Research

Ryan JB, Hicks M, Cropper JR, Garlick SR, Kesteven SH, Wilson MK, Feneley MP, Macdonald PS

Eur J Cardiothorac Surg 2003 Jun;23(6):898-906

PMID: 12829065

Abstract

OBJECTIVE: To determine if the initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation.

METHODS: A porcine model of orthotopic heart transplantation was used. Data from two control groups (CON(4) and CON(14)) and two treatment groups (CAR(4) and CAR(14)) were analysed. Hearts in CON(4) (n=6) and CAR(4) (n=6) were subjected to 4 h of ischaemia while hearts in CON(14) (n=3) and CAR(14) (n=6) were subjected to 14 h of ischaemia. All hearts were arrested and stored in the same extracellular preservation solution. Both donor and recipient animals in the CAR(4) and CAR(14) groups received a single intravenous dose of cariporide (2 mg/kg), prior to explantation and reperfusion, respectively.

RESULTS: Mean (SEM) plasma troponin I levels (microg/ml) 3 h post-reperfusion were: CON(4) 210+/-52, CAR(4) 68+/-21, CON(14) 633+/-177, CAR(14) 346+/-93. On multiple linear regression analysis, the rate of troponin I release over the first 3 h post-reperfusion was significantly lower in hearts stored for 4 h compared to hearts stored for 14 h (P<0.0001) and in hearts treated with cariporide compared to control hearts (P=0.0017). Early graft function was superior in hearts treated with cariporide, when compared to control hearts stored for the same period of time. All of the CAR(14) hearts could be weaned from cardiopulmonary bypass whereas none of the CON(14) could be weaned (6/6 vs. 0/3; P=0.012). While all hearts stored for 4 h could be weaned, contractility, as measured by the preload recruitable stroke work (PRSW) relationship, was significantly better preserved in CAR(4) hearts than in CON(4) hearts (P<0.0001).

CONCLUSIONS: The initial rate of troponin I release post-reperfusion is determined by the duration of cardiac allograft ischaemia. Altering the myocardial preservation strategy can reduce the rate of release. Such reductions are associated with improvements in early graft function. These findings validate the initial rate of troponin I release post-reperfusion as an end-point when comparing cardiac allograft preservation strategies. In addition, the present study provides indirect evidence that troponin I degradation during ischaemia-reperfusion is related to the accumulation of intracellular calcium.

Matuszek MA, Aristoteli LP, Bannon PG, Hendel PN, Hughes CF, Jessup W, Dean RT, Kritharides L

Atherosclerosis 2003 Jun;168(2):389-96

PMID: 12801624

Abstract

BACKGROUND: Molecules which egress from atherosclerotic arteries may function as plasma markers of arterial pathology, but such egress has not been proven with living human coronary arteries. We hypothesised that proteins eluting from the arterial wall may discriminate between atherosclerotic and non-atherosclerotic coronary arteries.

METHODS AND RESULTS: During cardiac bypass surgery, 155 sequential fractions of antegradely flushed coronary cardioplegia solution were collected by balloon-cuffed catheter from the coronary sinus in subjects with angiographically extensive (n=30) or minor (n=7) coronary disease. Although plasma was the major source of protein in heavily blood-contaminated samples, under conditions of low blood contamination (<0.5 mg/ml red cell Haemoglobin) coronary circulation-derived protein was detected. N-terminal sequencing of a major 40 kDa band detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated 100% homology with beta chain of Haptoglobin (Hpt). Comparison of perfusates from patients with and without significant coronary disease found that the concentration of Hpt was markedly increased in perfusates from atherosclerotic coronary arteries (0.099+/-0.017 microg Hpt/microg Hb) relative to controls (0.016+/-0.008 microg Hpt/microg Hb, P=0.0027). Analysis of peripheral plasma samples of the same subjects, and of a separate cohort of patients, confirmed greater Hpt in those with angiographic coronary disease than in those without disease.

