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Calcium channel blockers constitute a very important group of drugs that are commonly used in the treatment of cardiovascular and cerebrovascular disorders. Current indications for these medications include hypertension, angina, supraventricular arrhythmias, and prevention of coronary and cerebral vasospasm. Although calcium channel blockers originally held great promise in the treatment of myocardial and cerebral ischemia, clinical results have been discouraging. An understanding of the basic physiological mechanisms of actions for these drugs is important for the practising clinician and may explain the disappointing results for the treatment of ischemia to date. This paper is a narrative review, from a clinician's viewpoint, of the structure and role of calcium channels in cardiac and cerebrovascular tissues, as well as a review of the in vitro and clinical results of calcium channel blockade in myocardial and cerebral ischemia.

Idiopathic hypertrophic obstructive cardiomyopathy (HOCM) is characterized by regional myocardial hypertrophy. In our previous study, we demonstrated that mRNA levels for insulin-like growth factor-I (IGF-I) and transforming growth factor-beta 1 (TGF-beta 1) were elevated in HOCM tissue. In this study, we investigated IGF-I and TGF-beta 1 protein levels and their respective receptor levels and localization.Myocardial growth factor protein levels were quantified with the use of chemiluminescent slot blot analysis with monoclonal antibodies against IGF-I and TGF-beta. The growth factor receptor binding sites were evaluated with 125I-labeled IGF-I and TGF-beta 1. The receptors were localized with immunohistochemistry. Data were expressed as mean +/- SEM. IGF-I and TGF-beta protein levels in HOCM myocardium (351.8 +/- 46.5 and 17.4 +/- 2.0 ng/g tissue, respectively; n = 6) were significantly higher (P0.01 for all groups) than in non-HOCM myocardium obtained from patients with aortic stenosis (AS, 182.1 +/- 22.7 and 8.0 +/- 1.2 ng/g tissue, respectively; n = 5), stable angina (SA, 117.4 +/- 20.9 and 7.5 +/- 2.7 ng/g tissue, respectively; n = 5), and transplanted hearts (TM, 166.3 +/- 30.1 and 6.4 +/- 1.2 ng/g tissue, respectively; n = 5). Maximal and high-affinity binding sites for IGF-I receptor in the HOCM were greater (P0.01 and P0.05) than the levels in AS, SA, and TM. The maximal receptor binding sites for TGF-beta 1 in HOCM were greater (P0.05) than those for SA and TM. Immunohistochemistry demonstrated that IGF-I and TGF-beta 1 receptors were located on the cardiomyocytes and TGF-beta 1 receptors were located on the fibroblasts.Increased IGF-I and TGF-beta 1 gene expression previously observed in HOCM myocardium results in elevated protein levels. IGF-I and TGF-beta 1 signals may be further amplified by increased receptor numbers on cardiomyocytes and fibroblasts. The data suggest a possible autocrine mechanism of IGF-I-stimulated cardiomyocyte hypertrophy and a paracrine mechanism of TGF-beta 1-stimulated extracellular matrix overproduction in HOCM.

Current therapeutic options for myocardial infarction include medical therapy, of proven but limited benefit, and various surgical options, which have either restricted applicability or unproven benefit. New cellular-based therapeutic strategies are being developed in response to the shortcomings of available treatments. These include attempts to reinitiate cardiomyocyte proliferation in the adult, conversion of fibroblasts to contractile myocytes and transplantation of myocytes into injured myocardium. The development and current status of these techniques and their relative advantages, problems remaining to be solved and potential clinical applications are reviewed.

The collection and documentation of data from patients undergoing concurrent surgical treatment has been one of the most useful but least used methods of surgical clinical research. The advantages of intraoperative clinical research are obvious, whether it involves a descriptive cohort study or a randomized controlled clinical trial. Clinical application of new surgical techniques increases rapidly following perioperative documentation of their benefits. For example, the use of blood cardioplegia in cardiac surgery at our institution increased from approximately 10% in 1980 to almost 100% in 1995. This increased utilization of blood cardioplegia followed the intraoperative documentation of its metabolic and functional benefits, along with an improvement in morbidity and mortality rates associated with its use.1

Fetal rat cardiomyocytes transplanted into left ventricular scar tissue of the adult rat heart limit scar expansion and improve heart function. This study determined morphologic changes of transplanted fetal rat cardiomyocytes in myocardial scar tissue.The left ventricles of 500-g Sprague-Dawley rats were cryodamaged. At 4 weeks after myocardial injury, a transmural scar (54+/-11 mm2) (mean+/-1 SDak) formed at the apex (n=6). Cardiomyocytes freshly isolated from 18-day-gestation Sprague-Dawley rat hearts were transfected with plasmid containing the beta-galactosidase and then injected into the 4-week-old scar tissue. Cell culture medium was injected into the scar tissue of control animals. At 4 weeks posttransplantation, the cardiomyocytes had formed cardiac tissue (20.7+/-6.9 mm2, n=14), which stained positively for beta-galactosidase activity in the scar (90.4+/-25 mm2, n=14). The transplanted cardiomyocytes formed sarcomeres and were linked by junctions composed of desmosomes and fascia adherens. Lymphocyte infiltration occurred despite use of cyclosporin A. No myocardial tissue was found in the scar tissue of the control animals (n=14). More arterioles and venules were found (P.01) in the cardiomyocyte grafts (1.2+/-0.6 vessel/0.8 mm2; n=14) than in the control scar tissue (0.1+/-0.1 vessels/0.8 mm2; n=14). At 20 weeks post-transplantation, the transplant tissue size (6+/-6 mm2; n=7) was smaller (P=.007) than 4-week old transplant, and the scar (162+/-46 mm2; n=7) was larger (P=.005) than 4-week-old scar. Lymphocyte infiltration was still present among the remaining transplanted cells.This study demonstrated that cardiac tissue formed by transplanted fetal cardiomyocytes in the myocardial scar tissue decreased in size with time probably secondary to rejection.

Improved methods of donor heart preservation may allow for prolonged storage and permit remote procurement. Previous attempts to use oxygenated perfusion circuits during storage have not gained widespread acceptance because they were either too impractical or complicated to use for remote harvest. We hypothesized that collection and perfusion of donor blood during prolonged storage may improve myocardial recovery. Our aim was to devise a safe, simple, cost-effective system that could be used in any hospital setting.Yorkshire pigs (40 to 50 kg) were used to perform 16 orthotopic heart transplantations with either continuous perfusion with donor blood (BL, n = 8) or standard hypothermic storage (CON, n = 8). After administration of heparin, hypothermic (4 degrees C) cardioplegic arrest, and donor heart extraction, donor blood (2688 +/- 166 ml) was harvested in the BL group. After filtration for particulate matter, blood perfusion was initiated via a standard intravenous transfusion apparatus at room temperature (20 degrees C) and a pressure of 60 mm Hg and maintained during storage. Arterial and coronary sinus blood samples were obtained to examine myocardial oxygen extraction, lactate release, and acid production. A Millar micromanometer was used to measure left ventricular developed pressures at an end-diastolic pressure of 2 and 10 mm Hg both before and after transplantation.All pigs (eight of eight) in the BL group were successfully weaned off bypass compared to three of eight in the CON group (p0.01). Developed pressures (at left ventricular end-diastolic pressure = 10 mm Hg) was improved in the BL group (mean +/- SD: baseline: BL: 90 +/- 16 mm Hg vs CON: 83 +/- 12 mm Hg, p = NS; posttransplantation: BL: 66 +/- 8 mm Hg vs CON: 35 +/- 29 mm Hg, p0.05). Similarly, maximum dP/dt was higher in the BL group. Lactate release was higher at cross-clamp removal in the BL group (2.4 +/- 0.3 mmol/L vs 0.7 +/- 0.2 mmol/L, p0.01). There were no differences in oxygen extraction or acid production during reperfusion.Perfusion of donor blood improved the ability to wean off bypass after 4 hours of storage. Blood perfusion permitted persistent myocardial metabolism during the ischemic period, which led to improved functional recovery. Harvesting donor blood for subsequent perfusion during prolonged storage may improve the results of orthotopic heart transplantation and allow for more distant procurement of donor organs.

