Alan J. Bryan

The biology of saphenous vein graft occlusion - Etiology and strategies for prevention

Saphenous vein graft failure remains a significant clinical and economic burden. Although increased use of arterial conduits has improved long-term outcome, the majority of bypass procedures continue to use saphenous vein. Early vein graft patency is maximized by avoiding damage at the time of implantation, meticulous surgical technique, and appropriate use of antithrombotic therapy. No surgical technique or pharmacological intervention, however, has been shown to prevent late occlusion, which results from the progression of intimal vascular smooth muscle cell proliferation and superimposed atheromatous changes. Over the last few years, there has been a dramatic increase in our understanding of the biology of the vessel wall and the cellular and humoral influences on the process of intimal vascular smooth muscle cell proliferation. This has been possible principally through the advancement and application of molecular biological techniques. Although pharmacological therapies to prevent intimal hyperplasia continue to be evaluated, it is again the new series of strategies made possible by molecular biology that provide the most exciting prospects for treatment. Development of specific antibodies, antisense oligonucleotides, and vascular gene transfer represent potentially effective therapies, not only for the prevention of vein graft failure but also for a whole range of cardiovascular diseases.

Effects of Angiotensin-Converting Enzyme Inhibitor Therapy on Clinical Outcome in Patients Undergoing Coronary Artery Bypass Grafting

OBJECTIVES This study evaluates the effect of pre-operative angiotensin-converting enzyme inhibitor (ACEI) therapy on early clinical outcomes after coronary artery bypass grafting (CABG). BACKGROUND Therapy with ACEIs has been shown to reduce the rate of mortality and prevent cardiovascular events in patients with coronary artery disease. However, their pre-operative use in patients undergoing CABG is still controversial. METHODS A retrospective, observational, cohort study was undertaken of prospectively collected data on 10,023 consecutive patients undergoing isolated CABG between April 1996 and May 2008. Of these, 3,052 patients receiving pre-operative ACEI were matched to a control group by propensity score analysis. RESULTS Overall rate of mortality was 1%. Pre-operative ACEI therapy was associated with a doubling in the risk of death (1.3% vs. 0.7%; odds ratio [OR]: 2.00, 95% confidence interval [CI]: 1.17 to 3.42; p = 0.013). There was also a significant difference between the ACEI and control group in the risk of post-operative renal dysfunction (PRD) (7.1% vs. 5.4%; OR: 1.36, 95% CI: 1.1 to 1.67; p = 0.006), atrial fibrillation (AF) (25% vs. 20%; OR: 1.34, 95% CI: 1.18 to 1.51; p < 0.0001), and increased use of inotropic support (45.9% vs. 41.1%; OR: 1.22, 95% CI: 1.1 to 1.36; p < 0.0001). In a multivariate analysis, pre-operative ACEI treatment was an independent predictor of mortality (p = 0.04), PRD (p = 0.0002), use of inotropic drugs (p < 0.0001), and AF (p < 0.0001). CONCLUSIONS Pre-operative therapy with ACEI is associated with an increased risk of mortality, use of inotropic support, PRD, and new onset of post-operative AF.

The effects of cardiopulmonary bypass temperature on neuropsychologic outcome after coronary artery operations: A prospective randomized trial☆☆☆★★★♢

UNLABELLED The effect of systemic perfusion temperature on postoperative cognitive function was investigated in 96 adult patients undergoing elective coronary revascularization with cardiopulmonary bypass at 28 degrees C, 32 degrees C, or 37 degrees C. Neuropsychologic performance was assessed 1 day before the operation and 6 weeks after the operation. Five tests were adapted from the Wechsler Adult Intelligence Scale and two from the Wechsler Memory Scale. RESULTS No patients had major neurologic complications. Ninety-three patients completed the five Wechsler Adult Intelligence Scale tests, but only 70 went on to complete the Wechsler Memory Scale tests as well. In these, there was an effect of cardiopulmonary bypass temperature on the number of neuropsychologic tests in which there was a preoperative to postoperative deterioration (p = 0.021), the number with bypass at 37 degrees C being significantly greater than the number with bypass at 32 degrees C (p = 0.015). Subsidiary analyses using a multivariate linear model examined the effect of cardiopulmonary bypass temperature on the magnitude of change, with or without allowing for other possible confounding influences. There was an adverse effect of normothermic (37 degrees C) versus moderately hypothermic (32 degrees C) perfusion---more convincingly displayed in the analyses of all seven scores rather than just the Wechsler Adult Intelligence Scale scores. Further cooling to 28 degrees C conferred no additional benefit in terms of cognitive function. The importance of the deterioration is open to question.