CONCLUSIONS: Proteins such as Hpt elute from the human coronary vascular bed and may differentiate between arteries with minor or extensive atherosclerosis. Although the suitability of Hpt as a circulating plasma marker for atherosclerosis remains to be established, the approach used in the present study may permit identification of diverse plasma-detectable markers of atherosclerosis, and the subsequent non-invasive evaluation of in vivo arterial pathology.

Barakate MS, Bannon PG, Hughes CF, Horton MD, Callaway A, Hurst T

Ann. Thorac. Surg. 2003 May;75(5):1400-5

PMID: 12735553

Abstract

BACKGROUND: Emergency coronary artery bypass grafting (CABG) is occasionally necessary for failed percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to assess the outcome of patients receiving emergency CABG after unsuccessful PTCA over a 15-year study period.

METHODS: From January 1982 through December 1996, 74 patients underwent emergency CABG after unsuccessful PTCA (crash group). This group was compared with a matched group of 74 patients having primary elective CABG (control group).

RESULTS: All 74 crash group patients were to have PTCA of one coronary system. After PTCA failure, 58 patients (78.3%) developed electrocardiographic changes of evolving acute myocardial infarction (AMI). The overall rate of AMI was 8.1% for the crash group and 2.7% for the control group. Two patients in the crash group died, with no deaths in the control group. There was no significant difference between mean in-hospital length of stay.

CONCLUSIONS: With prompt, aggressive, and complete myocardial revascularization, patients who required emergency CABG after PTCA failure had an outcome not significantly different from that of patients having elective CABG.

Ryan JB, Hicks M, Cropper JR, Garlick SR, Kesteven SH, Wilson MK, Feneley MP, Macdonald PS

Transplantation 2003 Mar;75(5):625-31

PMID: 12640300

Abstract

BACKGROUND: Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury.

METHODS: A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively.

RESULTS: The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001).

CONCLUSIONS: Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.

Ryan JB, Hicks M, Cropper JR, Nicholson A, Kesteven SH, Wilson MK, Feneley MP, Macdonald PS

J. Heart Lung Transplant. 2003 Mar;22(3):347-56

PMID: 12633703

Abstract

BACKGROUND: U74389G (16-desmethyl tirilazad), a 21-aminosteroid or “lazaroid,” inhibits lipid peroxidation, which is an important element of ischemia-reperfusion injury. The aim of this study was to determine whether the addition of U74389G to the cardioplegic preservation solution could improve early cardiac allograft function.

METHODS: A porcine model of donor brain death and orthotopic cardiac transplantation was used. Hearts were arrested and preserved for 6 hours in an aspartate-enriched extracellular cardioplegia that had been supplemented with either U74389G and its carrier (n = 7) or the carrier alone (n = 9). Epicardial sonomicrometry and transmyocardial micromanometry were used to obtain pressure-volume loops before and after transplantation. Left ventricular wall volume was measured by volume displacement.

RESULTS: A higher proportion of U74389G-treated hearts were weaned successfully from cardiopulmonary bypass, but this difference did not achieve statistical significance (86% [6 of 7] vs 56% [5 of 9]; p = 0.308). In the hearts that were weaned successfully, preservation of left ventricular contractility, as judged by the pre-load recruitable stroke work relationship, was significantly better in the U74389G-treated hearts (p = 0.0271). In contrast, left ventricular compliance, as judged by the end-diastolic pressure-volume relationship, was significantly better preserved in the control group (p < 0.0001). U74389G-treated hearts developed less myocardial edema, as judged by the post-transplant left ventricular wall volume/baseline steady-state epicardial end-diastolic volume ratio (64 +/- 9% vs 76 +/- 11%; p = 0.045).

CONCLUSIONS: The benefit obtained from U74389G-supplemented cardioplegic preservation solution was marginal for hearts stored for 6 hours. After longer ischemic times, the benefit may be clearer.