Advances in surgical technique and perioperative myocardial protection have reduced the risk of aortic and mitral valve surgery. Improved methods of valve repair have reduced the proportion of patients who require valve replacement. However, patients who require valve replacement often have advanced disease and/or extensive calcification and may therefore be at increased risk for perioperative morbidity and mortality.We reviewed the results of 2898 patients who underwent aortic (AVR) or mitral (MVR) valve replacement at the Toronto Hospital. We compared patients who underwent surgery between January 1982 and December 1986 (early group) with those who were operated on between January 1989 and December 1993 (late group). The univariable and multivariable predictors of postoperative low-output syndrome (LOS) and operative mortality (OM) were determined for each time period. A total of 1779 patients underwent AVR (late, n = 997; early, n = 782). Multivariable analyses revealed that the late group had significantly more patients with independent pre-epidemiology operative risk factors for both OM and LOS. Despite the greater proportion of high risk patients, the incidence of postoperative LOS was lower in the late group (10% versus early, 14%; P = .012). There was no difference in OM between the two groups (late, 3.4% versus early, 3.7%; P = .732). A Total of 1119 patients underwent MVR (late, n = 493; early, n = 626). Compared with the early group, the late group had significantly more patients with preoperative multivariable risk factors for OM and LOS. There was no difference in postoperative LOS (late, 19% versus early, 21%; P = .361) or OM between the two groups (late, 5.8% versus early, 6.9%; P = .432).Despite an increase in high-risk patients, there was no significant increase in mortality or morbidity associated with aortic or mitral valve surgery.

At the request of the Councils of The Society of Thoracic Surgeons (STS) and The American Association for Thoracic Surgery (AATS) the Ad Hoc Liaison Committee for Standardizing Definitions of Prosthetic Heart Valve Morbidity "revisited" the "Guidelines" published in September 1988 [1-3]. The purpose of the review was to update and clarify definitions within the guidelines and to consider recommendations made by others [4, 5]. The variety of cardiac valvular procedures has expanded since 1988; therefore, in this document the term "operated valve" indicates prosthetic and bioprosthetic heart valves of all types: operated or repaired native valves and allograft and autograft valves. The term "operated valve" includes any cardiac valve altered by a surgeon during an operation. Much morbidity and mortality is a direct consequence of the interaction between the patient and operated valve(s), although patient variables (e.g., age, degree of coronary arterial disease, follow-up care) may be more responsible for outcomes than an operated valve. However, no set of guidelines can identify all possible patient factors that may affect morbidity and mortality. General agreement regarding the following definitions of terms and suggestions for reporting data do not preclude more detailed analyses or constructive recommendations and investigators are encouraged to identify relevant patient factors in addition to factors related to operated valves.

Concomitant lesions of the heart and lung are uncommon, but when present they pose a therapeutic challenge for thoracic surgeons. A combined procedure avoids the need for a second major thoracic procedure and may improve outcomes and provide economic benefit. However, cardiopulmonary bypass may adversely affect the natural history of pulmonary malignancies.The clinical records of 30 patients were reviewed who underwent simultaneous lung resection and cardiac operations between January 1982 and July 1995. Follow-up was obtained on all 30 patients (mean follow-up, 22 months; range, 1 to 100 months).Twenty-four patients underwent coronary artery bypass grafting in conjunction with pulmonary resection. Six patients underwent aortic (n = 4) or mitral (n = 2) valve replacement. The pulmonary resections consisted of pneumonectomy (n = 3), lobectomy (n = 14), wedge excision (n = 12), and tracheal resection (n = 1). Twenty-one patients had pathologic findings that confirmed adenocarcinoma (n = 10), squamous cell carcinoma (n = 5), small cell carcinoma (n = 2), or other malignancy (n = 4). Tumor stage of primary lung cancers was stage I, n = 12; stage II, n = 3; and stage IIIa, n = 2. Pathologic examination revealed benign disease in 9 patients. There were two operative deaths, one due to aspiration and one due to stroke. There were three late deaths, two cardiac and one of metastatic disease. Overall late survival was 85% +/- 7% and 73% +/- 16% at 1 and 5 years, respectively. Actuarial survival for patients with malignant disease was 64% at 5 years.Simultaneous cardiac operation and lung resection was not associated with increased early or late morbidity or mortality. Cardiopulmonary bypass does not adversely affect survival in patients with malignant disease. Cardiac valve replacement can be performed safely in conjunction with pulmonary resection.

Previous investigations from this institution and others support the role of University of Wisconsin solution for prolonged hypothermic cardiac storage. Modification of the divalent cation concentrations has been beneficial for cardioplegic investigations and may enhance cardiac recovery after extended preservation.To investigate this hypothesis, isolated rodent hearts were obtained from Sprague-Dawley rats and mounted on a Langendorff apparatus. Rat hearts were flushed (15 ml/kg) and stored (30 ml) for 8 hours at 0 degree C in unmodified University of Wisconsin solution (n = 16/group) or University of Wisconsin solution with calcium concentrations of 0.025 to 10 mmol/L or magnesium concentrations of 10 to 20 mmol/L (six to eight hearts/group). Finally, combinations of calcium and magnesium were examined. Rat hearts were studied before storage and after 45 minutes of reperfusion with an intraventricular balloon.Developed pressure (mean +/- standard deviation) was increased with calcium 0.1 mmol/L (University of Wisconsin solution: 69.2% +/- 7.0%; Ca++ 0.1 mmol/L: 78.9% +/- 6.1%, p0.05), whereas only the addition of the highest calcium concentration (10 mmol/L) was significantly harmful (developed pressure: 58.3% +/- 8.4%, p0.05; creatine kinase release: 408 +/- 200 versus 170 +/- 104 IU/gm, p0.05; lactate dehydrogenase release: 103 +/- 43 versus 37 +/- 26 IU/gm, p0.05). Coronary flow recovered to control values with magnesium 15 mmol/L, which was significantly greater than that achieved with unmodified University of Wisconsin solution (97.1% +/- 14.6% versus 72.1% +/- 8.4%, p0.05). Of the calcium-magnesium combinations tested, developed pressure was increased compared with unmodified University of Wisconsin solution with calcium 0.1 and magnesium 20 mmol/L (76.8% +/- 6.4%, p0.05). Diastolic function was reduced in all groups (p0.0001) and not significantly different between groups.The experiments indicated that recovery after storage with University of Wisconsin solution is enhanced with the addition of calcium and magnesium. The addition of high concentrations of calcium (or = 2.5 mmol/L) appears harmful.

