Leukocyte Depletion of Blood Cardioplegia Attenuates Reperfusion Injury

Background. Leukocytes are associated with myocardial injury during reperfusion after ischemia. Short periods of leukocyte depletion during reperfusion result in persistent attenuation of postischemic myocardial dysfunction.

Methods. Leukocyte depletion was examined in a canine model of regional myocardial ischemia and reperfusion. The extracorporeal circuit and cardioplegia circuits underwent leukocyte depletion by mechanical filtration. Animals were instrumented for baseline global function before 90-minute occlusion of the left anterior descending coronary artery. Global function during ischemia and at 5, 30, 60, and 90 minutes after a 60-minute cardioplegic arrest using continuous blood cardioplegia was assessed in leukocyte-depleted (n = 9) and control (n = 10) groups.

Results. No significant difference between groups was seen for systemic leukocyte counts, global function, or water content. Endothelial function was significantly protected as assessed by response to both calcium ionophore (endothelial-dependent, receptor-independent relaxation: leukocyte-depleted, 72% ± 19% of endothelin-induced constriction versus control, 46% ± 14%; p < 0.05) and acetylcholine (endothelial-dependent, receptor-dependent relaxation: leukocyte-depleted, 83% ± 11% versus control, 44% ± 15%; p < 0.05).

Conclusions. Leukocyte-mediated endothelial reperfusion injury can be attenuated by leukocyte depletion during reperfusion.     

Improved clinical outcomes in patients undergoing coronary artery bypass grafting with coronary endarterectomy

Background. Coronary artery bypass grafting (CABG) with coronary endarterectomy (CE) has been associated with increased morbidity and mortality. We sought to evaluate the impact of recent advances in operative and perioperative management on outcomes after CE.

Methods. One hundred fifty-one consecutive patients undergoing first-time CABG with CE between 1991 and 1997 were compared with a concurrent group of 757 patients undergoing CABG without CE (Control).

Results. Age, gender, left ventricular ejection fraction, percent nonelective were similar in both groups. Compared with control, the CE group had a higher incidence of hypertension (80% versus 71%, p = 0.02), diabetes (42% versus 32%, p = 0.01), prior myocardial infarction (MI) (68% versus 59%, p = 0.05), peripheral vascular disease (36% versus 16%, p < 0.001), renal failure (15% versus 4%, p < 0.001), and three-vessel coronary disease (81% versus 70%, p = 0.007), resulting in higher Society of Thoracic Surgeons database predicted mortality (4.9 ± 5.9% versus 3.9 ± 4.6%, p = 0.05). Despite the higher risk profile of the CE group, hospital mortality (CE 2.0%, Control 1.2%) and the incidence of major complications such as cerebrovascular accident (CVA) (0.7% versus 1.5%), major respiratory complications (8% versus 5%), and postoperative MI (3% versus 1.4%) were similar between the groups (all p = NS). In a multiple logistic regression analysis, prolonged cardiopulmonary bypass time was an independent predictor of postoperative MI (odds ratio 1.2, CI 1.05 to 1.39, p < 0.01) and the use of heparin-bonded cardiopulmonary bypass circuits of reduced MI rate (odds ratio 0.25, CI 0.08 to 0.76, p < 0.01). Mean follow-up for 94% of patients was 30 ± 19 months (range 1 to 83 months). Five-year survival after CE was 70 ± 5%, with 96% of patients in Canadian Cardiovascular Society class I/II.

Conclusions. In a contemporary series of carefully selected patients, mortality and major complications after CE are now similar to CABG without CE. CE itself is not an independent predictor of postoperative MI. Functional class of hospital survivors is excellent.     

Reduced blood loss and transfusion requirements with low systemic heparinization: preliminary clinical results in coronary artery revascularization