Allman C, Rajaratnam R, Kachwalla H, Hughes CF, Bannon P, Leung DY

J Am Soc Echocardiogr 2003 Feb;16(2):188-90

PMID: 12574748

Abstract

Hemolytic anemia is a well-known but uncommon complication in patients with prosthetic heart valves. It is most commonly a result of prosthetic valve dysfunction, periprosthetic valvular regurgitation, or both. We report a case of a 41-year-old man who had a previous aortic valve and root replacement for acute proximal aortic dissection, now presenting with hemolytic anemia. This was a result of flow obstruction at the distal anastomosis of the aortic conduit by the presence of multiple dissection flaps resulting in severe flow turbulence. Although the pathology was at the blind spot for transesophageal echocardiography, the dissection flaps, the flow turbulence, and the degree of obstruction were well-demonstrated by this technique after careful manipulation of the probe and a high index of suspicion.

Barakate MS, Hemli JM, Hughes CF, Bannon PG, Horton MD

Eur J Cardiothorac Surg 2003 Feb;23(2):179-86

PMID: 12559340

Abstract

OBJECTIVE: Patients who undergo successful percutaneous transluminal coronary angioplasty (PTCA) may subsequently require operative myocardial revascularization. This review examines whether prior successful PTCA alters outcomes following subsequent coronary artery bypass grafting (CABG). The costs of interventional cardiology procedures and definitive surgery were also examined.

METHODS: From January 1981 through December 1997, 361 patients underwent CABG following initially successful PTCA (interval group). This group was compared with 11,909 patients who underwent CABG as the primary intervention for coronary artery disease (control group).

RESULTS: The average time interval to CABG following initial PTCA was 13.7 months. The post-CABG myocardial infarction rate was 4% for patients in the interval group and 3% for patients in the control group. The 30-day mortality was similar for both patient groups (2%). For the interval group, the average cost of total interventional management was 24,220 dollars per patient. This included average costs of 13,873 dollars for CABG and 10,347 dollars for all preoperative interventional cardiology procedures.

CONCLUSION: There is little doubt that PTCA procedures may provide successful myocardial revascularization. However, these procedures often need to be repeated over time and may serve only to delay coronary surgery, at substantial financial and personal cost.

Ryan JB, Hicks M, Cropper JR, Garlick SR, Kesteven SH, Wilson MK, Macdonald PS, Feneley MP

Eur J Cardiothorac Surg 2002 Nov;22(5):738-45

PMID: 12414040

Abstract

OBJECTIVE: Paradoxically, it has been reported that after 1.5-4 h of hypothermic ischaemic preservation there is complete recovery of contractile function in canine cardiac allografts, as assessed by the preload recruitable stroke work (PRSW) relationship. This raises questions about the suitability of the canine heart as a model for preservation research and the PRSW relationship as an end-point. The aim of the present study was to evaluate the PRSW relationship as an index of left ventricular contractility in porcine cardiac allografts.

METHODS: Eighteen orthotopic heart transplants were performed in inbred Westran pigs. Brain death was induced in the donor pigs 1 h prior to explantation. The donor hearts were arrested with extracellular cardioplegia, which was stored in ice prior to administration. On explantation, the donor hearts were immersed in cardioplegia and stored in ice. The donor hearts were subjected to either 4 (IT4, n = 6), 6 (IT6, n = 9) or 14 (IT14, n = 3) h of ischaemia. Post-transplant, all hearts were supported with dobutamine (10 mcg/kg per min). The PRSW relationship was derived from pressure-volume loops obtained by epicardial sonomicrometry and transmyocardial micromanometry. Multiple linear regression was used to describe and compare the PRSW relationship before brain death in the donor and after weaning from bypass in the recipient.

RESULTS: Eleven hearts were weaned successfully from cardiopulmonary bypass: IT4 100% (6/6), IT6 56% (5/9) and IT14 0% (0/3) (IT4 versus IT14: P = 0.012). Analysis of the PRSW relationship revealed a reduction in contractility in both the IT4 and IT6 groups (both P < 0.0001), but a greater reduction in the IT6 group (P < 0.0001). Notably, the volume-axis intercept of the PRSW relationship was found to be a better discriminator of post-preservation contractile dysfunction than the slope of the PRSW relationship.