Adenosine pretreatment has been shown to be beneficial in several models of ischemia-reperfusion. We wished to evaluate whether adenosine pretreatment is cardioprotective for prolonged cardiac storage and whether the presence of adenosine in the storage media affects the results. Isolated rodent hearts were obtained from Sprague-Dawley rats, mounted on a Langendorff apparatus, instrumented with an intraventricular balloon, and ventricularly paced at 300 beats/min. Four groups of hearts were studied in a 2 x 2 factorial experiment (n = 8 to 12 per group). Hearts were subjected to normal perfusion or to solution supplemented with adenosine 50 mumol/L for 10 minutes followed by adenosine-free perfusion for 10 minutes. Hearts then were stored for 8 hours at 0 degrees C in either University of Wisconsin solution (adenosine 5 mmol/L) or St. Thomas' Hospital II solution (adenosine free). Adenosine pretreatment increased tissue levels of adenosine triphosphate before storage (p = 0.04). Nonfunction was less common after storage (1/19 versus 6/20 hearts, p0.05), and diastolic function was better preserved in the adenosine groups in the reperfusion phase (p = 0.01). The beneficial effects of adenosine pretreatment were independent of which storage solution was used. Developed pressure was increased (p0.05) and release of creatine kinase and lactate dehydrogenase was reduced (p0.0001) in hearts treated with University of Wisconsin solution compared with those treated with St. Thomas' Hospital solution. These studies suggest that adenosine pretreatment improves recovery after prolonged hypothermic storage and that the presence of adenosine in the preservation solution does not alter the results. The experiments provide further evidence that extended myocardial protection is better enhanced with University of Wisconsin solution than with St. Thomas' Hospital II solution.

The late hemodynamic effects of preserving the papillary muscles during mitral valve replacement have not been evaluated.Sixteen patients who had chronic mitral regurgitation due to myxomatous degeneration were randomized to preservation (Pres group, n = 8) or no preservation (No Pres group, n = 8) of the chordae tendineae and papillary muscles during mitral valve replacement. Rest and exercise nuclear ventriculograms were performed early (3 months) and late (5 years) after surgery. Early after surgery, the No Pres group had lower ejection fractions and stroke work indexes (P.05 by repeated-measures [rm] ANOVA) than the Pres group did at similar end-diastolic volume indexes. The No Pres group had similar cardiac indexes after exercise because heart rate increased (P.005 by rm ANOVA). Late after surgery, ejection fraction was greater at similar end-diastolic volume indexes (P.005 by rm ANCOVA), and preload recruitable stroke work indexes (P.001 by rm ANCOVA) were better in the Pres group.Preserving chordal attachments enhanced the late hemodynamic recovery after mitral valve replacement for mitral regurgitation.

Free radical lipid peroxidation contributes to the abnormal metabolism and ventricular function frequently seen after cardiac operations. Antioxidants may improve metabolic and functional recovery.A prospective, randomized, double-blind clinical trial was conducted to determine the effects of vitamin E (alpha-tocopherol) (n = 14) or a corn oil placebo (n = 14) in patients undergoing elective coronary bypass operations. The RRR-alpha-tocopheryl acetate doubled the alpha-tocopherol levels in the heart. Myocardial metabolism and ventricular function were assessed after the operation.Atrial pacing induced myocardial lactate production in the control patients but lactate consumption in the alpha-tocopherol-treated patients on bypass 25 minutes after crossclamp release. Left ventricular stroke work indices were higher, at similar ventricular volumes, in the alpha-tocopherol-treated group, which indicates improved preload recruitable stroke work, and diastolic compliance was greater 4 hours after the operation. The postoperative creatine kinase cardiac isoenzyme levels were lower in the patients who received alpha-tocopherol.Pretreatment with alpha-tocopherol sufficient to double the myocardial concentrations had a small but significant metabolic and functional effect after elective coronary bypass operations when compared with placebo. These results do not justify pretreatment of low-risk patients, but they do justify an evaluation in high-risk patients.

Retrograde delivery of warm blood cardioplegia may improve nutrient cardioplegic flow beyond coronary obstructions, but may not adequately perfuse the right ventricle and the posterior left ventricle. To determine the optimal flow rate for warm retrograde cardioplegia, we assessed 62 patients undergoing elective coronary artery bypass in two studies. In the low flow study, administration of 50 ml/min (n = 9), 75 ml/min (n = 11), or 100 ml/min (n = 7) was associated with high lactate production and oxygen extraction during cardioplegic administration. At 50 minutes of cardioplegic arrest, the coronary venous effluent pH was low in all groups. In the high flow study, 30 patients all received flow rates of 100, 200, and 300 ml/min in randomized order during the crossclamp period. In addition, five patients received cardioplegia at a rate of 500 ml/min for the duration of the crossclamp period. Administration of 200 ml/min or higher minimized lactate production and maintained coronary venous pH within the physiologic range, but flows of 300 ml/min or higher did not increase oxygen use or reduce lactate or acid production. Patients in the low flow groups had significantly greater myocardial lactate release during cardioplegic infusion and after removal of the crossclamp than the high flow group. Warm retrograde cardioplegia should be delivered at flow rates of at least 200 ml/min during elective coronary artery bypass operations.

Warm cardioplegia produced by essentially continuous infusion has been used as an alternative to traditional cold intermittent infusion techniques during cardiac surgery, but its effects on postoperative left ventricular function have not been defined. We performed a randomized clinical trial to assess the effects of warm and cold blood cardioplegia on load-independent indices of ventricular function. Fifty-three patients were randomized to warm (n = 27) or cold (n = 26) cardioplegia. Myocardial oxygen consumption, lactate production, adenine nucleotides, and adenine nucleotide degradation products were measured during cardioplegia and reperfusion. In 13 patients per group, pressure-volume loops were constructed and ventricular function was assessed 3 hours after the operation. Warm cardioplegia resulted in greater myocardial lactate production but improved recovery of oxygen consumption during reperfusion. Depletion of adenosine triphosphate was similar between groups, but total adenine nucleotides (adenosine triphosphate + adenosine diphosphate + adenosine monophosphate) fell further during warm cardioplegia. Cold cardioplegia was associated with an accumulation of adenosine diphosphate and adenosine monophosphate. Creatine kinase MB isoenzyme release was reduced in the warm group. Three hours after the operation, end-systolic elastance and preload-recruitable stroke work index were increased after warm cardioplegia, and early diastolic relaxation was also increased. Increased systolic function after warm cardioplegia may have been related to improved myocardial protection, elevated arterial lactate concentrations, or increased circulating catecholamine levels. Altered diastolic compliance in the warm group may reflect greater active relaxation during early diastolic filling.

Oxidant injury contributes to myocardial stunning, and cardiac ischemic and reperfusion injury. Vitamin E is the major--and perhaps the only--lipid soluble, chain-breaking antioxidant in the heart. Vitamin E and its analogues potentially offer significant advantages for the prevention of ischemic and reperfusion injury. Recent investigations have suggested that modified vitamin E analogues may be more efficacious than vitamin E and may permit myocardial salvage from acute myocardial ischemic injury.