In coronary artery revascularization, low systemic heparinization was compared to full systemic heparinization during perfusion with heparin surface-coated cardiopulmonary bypass equipment. Twelve patients were randomly assigned to two groups and perfused with low [activated clotting time (ACT) > 180 s] or full (ACT > 480 s) systemic heparinization. A standard battery of blood samples was taken before the procedure, after heparinization, and at regular intervals during and after cardiopulmonary bypass. No differences were seen between the two groups in regard to age, body surface area, preoperative hematocrit, duration of bypass, bypass hypothermia, cross-clamp time, and number of bypasses per patient. However, there were more internal thoracic artery (ITA) grafts in the group with low systemic heparinization (1.5 ± 0.8 ITA grafts per patient versus 0.8 ± 0.4 ITA grafts per patient with full heparinization; p < 0.05). The oxygenator gradient at the end of perfusion (before weaning) was 107 ± 40 mmHg for low versus 110 ± 10 mmHg for full heparinization (difference not significant). The total amount of heparin used was 7200 ± 1030 IU for low versus 51 400 ± 9700 IU for full (p < 0.05). Postoperative hematocrit was 35.0 ± 2.0% for low versus 24.7 ± 2.7% for full (p < 0.05). Total chest tube drainage was 428 ± 153 ml/m² for low versus 935 ± 414 ml/m² for full (p < 0.05). Homologous transfusions of blood products were necessary in 3/6 patients for low versus 6/6 patients for full (p < 0.10). The total volume of packed red cells transfused was 221 ± 228 ml/m² for low versus 842 ± 366 ml/m² for full (p < 0.05). Final hematocrit at day 7 was 31.0 ± 2.0% for low versus 33.0 ± 3.0% for full (difference not significant). Full systemic heparinization can be avoided during clinical cardiopulmonary bypass by the use of heparin-coated perfusion equipment. A low dose of heparin, similar to the amounts given during vascular surgery, results in reduced blood loss and transfusion requirements.     

Superiority of magnesium cardioplegia in neonatal myocardial protection

Background. We have shown that magnesium can offset the detrimental effects of normocalcemic cardioplegia in hypoxic neonatal hearts. It is not known, however, whether magnesium offers any additional benefit when used in conjunction with hypocalcemic cardioplegia.

Methods. Twenty neonatal piglets underwent 60 minutes of ventilator hypoxia (FiO₂ 8% to 10%) followed by 20 minutes of normothermic ischemia on cardiopulmonary bypass (hypoxic-ischemic stress). They then underwent 70 minutes of multidose blood cardioplegic arrest. Five (Group 1), received a hypocalcemic (Ca⁺² 0.2 to 0.4 mM/L) cardiologic solution without magnesium, whereas in 10, magnesium was added at either a low dose (5 to 6 mEq/L, Group 2) or high dose (10 to 12 mEq/L, Group 3). In the last 5 (Group 4), magnesium (10 to 12 mEq/L) was added to a normocalcemic cardioplegic solution. Function was assessed using pressure volume loops and expressed as percentage of control.

Results. Compared to hypocalcemia cardioplegic solution without magnesium (Group 1), both high- and low-dose magnesium enrichment (Groups 2 and 3) improved myocardial protection resulting in complete return of systolic (40% vs 101% vs 102%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (39% vs 102% vs 101%) (p < 0.001 vs Groups 2 and 3), and reduced diastolic stiffness (267% vs 158% vs 154%) (p < 0.001 vs Groups 2 and 3). Conversely, even high-dose magnesium supplementation could not offset the detrimental effects of normocalcemic cardioplegia resulting in depressed systolic (End Systolic Elastance [EES] 41% ± 1%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (40% ± 1%) (p < 0.001 vs Groups 2 and 3), and a marked rise in diastolic stiffness (258% ± 5%) (p < 0.001 vs Groups 2 and 3). Hypocalcemic magnesium cardioplegia has now been used successfully in 247 adult and pediatric patients.

Conclusions. Magnesium enrichment of hypocalcemic cardioplegic solutions improves myocardial protection resulting in complete functional preservation. However, magnesium cannot prevent the detrimental effects of normocalcemic cardioplegia when the heart is severely stressed. This study, therefore, strongly supports using both a hypocalcemic cardioplegic solution and magnesium supplementation as their benefits are additive.     

Intermittent Antegrade Tepid Versus Cold Blood Cardioplegia in Elective Myocardial Revascularization

Background. The ideal temperature for blood cardioplegia administration remains controversial.

Methods. Fifty-two patients who required elective myocardial revascularization were prospectively randomized to receive intermittent antegrade tepid (29°C; group T, 25 patients) or cold (4°C; group C, 27 patients) blood cardioplegia.