Influence of External Stent Size on Early Medial and Neointimal Thickening in a Pig Model of Saphenous Vein Bypass Grafting

BACKGROUND Late saphenous vein graft failure results from intimal and medial thickening due to migration and proliferation of vascular smooth muscle cells and superimposed atheroma. These changes may represent an adaptation by the vein to its insertion into the arterial system. Using a porcine model of arteriovenous bypass grafting, we recently demonstrated that supporting the graft with a nonrestrictive external Dacron velour stent significantly reduced intimal hyperplasia and total wall thickness. In the present study, we investigated the influence of different external stent sizes on graft wall dimensions and cell proliferation. METHODS AND RESULTS Three stent sizes were tested: mildly restrictive, nonrestrictive, and oversized (5, 6, and 8 mm in diameter, respectively). Four weeks after grafting, total wall thickness was decreased 40% by 5-mm stents (P = .02), 66% by 6-mm stents (P = .0004), and 81% by 8-mm stents (P = .02 versus unstented grafts). Neointimal thickness was reduced almost 62% by 6-mm and 72% by 8-mm stents (both P = .01) but not by 5-mm stents. As a result, the encroachment of the intima into the lumen was reduced approximately 70% by 6- or 8-mm stents (P = .02 and P = .01 versus unstented grafts, respectively). Both neointimal and medial cell proliferation were significantly reduced by all three stents compared with unstented grafts. CONCLUSIONS External stenting of saphenous vein bypass grafts reduces early intimal and medial hyperplasia. Oversized stents give equally profound suppression of intimal thickening, obviating the need for precise size matching with the graft and greatly simplifying the surgical procedure.

External stenting reduces early medial and neointimal thickening in a pig model of arteriovenous bypass grafting

The long-term clinical success of coronary artery bypass grafting with autologous saphenous vein is limited by progressive medial and neointimal thickening in the graft and superimposed atherosclerosis. We sought to reduce wall thickening by applying an external stent to experimental grafts in pigs. The diameter of the stent was designed to allow unrestricted initial expansion of the vein in response to arterial pressure and the stent material was highly porous so as to minimize adventitial [correction of advential] disruption. Four weeks after graft implantation, stented grafts had a larger lumen (11.2 +/- 6.2 [standard deviation] mm2 versus 7.6 +/- 3.4 mm2, p < 0.05, n = 9) and an almost fourfold thinner media (0.14 +/- 0.08 versus 0.49 +/- 0.22, p < 0.001) and neointima (0.10 +/- 0.07 versus 0.35 +/- 0.24, p < 0.001) than paired unstented grafts in the same animals. Cell proliferation was also greatly reduced by stenting in the neointimal and medial layers. The stenting procedure devised here is readily applicable to clinical coronary bypass grafts.

Cardiopulmonary bypass perfusion temperature does not influence perioperative renal function