University of Wisconsin solution (UWS) has been successfully used for liver transplantation and may be beneficial for hypothermic cardiac storage. The addition of glucose may enhance myocardial preservation.Cultured human ventricular myocytes (eight dishes per group) were stored at 0 degree C for 12 hours in either unmodified UWS or UWS with glucose (1, 3, 10, 30, or 100 mmol/l). Cells were assayed for protein by spectrofluorometry and adenine nucleotides by high performance liquid chromatography after storage. Protein recovery, adenosine triphosphate (ATP), adenosine diphosphate (ADP), and total adenine nucleotides (ATP+ADP+AMP) were all depleted after storage (p0.0001 by ANOVA). Protein recovery (p0.005), ATP (p0.05), and ADP (p0.05) were increased with glucose administration compared with unmodified UWS. Improvement was maximal using 30 mmol/l (protein, 0 mmol/l = 0.48 +/- 0.14 and 30 mmol/l = 0.65 +/- 0.11 mg per dish; ATP, 0 mmol/l = 3.08 +/- 0.63 and 30 mmol/l = 4.32 +/- 0.90 nmol/mg protein; ADP, 0 mmol/l = 3.76 +/- 0.80 and 30 mmol/l = 4.63 +/- 0.38 nmol/mg protein, mean +/- SD). Total adenine nucleotides tended to increase at any glucose concentration (p = 0.07 by ANOVA) and were significantly better with 30 mmol/l glucose (0 mmol/l = 7.61 +/- 1.58 and 30 mmol/l = 9.62 +/- 1.08 nmol/mg protein).Increasing the glucose concentration from 0 to 30 mmol/l improved adenine nucleotide and cellular protein preservation in this in vitro assessment.

Although normothermic cardioplegia has been used with acceptable clinical results, no studies have previously been performed to determine the metabolic consequences of these various techniques of myocardial protection. Therefore, we have performed a randomized clinical trial to assess the effects of three cardioplegic techniques on myocardial metabolic recovery.Seventy-four patients undergoing coronary artery bypass graft surgery were randomized to receive normothermic antegrade blood cardioplegia (n = 25), normothermic retrograde blood cardioplegia (n = 23), or intermittent cold antegrade blood cardioplegia (n = 26). Myocardial oxygen consumption and lactate production, adenine nucleotides, and adenine nucleotide degradation products were measured during the operation, and cardiac creatine kinase isoenzyme (CK-MB) release was assessed after surgery. Warm antegrade cardioplegia maximized myocardial oxygen consumption during cardioplegic delivery. Postoperative CK-MB release was less after warm antegrade cardioplegia, but the difference was not statistically significant. Warm retrograde cardioplegia resulted in the greatest degree of anaerobic lactate production but did not increase morbidity and mortality. Perioperative myocardial infarctions and postoperative low-output syndrome were most common after cold cardioplegia, but this trend was not statistically significant. During warm antegrade cardioplegia, adenosine triphosphate (ATP) was metabolized to diffusible precursors, which were washed out during cardioplegic infusion. Warm retrograde cardioplegia produced a breakdown of ATP to inosine and hypoxanthine, small molecules that accumulated during the cross-clamp period and were not washed out, perhaps because of inadequate perfusion with retrograde delivery. During cold cardioplegia, ATP was dephosphorylated, and adenosine diphosphate, adenosine monophosphate, and adenosine accumulated. These compounds were not regenerated to ATP but were not washed out of myocytes because they are large anionic molecules.Intermittent cold cardioplegia inhibited mitochondrial function but prevented the degradation of adenine nucleotides. Warm antegrade cardioplegia had the greatest myocardial oxygen consumption, and warm retrograde cardioplegia had the greatest anaerobic lactate production. There were no differences in clinical outcomes between cardioplegic groups.

Cardiac storage for transplantation is currently limited to 6 hours. To better understand the metabolic changes that occur during hypothermic (4 degrees C) storage, we monitored the morphologic and metabolic changes in the canine myocardium at 0, 12, and 24 hours of storage in University of Wisconsin solution. Attempts to isolate cardiac mitochondria resulted in a progressive decline in the yield (milligrams of mitochondria per gram of heart tissue), which decreased (p less than 0.05) from 9.2 +/- 0.4 at 0 hours (control) to 4.0 +/- 0.3 after 12 hours and further decreased (p less than 0.05) to 1.9 +/- 0.2 after 24 hours of cold storage. Mitochondrial state 3 respiration fell to 64% of control after 12 hours and 28% of control after 24 hours of cold storage (p less than 0.05). Citrate synthetase activity, but not cytochrome C oxidase activity, was significantly depressed after 12 and 24 hours of cold storage. Adenosine triphosphate content decreased to 67% of control after 12 hours and 50% of control after 24 hours. After 12 hours of storage, sufficient adenosine diphosphate and monophosphate were present to permit some restoration of adenosine triphosphate, provided mitochondrial function was normal after transplantation. However, restoration of mitochondrial function and adenosine triphosphate levels sufficient to support myocardial contractility was unlikely after 24 hours of storage. This study suggests that a return of adequate cardiac function after transplantation may be possible after 12 hours of cold storage in University of Wisconsin solution but not after 24 hours of cold storage.

Since the chronically cyanotic myocardium appears to be more susceptible to reperfusion injury after cardiac operations than the noncyanotic myocardium, we studied the association between the preoperative arterial oxygen tension and the myocardial superoxide dismutase, catalase, and glutathione peroxidase activities. Fourteen patients with tetralogy of Fallot scheduled for elective operations had baseline arterial blood gas measurements done before operation. During the operation right ventricular biopsy specimens were taken for enzyme analysis immediately before cold blood cardioplegic arrest and 20 minutes after crossclamp removal. The tissue antioxidant enzyme activities of the patients with tetralogy of Fallot were compared with the myocardial results in 15 adults with stable angina pectoris having elective aorta-coronary artery bypass graft operations. Myocardial tissues removed from two patients with hypertrophic obstructive cardiomyopathy who had corrective operations were analyzed for antioxidant activities. There were no changes in myocardial antioxidant enzyme activities during the operation in the patients with tetralogy of Fallot and coronary artery bypass graft. The myocardial superoxide dismutase, catalase, and glutathione peroxidase activities correlated (0.82, 0.68, and 0.89, respectively) significantly (p values were less than 0.01, 0.05, and 0.01, respectively) with the preoperative arterial oxygen tensions in the patients with tetralogy of Fallot. The myocardial glutathione peroxidase activities were at least four times higher in the myocardium of patients with coronary artery bypass graft and hypertrophic obstructive cardiomyopathy than in that of those with tetralogy of Fallot. This study provides putative evidence that the myocardium of patients with tetralogy of Fallot is a risk of oxygen-derived free radical injury during and immediately after corrective cardiovascular operations.

The effects of normothermic systemic perfusion (35 degrees to 37 degrees C; n = 73) were compared with those of moderately hypothermic systemic perfusion (25 degrees to 29 degrees C; n = 73) with respect to blood loss, transfusion requirements, and platelet levels in 146 patients undergoing isolated, primary coronary artery bypass grafting. In addition, most patients were given an antifibrinolytic medication during operation as follows: tranexamic acid (10 gm intravenously; n = 63), epsilon-aminocaproic acid (15 gm intravenously; n = 63), or no drug as a control. (n = 20). Normothermic patients tended to bleed less at 24 hours (warm, 864 +/- 42 ml and cold, 918 +/- 68 ml), but these differences were not statistically significant. Patients receiving either tranexamic acid or epsilon-aminocaproic acid, regardless of perfusion temperature, bled less after 6, 12, and 24 hours than did cold control patients (p less than 0.05). Warm control patients also bled less than did cold control patients after 6 or 12 hours (p less than 0.05), and neither drug further reduced blood loss in these patients. Circulating platelet levels were better preserved in patients receiving either tranexamic acid or epsilon-aminocaproic acid and in patients with warm perfusion and no drug than in cold control patients. Normothermic systemic perfusion, tranexamic acid, and epsilon-aminocaproic acid each reduced postoperative blood loss and preserved platelets.