Results. The two cohorts were similar with respect to all preoperative and intraoperative variables. The mean septal temperature was higher in group T (T, 29.6° ± 1.1°C versus 17.5° ± 3.0°C; p < 0.0001). After reperfusion, group T exhibited significantly greater lactate and acid release despite similar levels of oxygen extraction (p < 0.05). The creatine kinase-MB isoenzyme release was significantly lower in group T (764 ± 89 versus 1,120 ± 141 U · h/L; p < 0.04). Hearts protected with tepid cardioplegia demonstrated significantly increased ejection fraction with volume loading, improvement in left ventricular function at 12 hours, and decreased need for postoperative inotropic support (p < 0.05). The frequency of ventricular defibrillation after cross-clamp removal was lower in this cohort (p < 0.05). There were no hospital deaths, and both groups had similar postoperative courses.

Conclusions. Intermittent antegrade tepid blood cardioplegia is a safe and efficacious method of myocardial protection and demonstrates advantages when compared with cold blood cardioplegia in elective myocardial revascularization.     

Adenosine-enhanced ischemic preconditioning provides enhanced cardioprotection in the aged heart

Background. Recently we have reported a novel myoprotective protocol “adenosine-enhanced ischemic preconditioning” (APC), which extends and amends the protection afforded by ischemic preconditioning (IPC) by both reducing myocardial infarct size and enhancing postischemic functional recovery in the mature rabbit heart. However, the efficacy of APC in the senescent myocardium was unknown.

Methods. The efficacy of APC was investigated in senescent rabbit hearts and compared with magnesium-supplemented potassium cardioplegia (K/Mg) and IPC. Global ischemia (GI) hearts were subjected to 30 minutes of global ischemia and 120 minutes of reperfusion. Ischemic preconditioning hearts received 5 minutes of global ischemia and 5 minutes of reperfusion before global ischemia. Magnesium-supplemented potassium cardioplegia hearts received cardioplegia just before global ischemia. Adenosine-enhanced ischemic preconditioning hearts received a bolus injection of adenosine in concert with IPC. To separate the effects of adenosine from that of APC, a control group (ADO) received a bolus injection of adenosine 10 minutes before global ischemia.

Results. Infarct size was significantly decreased to 18.9% ± 2.7% with IPC (p < 0.05 versus GI); 17.0% ± 1.0% with ADO (p < 0.05 versus GI); 7.7% ± 1.3% with K/Mg (p < 0.05 versus GI, IPC, and ADO); and 2.1% ± 0.6% with APC (p < 0.05 versus GI, IPC, ADO, and K/Mg; not significant versus control). Only APC and K/Mg significantly enhanced postischemic functional recovery (not significant versus control).

Conclusions. Adenosine-enhanced ischemic preconditioning provides similar protection to K/Mg cardioplegia, significantly enhancing postischemic functional recovery and decreasing infarct size in the senescent myocardium.     

Optimizing timing of early extubation in coronary artery bypass surgery patients

Background. This study was designed to assess the safety and efficacy of extubation performed within 4 hours of the patient’s arrival in the surgical intensive care unit after coronary artery bypass graft surgery.

Methods. A matched retrospective cohort study was performed including 412 consecutive patients undergoing isolated coronary artery bypass graft surgery between January 1996 and December 1997, constituting the experience of a single surgeon (J.H.L.). Early extubation (defined as extubation within 8 hours of arrival at the surgical intensive care unit) was achieved in 308 of 412 patients (75%). Patients extubated in fewer than 4 hours after arrival (n = 200) were compared with patients extubated within 4 to 8 hours (n = 108).

Results. Four deaths occurred in 412 patients, for an overall operative mortality rate of 1.0%. Patients extubated in fewer than 4 hours were younger than those extubated 4 or more hours after admission (62 versus 67 years old, respectively; p = 0.001), more likely to be male (74% versus 63%, p < 0.05), and had shorter aortic cross-clamp times (49.4 ± 15.0 versus 53.5 ± 14.0 minutes, p < 0.05) and cardiopulmonary bypass (CPB) times (65.2 ± 18.6 versus 72.1 ± 19.1 minutes, p < 0.05) compared to patients extubated later. Moreover, patients extubated in fewer than 4 hours had a shorter surgical intensive care unit length of stay (33.8 ± 25.7 versus 43.1 ± 43.0 hours, p < 0.05) and shorter postoperative length of stay (5.4 ± 2.4 versus 6.2 ± 2.6 days, p = 0.01) than those extubated later.