BACKGROUND The recent introduction of normothermic cardiopulmonary bypass (CPB) perfusion has raised concerns regarding the associated risk of renal dysfunction through its potential to exacerbate the systemic inflammatory response and end-organ injury. This study was designed to investigate the influence of CPB perfusion temperature on renal function. METHODS A prospective, randomized, controlled trial of CPB perfusion temperature (28 degrees C, 32 degrees C, and 37 degrees C) was performed in 30 patients undergoing routine coronary artery bypass grafting with normal preoperative renal function. Creatinine clearance was measured before induction of anesthesia, during CPB, and during every 12-hour period thereafter for 48 hours postoperatively. Glomerular and tubular function were assessed further by measurement of urinary creatinine, albumin, total protein, and retinol binding protein levels preoperatively, during CPB, and on days 1 and 3 postoperatively. RESULTS Creatinine clearance increased on CPB by 51% (28 degrees C), 185% (32 degrees C), and 112% (37 degrees C) (all p < 0.01 versus preoperative values) and returned to preoperative values by 24 hours postoperatively in all three groups. Urinary albumin/creatinine ratios rose significantly from a mean of 0.4 +/- 0.1 (standard deviation) to 10 +/- 12.5 (28 degrees C), from 0.55 +/- 0.3 to 5.2 +/- 4.9 (32 degrees C), and from 0.96 +/- 0.8 to 7.8 +/- 7.0 (37 degrees C) during CPB (all p < 0.001) but decreased gradually thereafter. Also, urinary total protein/creatinine ratios rose significantly from a mean of 0.009 +/- 0.007 to 0.034 +/- 0.02 (28 degrees C), from 0.01 +/- 0.006 to 0.026 +/- 0.01 (32 degrees C), and from 0.011 +/- 0.008 to 0.033 +/- 0.02 (37 degrees C) during CPB (all p < 0.005); however, there was a further increase by 24 hours, and ratios decreased gradually thereafter. Similarly, urinary retinol binding protein/creatinine ratios rose significantly in all three groups during CPB (all p < 0.0001) and increased further by 24 hours. There was no statistically significant difference between the renal markers in the three temperature groups in any of the observations. CONCLUSION These data suggest that cardiopulmonary bypass perfusion temperature does not influence renal function in patients undergoing coronary artery bypass grafting.

Myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using cold or warm blood cardioplegia

OBJECTIVES Myocardial protection techniques during cardiac surgery have been largely investigated in the clinical setting of coronary revascularisation. Few studies have been carried out on patients with left ventricular hypertrophy where the choice of delivery, and temperature of cardioplegia remain controversial. This study investigates metabolic changes and myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using antegrade cold or warm blood cardioplegia. METHODS Thirty-five patients were prospectively randomised to intermittent antegrade cold or warm blood cardioplegia. Left ventricular biopsies were collected at 5min following institution of cardiopulmonary bypass, 30min after cross-clamping the aorta and 20min after cross-clamp removal, and used to determine metabolic changes during surgery. Metabolites (adenine nucleotides, amino acids and lactate) were measured using high pressure liquid chromatography and enzymatic techniques. Postoperative myocardial troponin I release was used as a marker of myocardial injury. RESULTS Ischaemic arrest was associated with significant increase in lactate and alanine/glutamate ratio only in the warm blood group. During reperfusion, alanine/glutamate ratio was higher than preischaemic levels in both groups, but the extent of the increase was considerably greater in the warm blood group. Troponin I release was markedly (P<0.05, Mean+/-SD) lower at 1, 24 and 48h postoperatively in the cold compared to the warm blood group (0.51+/-0.37, 0.37+/-0.22 and 0.27+/-0.19 vs. 0.75+/-0.42, 0.73+/-0.51 and 0.54+/-0.38ng/ml for cold vs. warm group, respectively). CONCLUSIONS Cold blood cardioplegia is associated with less ischaemic stress and myocardial injury compared to warm blood cardioplegia in patients with aortic stenosis undergoing valve replacement surgery. Both cardioplegic techniques, however, confer sub-optimal myocardial protection.

Patient-Prosthesis Mismatch Is Negligible With Modern Small-Size Aortic Valve Prostheses

BACKGROUND Concern has been raised about residual significant gradients when small aortic prostheses are used, particularly in patients with large body surface areas. We studied the performance of six types of small aortic prostheses using dobutamine stress echocardiography. METHODS Sixty-three patients (mean age, 67 +/- 7 years) who had undergone aortic valve replacement 17 +/- 6 months previously were studied. Two bileaflet mechanical prostheses (St. Jude Medical and CarboMedics: sizes, 19 mm and 21 mm) and two biological prostheses (Medtronic Intact and St. Jude BioImplant: size, 21 mm) were evaluated. A graded infusion of dobutamine was given and Doppler studies of valve performance were carried out. RESULTS All prostheses except one biological valve had acceptable hemodynamic performance under stress. Using regression modeling, gradient at rest was the only variable found to predict gradient under stress (p < 0.001). Moreover, the most important predictor of gradient at rest was valve design, which accounted for 72% of the variance (p < 0.001). This relationship was independent of valve size (19 mm or 21 mm) or material (ie, mechanical or biological). Body surface area accounted for 4% of the variance in gradient only. CONCLUSIONS The main predictor of transprosthetic gradient is the inherent characteristics of each particular prosthesis, with relatively insignificant contribution from variations in body surface area. Patient-prosthesis mismatch is not a problem of clinical significance when certain modern valve prostheses are used.