Although patients with severe ventricular dysfunction have improved long-term survival times after coronary bypass procedures, operative morbidity and mortality rates remain high. This study was designed to identify the contemporary risk factors for isolated coronary artery bypass grafting in this high-risk subgroup. Between January 1982 and December 1990, a total of 12,471 patients underwent isolated coronary artery bypass grafting. The 9445 patients with preoperative ejection fractions greater than 40% had a lower operative mortality rate (2.3%) than that of the 2539 patients with ejection fractions between 20% and 40% (4.8%) and that of the 487 patients with ejection fractions less than 20% (9.8%; p less than 0.001). However, patients with ejection fractions of less than 20% were demographically distinct from those with higher ejection fractions. This group was older, with fewer women, a higher frequency of left main stenosis, and more frequent requirement of urgent operation for unstable angina. The risk factors for operative death also varied with preoperative ejection fraction. The traditionally accepted risk factors--urgency of operation, left main coronary artery stenosis, reoperation, sex, and age--were predictive of risk of operative death for patients with ejection fractions greater than 40%. The risk of operative death for patients with ejection fractions between 20% and 40% was predicted by urgency of operation, reoperation, sex, myocardial protection, and age. The only predictor of risk of operative death for patients with ejection fractions less than 20% was urgency of operation. Patients undergoing isolated coronary artery bypass grafting who have severe ventricular dysfunction are therefore a highly selected, high-risk subgroup of patients who risk depends on the urgency of operation. Strategies to improve the results in these patients should be focused on patient selection, improvement of myocardial protection, and more aggressive preoperative treatment of myocardial ischemia.

Between 1982 and 1989, 119 patients had repair of thoracic aortic pathology. Thirty-seven had repair of ascending aortic aneurysms, with an 11% hospital mortality. Forty-one patients had urgent repair of acute type A aortic dissections, with a 32% hospital mortality. The independent predictors of mortality were the use of crystalloid cardioplegia, aortic dissection, and the use of an intraluminal prosthesis or the inclusion surgical technique. Better grafts and the resection technique has reduced mortality since 1986. Seventeen patients had their primary pathology in the aortic arch, with a 47% hospital mortality. The urgency of the procedure and crystalloid cardioplegia predicted an unsuccessful outcome. Seventeen patients had descending aortic aneurysms repaired, with an 18% mortality. The urgency of surgery was the predictor of mortality. Seven patients had a descending thoracic aortic disruption repaired, with one death (14%). Better graft materials, surgical techniques, and methods of myocardial protection have contributed to the improved results of thoracic aortic surgery in recent years.

Hypothermic storage of cardiac allografts is routinely used for transplantation but is associated with an increased mortality when ischemic times are greater than 4 hours. The ideal storage conditions (solution and temperature) could extend the current limits of cold ischemia. Human endothelial cells and ventricular myocytes were studied to screen various solutions and temperatures for organ preservation. Four solutions (modified Euro-Collins, phosphate-buffered saline, Stanford cardioplegia, and University of Wisconsin) were evaluated. Endothelial cells were evaluated after prolonged hypothermic storage consisting of 0 degree, 4 degrees, and 8 degrees C for 36 hours, and ventricular myocytes were stored at 0 degree and 8 degrees C for 24 hours. Cell viability was determined by morphology (10 dishes per group), and trypan blue exclusion (5 dishes per group) in addition to a cell adhesion assay (endothelial cells 5 dishes per group) and adenine nucleotide analysis with high-performance liquid chromatography techniques (ventricular myocytes 5 dishes per group). Endothelial cell morphology was best preserved by University of Wisconsin solution (p less than 0.001, chi 2) and at 0 degree C (p less than 0.01, chi 2). Endothelial cells stored with University of Wisconsin solution excluded trypan blue better (1.0% +/- 0.5% cells stained, p less than 0.001. Analysis of variance [ANOVA]). Cell adhesion was poorly protected with Stanford cardioplegia (p less than 0.001, ANOVA). Myocyte morphology was preserved best with University of Wisconsin solution at 0 degree C (p less than 0.001, chi 2). According to trypan blue staining, Euro-Collins and University of Wisconsin solutions were superior to Stanford cardioplegia or phosphate-buffered solutions (p less than 0.001, ANOVA). Temperature did not influence the trypan blue results. Adenosine triphosphate was maintained best with University of Wisconsin solution at 0 degree C (p less than 0.01, ANOVA). Myocytes were more sensitive to the effects of prolonged storage compared with endothelial cells by morphologic criteria and trypan blue staining characteristics, irrespective of the shorter preservation times. University of Wisconsin solution was the most effective solution tested. Colder temperatures (0 degree to 4 degrees C) provided better protection than 8 degrees C. Myocytes were more sensitive to prolonged preservation than endothelial cells. Furthermore, the technique used appears helpful as a model of prolonged hypothermic storage and could be expanded to assess other interventions.

A prospective randomized controlled trial was performed to determine optimal flow rates and hemoglobin concentrations for continuous normothermic blood cardioplegia and to compare warm heart surgery with standard intermittent cold blood cardioplegia. Thirty-five patients received intermittent cold blood cardioplegia, low hemoglobin low flow, low hemoglobin high flow, high hemoglobin low flow, or high hemoglobin high flow warm blood cardioplegia (seven patients per group: low hemoglobin, 50 g/l; high hemoglobin, 80 g/l; low flow, less than 80 ml/min; high flow, greater than 80 ml/min). Hypothermia resulted in a significantly greater accumulation of ADP and AMP during cross clamp, consistent with impaired mitochondrial function. Low hemoglobin low flow warm blood cardioplegia increased myocardial oxygen consumption and coronary sinus blood flow after cross clamp release, and also decreased lactate consumption. Postoperative myocardial performance and diastolic compliance were reduced in low hemoglobin low flow warm patients, and diastolic compliance was increased with high hemoglobin high flow warm blood cardioplegia when compared with cold patients. In this study, continuous normothermic cardioplegia was safe when delivered at 80 ml/min or greater, with a hemoglobin concentration of at least 80 g/l, affording myocardial metabolic and functional recovery comparable to that found after intermittent cold blood cardioplegia.

Collection and documentation of data from patients during surgical procedures are highly useful but seldom used methods of surgical research. Intraoperative clinical research provides important information, whether the reports are descriptive or randomized controlled interventional trials. Clinical application of surgical techniques has increased dramatically following perioperative documentation of their benefits. At the University of Toronto, the use of blood cardioplegia in cardiac surgery increased from approximately 10% in 1980 to 98% in 1989, following identification of its beneficial effects on myocardial metabolism, ventricular function, morbidity, and mortality. Although the benefits of a surgical technique evaluated in the laboratory may influence many surgeons, improved clinical results have a greater impact on clinical practice. Extended tracheal resections were performed in dogs for many years, but Grillo and Pearson’s validation of the techniques in humans permitted their widespread clinical use.