Conclusions. Extubation in fewer than 4 hours may offer a substantial advantage in terms of accelerated recovery compared with extubation within 4 to 8 hours. Very few differences in clinical parameters were noted between the two groups we studied, suggesting that efforts to reduce extubation times further might be worthwhile.     

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.     

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.     

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.     

Economic outcome of off-pump coronary artery bypass surgery: a prospective randomized study

Background. Emphasis on cost containment in coronary artery bypass surgery is becoming increasingly important in modern hospital management. The revival of interest in off-pump (beating heart) coronary artery bypass surgery may influence the economic outcome. This study examines these effects.

Methods. Two hundred patients undergoing first-time coronary artery bypass surgery were prospectively randomized to either conventional cardiopulmonary bypass and cardioplegic arrest or off-pump surgery. Variable and fixed direct costs were obtained for each group during operative and postoperative care. The data were analyzed using parametric methods.

Results. There was no difference between the groups with respect to pre- and intraoperative patient variables. Off-pump surgery was significantly less costly than conventional on-pump surgery with respect to operating materials, bed occupancy, and transfusion requirements (total mean cost per patient: on pump, $3,731.6 ± 1,169.7 vs off-pump, $2,615.13 ± 953.6; p < 0.001). Morbidity was significantly higher in the on-pump group, which was reflected in an increased cost.

Conclusions. Off-pump revascularization offers a safe, cost-effective alternative to conventional coronary revascularization with cardiopulmonary bypass and cardioplegic arrest.     

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.     

The Brain Uses Mostly Dissolved Oxygen During Profoundly Hypothermic Cardiopulmonary Bypass

Background. During profoundly hypothermic cardiopulmonary bypass, cerebral venous oxygen saturation increases (eg, to 98% at 15°C). We reanalyzed results of clinical studies to learn why.

Methods. One hundred sixty-eight cerebral oxygen transport measurements were available from 96 infants and children undergoing profoundly hypothermic cardiopulmonary bypass during repair of congenital heart defects.

Results. Dissolved oxygen accounted for 2% to 17% of arterial oxygen content, depending on the arterial oxygen partial pressure and hemoglobin concentration. The fraction of the cerebral metabolic rate for oxygen obtained from dissolved oxygen depended on pump flow, temperature, hemoglobin concentration, and arterial oxygen partial pressure (all p < 10⁻³). For “full-flow” cardiopulmonary bypass, temperatures less than 18°C, and arterial oxygen partial pressure measurements more than 180 mm Hg, the mean ± standard deviation of the fraction of cerebral metabolic rate for oxygen obtained from dissolved oxygen equaled 77% ± 19%.

Conclusions. Dissolved oxygen satisfies most of the brain's oxygen requirements during profound hypothermic cardiopulmonary bypass. This result reflects four properties of profound hypothermic cardiopulmonary bypass: (1) increases in hemoglobin's oxygen affinity due to profound hypothermia (which impairs oxygen transfer from hemoglobin to cerebral tissue), (2) use of hemodilution, (3) use of high arterial oxygen partial pressure, and (4) low cerebral metabolic rate of oxygen.     

Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion

Background. Ischemic preconditioning (IP) is gaining more acceptance as a protective method in beating heart surgery. Yet it remains controversial whether preconditioning can attenuate myocardial dysfunction during reperfusion after severe coronary hypoperfusion. We examined this issue and also the issue of whether this protection is mediated by adenosine A₁ receptors.

Methods. In isolated, blood-perfused rabbit hearts, the effects of IP (3 minutes of no flow ischemia and 8 minutes of reperfusion) during 30 minutes of coronary hypoperfusion and 60 minutes of reperfusion were investigated. In two groups (n = 8 each) with and without (control group) preconditioning, ventricular function was assessed by load-insensitive measures: slope of the end-systolic pressure–volume relation (E_max), slope of the stroke work/end-diastolic volume relation (M_w), and end-diastolic pressure–volume relation. External efficiency was calculated, and contractile efficiency was assessed using the reciprocal of the myocardial oxygen consumption–pressure–volume area relationship. To investigate the possible role of adenosine, the adenosine A₁ receptor antagonist DPCPX (2.5 μmol/L) was administered before preconditioning in a third group (n = 7).