Comparison of hemodynamic performances of St. Jude Medical and Carbomedics 21 mm aortic prostheses by means of dobutamine stress echocardiography

Dobutamine stress Doppler echocardiography was used to compare the hemodynamic performance of two small aortic bileaflet prostheses. Nineteen patients (14 female, mean age 64 years) who had undergone aortic valve replacement with 21 mm bileaflet valve prostheses (St. Jude Medical valve, n = 9, or CarboMedics valve, n = 10) were studied. Dobutamine infusion was started at a rate of 5 micrograms.kg-1.min-1 and increased to 10 and 20 micrograms.kg-1.min-1 at 15-minute intervals. Under maximum stress, heart rate and cardiac output increased by 70% and 120%, respectively, and mean arterial blood pressure decreased by 9%. Pulsed-wave and continuous-wave Doppler studies were performed at rest and at the end of each stage. Velocity ratio, effective orifice area, performance index, and discharge coefficient of the valve were calculated, and peak and mean velocities and pressure drops across the prostheses were measured. Dobutamine infusion produced similar increases in cardiac output in all patients. Effective orifice areas, discharge coefficients, and performance indexes were comparable for the two valve groups both at rest and maximum stress. Transvalvular velocities and pressure drops were also similar in the two valve groups. Transvalvular pressure drops were also comparable in patients with large body surface area. Dobutamine stress echocardiography is useful in the evaluation of the hemodynamic performance of prosthetic heart valves. St. Jude Medical and CarboMedics 21 mm prostheses have equally favorable hemodynamic performances in most patients under conditions of high cardiac output.

Effects of cardiopulmonary bypass temperature on pulmonary gas exchange after coronary artery operations

BACKGROUND Pulmonary dysfunction is one aspect of the postoperative morbidity associated with cardiopulmonary bypass. Normothermic systemic perfusion can result in shorter intubation times, which have been attributed to improved pulmonary gas exchange, but the influence of perfusion temperature on pulmonary gas exchange itself is not known. METHODS Pulmonary gas exchange was assessed using alveolar-arterial oxygen pressure gradients in 45 patients undergoing routine coronary revascularization who were randomized to undergo cardiopulmonary bypass at 28 degrees C, 32 degrees C, or 37 degrees C. This was part of a more comprehensive study of the effects of temperature on bodily systems. The gradients were estimated preoperatively with the patients breathing air, again over a period between 2 and 4 hours postoperatively during mechanical ventilation with three different oxygen concentrations (30%, 40%, and 60%), and again 1 hour after extubation while breathing the same three oxygen concentrations. RESULTS Preoperative alveolar-arterial oxygen pressure gradients on air were 24.4 +/- 8.2 mm Hg (mean +/- standard deviation) (28 degrees C), 24.5 +/- 20.4 mm Hg (32 degrees C), and 20.5 +/- 9.5 mm Hg (37 degrees C). Postoperatively, during ventilation and after rewarming, the gradients increased with the increase in inspired oxygen fraction concentrations (30% to 60%) from 67.1 +/- 12.0 mm Hg to 193.1 +/- 30.5 mm Hg (28 degrees C), from 76.4 +/- 20.6 mm Hg to 246.7 +/- 47.7 mm Hg (32 degrees C), and from 79.0 +/- 18.0 mm Hg to 222.9 +/- 40.5 mm Hg (37 degrees C), respectively. A similar pattern was noted 1 hour after extubation, when the gradients increased from 72.4 +/- 12.5 mm Hg to 256.6 +/- 26.5 mm Hg (28 degrees C), from 75.7 +/- 13.9 mm Hg to 252.7 +/- 38.3 mm Hg (32 degrees C), and from 69.1 +/- 19.3 mm Hg to 253.1 +/- 33.0 mm Hg (37 degrees C). There were no significant differences in alveolar-arterial oxygen pressure gradient between the three groups during ventilation or after extubation. CONCLUSIONS Cardiopulmonary bypass perfusion temperature does not influence alveolar-arterial oxygen pressure gradients in the first 12 hours after routine coronary artery bypass grafting in patients with uncompromised pulmonary and left ventricular function.