Four hundred thirteen consecutive patients underwent valve replacement with a bioprosthesis between 1976 and 1982. Aortic valve replacement was performed in 240 patients, mitral valve replacement in 132 patients, and multiple valve replacement in 41. The Carpentier-Edwards porcine (n = 336), Angell-Shiley porcine (n = 23), Hancock porcine (n = 11), and the Ionescu-Shiley pericardial valves (n = 43) were inserted. Follow-up between 5 and 12 years postoperatively was 98% complete. Freedom from structural valve deterioration was 72 +/- 7%, 59 +/- 9%, and 59 +/- 9%, respectively, after aortic, mitral, and double valve replacement. The risk of structural valve deterioration and reoperation for valve-related complications was significantly increased with the Ionescu-Shiley pericardial prosthesis. The risk for reoperation was inversely related to patient age. Postoperative Doppler echocardiographic studies in 87% of available patients revealed a subgroup of asymptomatic patients with evidence of structural valve deterioration. These patients (n = 61) had significantly reduced prosthetic valve areas (aortic less than 1 cm2, mitral less than 1.7 cm2), elevated resting transvalvular gradients (aortic greater than 40 mm Hg), or moderate-to-severe regurgitation. In summary, postoperative Doppler echocardiographic examination identified asymptomatic patients with structural valve dysfunction. These patients must be followed up carefully to determine the optimal timing of reoperation.

Right ventricular protection may be limited with current methods of cardioplegic delivery. Sensitive measurements of right and left ventricular function and metabolism were made in 30 patients undergoing elective coronary artery bypass surgery with cold cardioplegic arrest. Myocardial adenine nucleotide concentrations decreased with cardioplegia and reperfusion in both the right and left ventricles despite adequate levels of precursors, suggesting perioperative mitochondrial dysfunction. Postoperatively, right and left ventricular pressures were measured with micromanometer catheters and volumes were measured by nuclear ventriculography. Right and left ventricular systolic elastance was calculated by the isochronic method and by the end-systolic method. Both methods provided sensitive indexes of end-systolic elastance. This study demonstrated that right ventricular function and metabolism can be evaluated by methods analogous to methods used in the left ventricle. These results suggest that right ventricular functional and metabolic recovery are delayed despite apparently adequate myocardial protection. Sensitive measurements may permit improved assessment of alternative methods of right ventricular protection.

Impaired myocardial fatty acid and glucose metabolism following ischemia and cardioplegia may limit the recovery of myocardial oxidative metabolism and ventricular function. Lactate, a simple three carbon compound, can be readily metabolized to pyruvate and is possibly the preferred substrate for aerobic metabolism. Therefore, increasing arterial lactate concentrations may improve myocardial metabolic recovery after ischemia and cardioplegia. Myocardial lactate metabolism and ventricular function were assessed in a canine model of 45 mins of global normothermic ischemia followed by 60 mins of cold potassium cardioplegic arrest. Thirteen dogs received a perioperative infusion of sodium lactate to elevate arterial concentrations (from 6 to 12 mmol/L) and 12 dogs received an equivalent amount of saline. The high arterial lactate concentrations were associated with an increased myocardial lactate consumption and oxidation (as assessed by 14C-labelled lactate) during reperfusion. Myocardial ATP concentrations fell during reperfusion despite improved myocardial oxidation. The recovery of ventricular function (as assessed by a compliant intraventricular balloon) was incomplete and only marginally better with the high arterial lactate concentrations. An infusion of lactate improved myocardial oxidative metabolism following ischemia and cardioplegia. However, the recovery of ventricular function was incomplete perhaps because of inadequate preservation of myocardial ATP.

To identify the independent predictors of operative mortality, we examined 31 preoperative clinical and hemodynamic variables in 2,488 patients undergoing valvular surgery between 1982 and 1986. The operative mortality was 5.3% in 1,098 patients after aortic valve surgery, 6.6% in 1,107 after mitral valve surgery, and 10.1% in 283 after double valve surgery. Multivariate statistical analysis demonstrated that urgent surgery, endocarditis requiring urgent surgery, previous aortic valve surgery, coronary artery disease, and age were independent risk factors for aortic valve surgery. Urgent surgery, endocarditis, age, coronary artery disease, and preoperative ventricular ejection fraction were independent predictors of mortality after mitral valve surgery. The predictors of mortality after double valve surgery were urgent surgery, age, preoperative ventricular ejection fraction, and tricuspid valve disease. Gender and the type of valvular lesion, procedure, and prosthesis did not independently influence operative mortality. Strategies to diminish operative mortality should include careful assessment of the risks and benefits in elderly patients, early operative intervention before deterioration that necessitates urgent surgery, and use of improved techniques of myocardial protection in high-risk subgroups.

Postoperative low cardiac output is the most common cause of death in patients undergoing elective repair of tetralogy of Fallot. The incidence is much higher than in elective adult bypass operations for coronary artery disease. To explain this difference, we investigated 16 children having elective repair of tetralogy (mean age 6.3 years). Myocardial biopsy specimens obtained during bypass before arrest, at the end of cold arrest by blood cardioplegia, and after 30 minutes of reperfusion were studied for adenosine triphosphate and lactate levels. Myocardium was submitted for microscopic study shortly after the onset of ischemia. The operation was successful in reducing right ventricular-pulmonary artery gradients from 82 +/- 28 to 9 +/- 1 mm Hg, yet seven patients required significant inotropic support (dopamine, greater than 5 micrograms/kg/min) for more than 24 hours and 12 patients needed prolonged use of digoxin and diuretics for right ventricular failure. Tissue levels of adenosine triphosphate and lactate in the tetralogy groups were compared with those in 20 adults with coronary artery disease having similar myocardial protection techniques. Adenosine triphosphate levels in the tetralogy group decreased during cross-clamping (41 +/- 8 minutes) from 24 +/- 3 to 16 +/- 2 mmol/kg dry weight (mean +/- 1 standard error), with a marked further drop after reperfusion to 9 +/- 2 mmol/kg (p less than 0.01). Adenosine triphosphate levels in the group with coronary disease also decreased from 20 +/- 1 to 16 +/- 1 mmol/kg after a longer cross-clamp time (70 +/- 17 minutes) but remained at 15 +/- 2 mmol/kg after reperfusion. Tissue lactate levels in the tetralogy group rose markedly during ischemia and remained elevated after reperfusion. In contrast, lactate levels in the group with coronary disease rose moderately during ischemia and returned to normal early on reperfusion. Microscopic study revealed focal myocyte necrosis in tetralogy of Fallot. Our findings, which demonstrate inadequate myocardial protection of patients with tetralogy during repair, with depression of adenosine triphosphate and increased lactate during ischemia and reperfusion, suggest a defect in oxidative metabolism. The drop in adenosine triphosphate after reperfusion in the patients with tetralogy implicates reperfusion injury as a mechanism of myocardial damage.

Intra-aortic balloon pump assistance (IABPA) for cardiogenic shock is well established. The response to balloon pumping and patient survival are better after low output from cardiotomy than after myocardial infarction. Elective use of IABPA preoperatively allows an extra margin of safety for patients with acute coronary insufficiency, significant left main coronary artery stenosis, or depressed left ventricular function. However, advances in monitoring techniques during the induction of anesthesia and weaning from cardiopulmonary bypass support, as well as improved methods for myocardial preservation, have reduced the requirements for elective IABPA. Current indications for preoperative IABPA include: patients with acute coronary insufficiency who are totally unresponsive to full medical management and who continue to have pain and electrocardiographic changes at rest, and patients with serious left main coronary artery stenosis who also have acute coronary insufficiency or depressed left ventricular function. The survival of patients with valvular heart disease and left ventricular dysfunction is not improved with preoperative IABPA, while most patients with depressed left ventricular function from coronary artery disease may now undergo revascularization uneventfully, although inevitably some will still require postoperative IABPA.