Results. The effects of hypoperfusion on systolic function, diastolic function (dP/dt_min, end-diastolic pressure–volume relation), external efficiency, and contractile efficiency were similar in both the IP and control groups. Lactate efflux was significantly reduced after preconditioning (p = 0.02). During reperfusion, recovery of systolic function and coronary flow were significantly improved in the IP group compared with controls: aortic flow, 85% versus 63% (p = 0.01); dP/dt_max, 91% versus 67% (p = 0.001); pressure–volume area, 97% versus 68% (p = 0.01); E_max, 74% versus 62% (p = 0.03); and M_w, 94% versus 84% (p = 0.04). Release of creatine kinase was reduced in the IP group, 9.6 ± 1.3 U · 5 min⁻¹ · 100 g⁻¹ wet weight, versus controls, 12.7 ± 2.7 U · 5 min⁻¹ · 100 g⁻¹ wet weight (p = 0.04). During reperfusion, contractile efficiency (p = 0.03) and external efficiency (p = 0.02) recovered better in preconditioned than in untreated hearts. Recovery was less pronounced in the DPCPX group compared with the IP group (p, not significant).

Conclusions. The results, derived from load-insensitive measures, confirm that IP provides protection after episodes of severe hypoperfusion by attenuating systolic dysfunction without improving diastolic dysfunction and reduces the severity of anaerobic metabolism as well as ischemic injury. Contractile efficiency and external efficiency both indicate improved energetics after IP (oxygen utilization by the contractile apparatus). The protective effect, at least in part, is mediated by adenosine A₁ receptors.     

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.     

Myocardial metabolism and efficiency after warm continuous blood cardioplegia

Background. Warm continuous blood cardioplegia (WCBCP) has been recommended during prolonged cardiac arrest to minimize functional deterioration. Myocardial metabolism and efficiency after this cardioplegic modality are not well described.

Methods. Substrate oxidation, blood flow, and myocardial function were measured before, during, and after 3 hours of WCBCP in 7 pigs.

Results. Free fatty acid and glucose oxidation decreased by 60% ± 3.8% and 94% ± 1.2%, respectively, during cardioplegia (both p < 0.05) and increased to 62% ± 28% and 122% ± 62% of baseline during the early recovery phase (p < 0.05 for glucose). One hour after WCBCP oxidation rates were similar to baseline. The transient postcardioplegic increase in substrate oxidation was associated with a 43% ± 23% elevation of oxygen consumption (MVO₂) compared with baseline and a 62% ± 18% increase in myocardial blood flow. Cardiac output and mean arterial pressure did not change significantly after WCBCP, although myocardial function (stroke work, left ventricular end-systolic pressure, end-diastolic pressure, contractility, and efficiency) was depressed (p < 0.05). End-diastolic pressure and contractility improved from early to late phase of recovery, whereas the other indicators of ventricular function remained depressed.

Conclusions. Myocardial substrate oxidation was preserved after 3 hours of WCBCP, although ventricular function was moderately impaired. Thus, WCBCP with a seemingly normal substrate and oxygen supply was associated with a reduced cardiac efficiency.     

Esmolol and cardiopulmonary bypass during reperfusion reduce myocardial infarct size in dogs

Background. Infarct size can be reduced by β-blockade in acute myocardial ischemia. However it is unknown whether myocardial salvage is still effective when β-blockade is limited to reperfusion.

Methods. After initiation of cardiopulmonary bypass, 20 dogs were submitted to 2 hours of regional left ventricular ischemia, followed by 2 hours of reperfusion. In 11 dogs β-blockade was started with the onset of reperfusion (esmolol group). The remaining dogs received no treatment (control, n = 9). Infarct size was determined by tetrazolium chloride staining. Myocardial water content (MWC) and ultrastructural damage (electronmicroscopy) were determined from transmural biopsies.

Results. Infarct size was significantly smaller in the esmolol group compared with control (49% versus 68%, p < 0.05). After 2 hours ischemia there was no difference in MWC between groups, whereas after 2 hours reperfusion MWC of ischemic myocardium was significantly lower in the esmolol group than in the control (p < 0.05). Ultrastructural changes were typical for ischemia-reperfusion injury in both groups.

Conclusions. β-Blockade may be cardioprotective during reperfusion through various mechanisms and may enhance myocardial salvage, even when treatment is initiated as late as with the onset of reperfusion.     

