groups. Internal mammary artery free flow and hemodynamic measurements were evaluated before and 10 minutes after the intravenous infusion of dobutamine (3 μg · kg⁻¹ · min⁻¹), enoximone (200 μg/kg), or epinephrine (0.05 μg · kg⁻¹ · min⁻¹).

Results. A significant increase in free flow occurred only in the dobutamine group (33 ± 7.5 and 42.2 ± 7.9 mL/min before and after drug infusion, respectively; p = 0.013). Comparison of the increase in flow between the groups, however, showed no difference. These drugs, at doses designed to produce a positive inotropic effect, caused little increase in the free flow of the internal mammary artery.

Conclusions. The use of dobutamine, enoximone, and epinephrine as low-dose positive inotropic treatments in the perioperative and postoperative periods of coronary artery bypass grafting should depend on their positive inotropic effects rather than their vasodilative effects on the arterial grafts.     

Adjustable Model of Chronic Left Ventricular Dysfunction

Background. As an adjunct to the development of skeletal muscle-powered left ventricular assist devices, an adjustable model of chronic left ventricular failure was developed.

Methods. Implantation of a left ventricular balloon to induce heart failure was accomplished via left thoracotomy. Upon recovery, left ventricular failure was simulated by manipulation of left ventricular balloon volume to chronically raise left atrial pressure.

Results. Left atrial pressure increased from a baseline of 9.3 ± 0.7 mm Hg to 18.5 ± 1.2 mm Hg, 20.2 ± 1.8 mm Hg, and 26.0 ± 1.2 mm Hg by the 2nd, 6th, and 10th postoperative week, respectively. Cardiac index declined from a baseline of 4.4 ± 0.3 L · min⁻¹ · m⁻², reaching stability by the 8th postoperative week at 3.0 ± 0.4 L · min⁻¹ · m⁻². Stroke volume index declined from 1.12 ± 0.1 mL · kg⁻¹ · beat⁻¹ to 0.60 ± 0.1 mL · kg⁻¹ · beat⁻¹ by the 10th postoperative week. Mean survival was 75 ± 7 days. Causes of death included left ventricular failure, thromboembolism, and euthanasia.

Conclusions. This method of simulating chronic left ventricular dysfunction proved to be stable and adjustable and has been useful in the development of ventricular assist systems.     

Preliminary experience with the St. Jude Medical Regent mechanical heart valve in the aortic position: early in vivo hemodynamic results

Background. The St. Jude Medical Regent is a new generation mechanical aortic valve.

Methods. Between March 2000 and July 2001, this valve was implanted in the aortic position in 40 patients (21 men; mean age 59.1 ± 9.0 years). Preoperatively, 24 patients (60%) were in New York Heart Association functional class III or IV. Eighteen patients (45%) underwent associated procedures. Mean valve size was 21.4 ± 2.4 mm. The mean duration of follow-up was 8.5 ± 4.5 months (range, 1 to 16 months).

Results. There were no operative deaths. Early complications included one reoperation for bleeding and one transient low output syndrome. Valve replacement was followed by a significant reduction in mean and peak transaortic gradients over time (p < 0.001) and analysis of variance failed to demonstrate statistical differences between valve size over time (p = not significant). A significant reduction in left ventricular hypertrophy occurred over time (p = 0.01) in all valve sizes (p = not significant between groups): baseline left ventricular mass index was 194 g/cm²; it reduced by 22 g/cm² (p = 0.006) at discharge. Left ventricular mass index decreased from 172 ± 55 g/cm² to 156 ± 44 g/cm² (p = 0.03) from discharge to 2 months. Further reductions were not significant. Relative wall thickness decreased from 0.57 ± 0.13 preoperatively to 0.42 ± 0.06 at discharge (p = 0.001), and again at 2 months (−0.2; p = not significant), and at 1 year (−0.02; p = not significant).

Conclusions. The early experience with the St. Jude Medical Regent valve has been satisfactory.     

Sodium Nitroprusside Exacerbates Myocardial Ischemia–Reperfusion Injury

Background. The role of nitric oxide in myocardial ischemia–reperfusion is controversial. Although many studies claim that nitric oxide ameliorates reperfusion injury, others suggest that it exacerbates such injury, possibly through peroxynitrite production. These discordant results may be attributable to a dose-dependent phenomenon.

Methods. Isolated rabbit hearts sustained sequential periods of blood perfusion (20 minutes), warm ischemia (30 minutes), and reperfusion (20 minutes). During reperfusion, four groups underwent intracoronary infusion of saline solution (n = 6), or the nitric oxide donor sodium nitroprusside (100 nm/min [SNP100, n = 6], 1 nmol · L⁻¹/min⁻¹ [SNP1, n = 6], or 0.01 nmol · L⁻¹ · min⁻¹ [SNP0.01]). Left ventricular-developed pressure and oxygen consumption were measured after preischemic perfusion and reperfusion. Levels of myocardial nitrotyrosine, a marker for peroxynitrite, were measured after reperfusion with an immunoradiochemical assay.

Results. Postischemic-developed pressure and myocardial oxygen consumption were significantly higher in the saline group than all nitroprusside-reperfused groups (p < 0.01 for both parameters). However, there were no differences in either parameter between SNP100, SNP1, or SNP0.01. Nitrotyrosine levels were similar among the four groups (p = 0.43).

Conclusions. Nitroprusside exacerbates myocardial ischemia–reperfusion injury over a wide range of doses, although the mechanism does not appear to be mediated by peroxynitrite.