The low mortality and perioperative infarction rates for aortocoronary bypass (ACB) make them unsuitable for evaluating the adequacy of myocardial protection. Enzymatic and functional measurements were found to be sensitive and specific indicators of myocardial injury. A prospective concurrent study of 78 patients undergoing triple ACB was conducted to evaluate the effectiveness of three popular methods of myocardial protection. Group I (32 patients) had a single dose of cold (4 degrees C) potassium cardioplegic (CPC) solution infused inducing a mean myocardial temperature (MMT) of 31 +/- 4 degrees C/min. Group II (23 patients) had multiple doses of CPC solution 8nducing a MMT of 22 +/- 2 degrees C/min. Group III (23 patients) had intermittent anoxic arrest at a MMT of 28 +/- 1 degrees C. The groups were not randomized but had comparable clinical symptoms and catheterization findings. Serial measurements of cardiac specific creatine kinase (CK-MB) revealed a peak in enzymatic activity occurring 60 minutes following ACB. The highest CK-MB was significantly (P less than 0.01) lower in group II (25 +/- 8 IU/liter) than group I (50 +/- 8 IU/liter), or group III (68 +/- 14 IU/liter). Myocardial performance was evaluated after ACB by serially measuring left ventricular stroke work index (SW) and left atrial pressure (LAP) in response to volume loading. The rise in SW was significantly (P less than 0.01) greater in group II (3.0 +/- 0.7 gm.m/sq m/mm Hg) than in group I (1.4 +/- 0.7) or group III (1.8 +/- 0.9). The highest SW attained was higher (P less than .01) in group II (43 +/- 7 gm.m/sq m) than group I (19 +/- 6) or group III (34 +/- 8) at comparable LAP values (group I: 20 +/- 5 mm Hg; group II: 18 +/- 3; group III: 18 +/- 4). Post-operative clinical evaluation failed to differentiate among the three groups. The more sensitive indices, however, demonstrated the superiority of cold, multidose cardioplegia in providing optimal myocardial protection.

The myocardial oxidation of fatty acids and glucose, the predominant substrates for aerobic metabolism, is impaired after cardioplegic arrest for coronary revascularization. Because lactate can be readily metabolized to pyruvate, it may be the preferred substrate for aerobic metabolism after cardioplegic arrest when arterial concentrations are elevated. Nineteen patients undergoing elective coronary revascularization with blood cardioplegia were randomized to receive LOW (nine patients, no exogenous lactate) or HIGH (10 patients, a perioperative infusion of Ringer's lactate) arterial lactate concentrations. Coronary sinus catheterization and lactate labeled with carbon 14 permitted calculation of myocardial oxygen consumption and lactate oxidation which were significantly increased during reperfusion in the group with HIGH arterial lactate concentrations. Atrial pacing at 110 beats/min on cardiopulmonary bypass resulted in myocardial lactate production (suggesting ischemic anaerobic metabolism) in the LOW lactate group, but atrial pacing increased lactate consumption and oxidation in the HIGH lactate group (suggesting increased aerobic metabolism). Systolic function (the relation between end-systolic pressure and volume) as assessed by nuclear ventriculography 3 hours postoperatively was significantly better (p less than 0.05 by analysis of covariance) in the HIGH lactate group. Postoperative myocardial creatine kinase release was significantly lower in the HIGH lactate group, which suggested less perioperative ischemic injury. Lactate was the preferred substrate for myocardial oxidative metabolism after cardioplegic arrest, and the higher arterial lactate concentrations improved myocardial metabolic and functional recovery and reduced perioperative ischemic injury.

Cardiac surgery stimulates the systemic synthesis of prostacyclin and thromboxane A2, but the cardiac release of these prostanoids has been reported infrequently. Fifty-four patients undergoing elective coronary artery bypass had coronary sinus catheters inserted to evaluate the cardiac release of the stable metabolites of prostacyclin (6-keto-prostaglandin F1 alpha) and thromboxane A2 (thromboxane B2). Arterial concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were elevated after cardiac cannulation and during cardiopulmonary bypass. The cardiac release of 6-keto-prostaglandin F1 alpha was observed after cannulation and during, but not after, cardiopulmonary bypass. Cardiac thromboxane B2 release was detected after cross-clamp release and persisted during the early postoperative period when cardiac 6-keto-prostaglandin F1 alpha release was no longer detectable. Cardiopulmonary bypass stimulated the systemic production of thromboxane and prostacyclin. The cardiac release of thromboxane was unopposed by cardiac prostacyclin production in the early postoperative period and may contribute to reperfusion injury.

Coronary artery disease accounts for more than half of the morbidity and mortality associated with abdominal aortic surgery. To improve the results of vascular surgery, the risk of perioperative cardiac ischemia should be evaluated in each patient. Routine coronary angiography demonstrated severe correctable coronary artery disease in 14% of patients who had no history or electrocardiographic evidence of coronary artery disease. Exercise testing before abdominal aortic aneurysm repair will identify patients at high risk of cardiac ischemia. Dipyridamole-thallium imaging will identify high-risk patients before surgery for aortoiliac occlusive disease. Some patients with symptomatic coronary disease who are at extremely high risk should undergo preoperative coronary revascularization. Others should have their vascular surgery deferred, because their cardiac risk may exceed the anticipated benefit of the vascular surgery. Patients at moderate risk may need more intensive intraoperative monitoring. Patients without evidence of cardiac ischemia with stress may undergo vascular surgery with a low risk of perioperative cardiac ischemia. Finally, patients who have evidence of ischemic heart disease should be considered for coronary revascularization following successful vascular repair in order to prolong their survival.

Changes in regional coronary flow after administration of intracoronary nitroglycerin were assessed by measuring total coronary blood flow (using coronary sinus flow catheters) and its regional distribution (by quantitative single-photon emission tomography of injected radioactive microspheres). After pacing to angina, 10 patients with coronary artery disease received serial selective left coronary injections of technetium-99m microspheres, 40 micrograms of nitroglycerin, and indium-111 microspheres. Significant changes in coronary flow distribution were determined by subtracting prenitroglycerin from postnitroglycerin tomographic profiles. Perfusion of each myocardial segment was classified as normal mildly, moderately or severely compromised, based on upstream coronary anatomy. The overall increase in coronary flow was 23% in the normal territories and 33%, 44% and 15% (p less than 0.05), in the mildly, moderately and severely compromised territories, respectively, compared with control values. Thus, intracoronary nitroglycerin increased coronary blood flow to all perfusion territories. The increase in distribution of coronary flow was greatest in the mildly and moderately compromised regions and the least in the most severely compromised regions; this is probably a reflection of the underlying coronary reserve.

A total of 130 axillofemoral grafts were peformed in 120 patients from 1966 to present; 66 were axillobilateral femoral moral and 64 were axillounilateral femoral grafts. The average patient age was 66 years. The indications for operation were occlusive disease with rest pain or gangrene in 102 patients, severe claudication four, and bypass of a thoracic aneurysm in one. The one month operative mortality rate was 8 percent (ten patients). Four deaths occurred in elderly patients operated upon as emergencies with acute aortic occlusion. In the 126 elective cases, there were six postoperative deaths (4.7 percent). Twenty thrombectomies were performed in 15 axillobilateral femoral grafts of which 15 (75 percent) were successful. In the unilateral grafts there were 25 thrombectomies in 22 grafts, of which only eight (32 percent) were successful. The 5 year patency rate by the life-table method was 74 percent for axillobilateral femoral grafts and 37 percent for axillounilateral femoral grafts. This difference in patency rates is statistically significant (p0.01). Average flow measured by electromagnetic flow meter in six axillobilateral femoral grafts was 621 c.c. per minute and in 11 unilateral femoral grafts was 273 c.c. per minute. We attribute the higher patency rate in axillobilateral femoral grafts to this increased flow. These data indicate that axillobilateral femoral grafts may be performed with anticipation of a 5 year patency rate comparable to that with conventional aortoiliac reconstruction and that axillobilateral femoral grafts should be performed in preference to axillounilateral femoral grafts in poor-risk patients requiring extra-anatomic bypass for aortoiliac occlusive disease.