Calcitonin Gene-Related Peptide-Induced Preconditioning Improves Preservation With Cardioplegia

Background. Our recent work has shown that calcitonin gene-related peptide (CGRP) may play an important role in mediation of ischemic preconditioning. Therefore, we tested the hypothesis that CGRP-induced preconditioning protects against myocardial damage after prolonged cardioplegic arrest in isolated rat hearts.

Methods. Six groups were studied: the control, ischemic preconditioning, and CGRP-pretreated groups for both 4- and 8-hour hypothermic ischemia. All hearts were arrested using St. Thomas Hospital cardioplegia, and then reperfused with normothermic Krebs-Henseleit solution for 60 minutes after the 4- or 8-hour hypothermic ischemic period. Hearts were subjected to two cycles of 5-minute ischemia and 10-minute reperfusion in the ischemic preconditioning group. In the CGRP-pretreated group, Krebs-Henseleit solution containing CGRP (5 × 10⁻⁹ mol/L) was substituted for the ischemic period.

Results. At 30 minutes of reperfusion after 4-hour storage, left ventricular pressure (mm Hg) and its first derivative (dp/dt_max, mm Hg/s) in the control, ischemic preconditioning, and CGRP groups were 65.2 ± 5.93 and 1,170 ± 119, 94.13 ± 4.93 and 1,825 ± 145.83, and 85.47 ± 4.17 and 1,900 ± 123.13, respectively (p < 0.01). After 8-hour storage, left ventricular pressure (mm Hg) and dp/dt_max (mm Hg/s) in the same groups were 51.07 ± 5.83 and 815 ± 107.17, 83.47 ± 6.54 and 1,480 ± 120.91, and 84.8 ± 8.49 and 1,396 ± 126.16 (p < 0.01). Ischemic preconditioning and CGRP-induced preconditioning also significantly reduced the release of myocardial enzymes.

Conclusions. The present studies suggest that ischemic preconditioning protects against ischemia-reperfusion injury even after 8 hours of hypothermic preservation in isolated rat hearts, and that CGRP exerts preconditioning-like cardioprotection.     

Expression of Immediate Early Genes After Cardioplegic Arrest and Reperfusion

Background. Induction of protooncogenes such as c-fos, c-jun, and EGR-1 has been implicated in cellular growth and differentiation. Heat-shock proteins (HSPs) such as hsp 70 may mediate resistance to ischemia after heat shock and ischemic preconditioning. The effects of cardioplegia on the regulation of these immediate early genes are unclear.

Methods. Isolated rat hearts were subjected to different cold (5°C) or normothermic (35°C) cardioplegic solutions and reperfused with normothermic Krebs-Henseleit buffer. Right atrial biopsy specimens from patients undergoing coronary artery bypass grafting with cold cardioplegic arrest were taken before and after cardiopulmonary bypass. Analysis of immediate early gene messenger RNAs was performed using Northern blots. Related proteins were localized by immunohistochemistry.

Results. In rat hearts, cold cardioplegia for 40 minutes with Bretschneider or St. Thomas' II solution followed by 40 minutes' reperfusion resulted in a significant increase in left ventricular c-fos, EGR-1, and c-jun messenger RNA levels (4.0-, 3.1-, and 3.0-fold, respectively, with Bretschneider solution and 3.7-, 2.8-, and 2.1-fold, respectively, with St. Thomas' II solution) compared with control hearts perfused at 35°C with Krebs-Henseleit buffer. Normothermic cardioplegia with St. Thomas' II solution was without effect, whereas sequential perfusion with Krebs-Henseleit buffer at 5°C and 35°C resulted in a similar increase in protooncogene messenger RNA levels. Only cold Bretschneider solution was related to a 5.2-fold induction of hsp 70 messenger RNA levels. Likewise, rat atrial tissues and samples from patients after cardiopulmonary bypass displayed a significant induction of these immediate early genes. Monoclonal antibodies against c-FOS and HSP 70 proteins stained nuclei and perinuclear spaces of endothelial cells and cardiac myocytes.

Conclusions. Cold cardioplegic arrest and normothermic reperfusion are potent triggers for immediate early gene induction. Hypothermia emerged as the prime stimulus for the examined protooncogenes. In contrast, hsp 70 induction was dependent on the cardioplegic solution.     

Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non-heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.

Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non-heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non-heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.

Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).

Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.