Sleeve lobectomy for non-oat cell carcinoma involving a major bronchus preserves functioning lung tissue and, in carefully selected patients, provides long-term survival comparable to pneumonectomy. Seventy patients underwent sleeve lobectomy between 1967 and 1978. Twenty-seven patients were considered compromised (Group I) because they had severe respiratory impairment which contraindicated pneumonectomy. Forty-three patients were considered uncompromised (Group 2) and underwent elective sleeve lobectomy. Seventy patients with a similar non-oat cell carcinoma involving the proximal bronchi underwent pneumonectomy (Group 3) during this period. Perioperative complications occurred more frequently in Group 1 (59%) than in Group 2 (21%) or Group 3 (23%). Both periopeative mortality rate and the incidence of bronchial disruption (bronchovascular and bronchopleural fistulas) were higher in Group I (19% and 22%) than in Group 2 (9% and 5%) or Group 3 (3% and 7%). Survival depended primarily on the surgeon's ability to perform a complete resection of the tumor. An incomplete resection resulted when tumor was found in the highest lymph node or in the last bronchial resection margin when paraffin sections were reviewed. The 5 year survival rate was 18% for compromised patients (Group 1) who underwent complete resection, and there were no survivors among patients undergoing incomplete resections. Uncompromised patients ( Group 2) had a 5 year survival rate of36% with complete and 12% with incomplete resections. Pneumonectomy patients (Group 3) had a 64% 5 year survival rate with a complete resection and 16% with an incomplete resection. The stage of the disease at the time of operation had a profound effect on the survivail. There was no difference inthe 5 and 8 year survival rates between uncompromised patients undergoing sleeve resection ( Group 2) and patients undergoing peneumonectomy (Group 3) for comparable stage of their disease. A careful pre- and postoperative functional assessment revealed that pulmonary performance was improved in 44% of Group 1, 63% of Group 2, and only 14% of Group 3 patients. Patients wiht impaired pulmonary reserve underwent sleeve lobectomy with an adequate disease-free interval when complete tumor excision was possible. Uncompromised patients whose extensive disease required incomplete resection had palliation by sleeve lobectomy equivalent to that by pneumonectomy. When complete t-mor resection was possible, patients with uncompromised pulmonary reserve had a perioperative complication rate and long-term survival equivalent to that of pneumonectomy while preserving pulmonary parenchyma, which permitted an improvement in postoperative pulmonary performance.

The mortality rate for elective abdominal aortic operations remains between 3% and 8% despite careful hemodynamic monitoring, and half of these deaths are cardiac in origin. An extensive evaluation of ventricular function was performed during abdominal aortic operation to detect subtle abnormalities in systolic or diastolic ventricular function that could precipitate progressive ischemic cardiac injury. Twenty-three patients undergoing elective abdominal aortic operations (14 patients with abdominal aortic aneurysm [AAA] and nine patients with aortoiliac occlusive disease [AIOD] ) had hemodynamic and nuclear ventriculographic measurements performed preoperatively, during aortic clamping, and immediately after aortic declamping. No differences were found in the hemodynamic response to operation between patients with AAA or AIOD. Volume loading was performed at each time period to assess ventricular function. Myocardial performance (the relation between cardiac index and end-diastolic volume index) and systolic function (the relation between systolic blood pressure and end-systolic volume index) were depressed during aortic clamping (p less than 0.05), suggesting decreased contractility, but returned to baseline values after declamping. Diastolic compliance (the relation between pulmonary capillary wedge pressure and end-diastolic volume index) decreased after declamping (p less than 0.05), suggesting early myocardial ischemia. The decrease in diastolic compliance rendered pulmonary capillary wedge pressure a poor index of left ventricular preload after declamping. Higher pressures were required to maintain adequate diastolic volumes. Despite careful hemodynamic monitoring, potentially ischemic ventricular dysfunction was found during abdominal aortic operation.

In previous studies from this university, advanced age was identified as an independent predictor of operative mortality for valvular surgery. Therefore, between January 1982 and December 1986, early results were compared in 469 patients greater than 70 years old (Old; 74.0 +/- 3.4 years, mean +/- SD) and in 2,040 patients less than 70 years old (Young; 53.7 +/- 12.1 years). Patients underwent single- or multiple-valve repair or replacement with or without concomitant coronary artery bypass surgery. Data consisting of 31 clinical and angiographic variables were collected prospectively and were analyzed by univariate and multivariate statistics. Old patients were characterized by having more frequent left ventricular dysfunction (left ventricular ejection fraction less than 40%: Old, 33.5%; Young, 22.4%; p less than 0.001), coronary artery disease (Old, 54.5%; Young, 24.2%; p less than 0.001), and urgent surgery (Old, 15.6%; Young, 11.8%; p = 0.02). Aortic valve procedures (Old, 59.7%; Young, 40.1%; p less than 0.001) and concomitant coronary artery bypass surgery (Old, 46.4%; Young, 20.3%; p less than 0.001) were performed more commonly in the Old patient. Operative mortality occurred in 10.0% of Old patients compared with 5.6% of Young patients (p less than 0.001), and major morbidity (low-output syndrome, perioperative myocardial infarction, intra-aortic balloon pump counterpulsation, and stroke) occurred significantly more frequently (p less than 0.001) in the Old. Stepwise logistic regression identified that urgent operation (p = 0.002), mitral or double-valve surgery (p = 0.004), coronary artery disease especially when not treated by bypass surgery (p = 0.02), female gender (p = 0.02), and left ventricular dysfunction (p = 0.05) independently predicted operative death in the Old population. The significant predictors of mortality in the Young patient were urgent operation (p less than 0.001), New York Heart Association class IV (p less than 0.001), associated tricuspid valve disease (p = 0.002), decreased left ventricular function (p = 0.01), valvular re-replacement (p = 0.02), and increasing age (p = 0.03). The predicted probability of operative mortality in Old patients ranged between 0.9 +/- 0.5% and 76 +/- 16%. Elderly patients in good risk categories should be offered surgical intervention for correction of valvular lesions. Alternative therapy may be indicated in patients with multiple risk factors.

To determine the risk factors for operative mortality and morbidity, we performed a prospective analysis of 1,980 patients undergoing isolated coronary artery bypass operations between 1982 and 1984. The operative mortality was 3.5%, and the incidence of perioperative myocardial infarction was 8.6% and low output syndrome, 12.0%. Stepwise logistic regression identified sex, preoperative left ventricular ejection fraction, and the urgency of operation as independent risk factors for postoperative mortality. Urgent revascularization was performed in patients with unstable angina refractory to maximal medical therapy. In these patients the operative mortality was 8.5%. Independent risk factors of postoperative morbidity, in addition to sex, ejection fraction, and urgent revascularization, included a previous bypass procedure, age, and New York Heart Association functional class. Unstable angina unresponsive to medical therapy contributed significantly to the operative risk. Interventions to reduce perioperative ischemic injury, such as improved methods of myocardial protection, may improve the results in high-risk patients.