CONCLUSIONS: The porcine heart’s susceptibility to ischaemic injury makes it ideal for evaluating the effect of different preservation strategies on contractile recovery. The PRSW relationship can be used to evaluate the differences in contractile recovery, though the nature of the effect of ischaemic preservation necessitates analysis by multiple linear regression.

Vallely MP, Bannon PG, Hughes CF, Kritharides L

J. Thorac. Cardiovasc. Surg. 2002 Oct;124(4):758-67

PMID: 12324734

Abstract

OBJECTIVE: Endothelial cell dysfunction has been implicated in the inflammatory response to cardiopulmonary bypass, and the upregulation of endothelial cell expression of adhesion molecules might promote leukocyte extravasation in vivo. Soluble endothelial cell adhesion molecules are increased after bypass. The aim of this study was to investigate the relationship between endothelial cell-surface expression of adhesion molecules and their concentration in plasma after coronary artery bypass grafting.

METHODS: Ten patients undergoing coronary artery bypass with cardiopulmonary bypass had 5 plasma samples taken at defined intervals before, during, and after cardiopulmonary bypass. Plasma was incubated with human umbilical vein endothelial cell monolayers, and expression of E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 on the surface of human umbilical vein endothelial cell monolayers was measured by means of enzyme-linked immunosorbent assay. Plasma soluble adhesion molecules, C-reactive protein, interleukin 8, interleukin 10, transforming growth factor beta1, and neutrophil counts were determined for each patient.

RESULTS: Markers typical of acute inflammation (ie, interleukin 8, neutrophils, and C-reactive protein) were all increased after bypass. Soluble plasma intercellular and vascular cell adhesion molecule 1 (but not E-selectin) were increased after bypass. However, endothelial cell expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 (but not E-selectin) were significantly decreased by exposure to postbypass plasma. Additionally, postbypass plasma inhibited interleukin 1beta-stimulated endothelial cell expression of vascular cell and intercellular adhesion molecule 1. Interleukin 10 and transforming growth factor beta1, both of which are known to inhibit endothelial cell adhesion molecule expression, were respectively increased 10-fold and 3-fold (P <.05) after bypass.

CONCLUSIONS: Despite containing increased soluble intercellular and vascular cell adhesion molecule 1, postbypass plasma inhibits endothelial cell expression of intercellular and vascular cell adhesion molecule 1. Upregulated vascular expression of adhesion molecules might not be essential for endothelial activation after bypass.

Dalrymple-Hay MJ, Crook T, Bannon PG, Ohri SK, Haw MP, Bayfield MS, Hendel NP, Livesey SA, Hughes CF, Monro JL

J. Heart Valve Dis. 2002 May;11(3):419-23

PMID: 12056737

Abstract

BACKGROUND AND AIM OF THE STUDY: The study aim was to assess the risk of reoperation for patients with a failing stented tissue valve.

METHODS: Between 1980 and 1999, 259 patients (118 males, 141 females; mean age 60.1+/-15.4 years) underwent redo valve replacement to replace a failing stented tissue valve. Of these patients, 94 (36.3%) underwent redo aortic valve replacement (AVR), 105 (40.5%) redo mitral valve replacement (MVR), and 60 (23.2%) redo aortic and mitral valve replacement (DVR). Twenty patients (7.7%) had previous coronary artery bypass grafting (CABG); further CABG were performed in 32 cases (12.4%). Preoperatively, 216 patients (83.3%) were in NYHA functional class III or IV.

RESULTS: The early mortality was (6.5%; n = 17), including three patients who had AVR, five DVR, and nine MVR. A higher preoperative NHYA status (p <0.0004) and emergency surgery (p <0.0001) were significantly associated with an increased risk of operative death (univariate analysis). Age at surgery (p = 0.45), previous CABG (p = 0.45), position of the valve replaced (p = 0.2), type of implant (p = 0.06) and presence of coronary artery disease (p = 0.51) were not associated with a significant risk of operative mortality. Including those patients who died, 88 (34.0%) experienced a peri- or postoperative complication, seven of which (2.7%) were permanent.

CONCLUSION: A failing tissue valve can be replaced, with acceptable operative mortality and morbidity. The choice of valve is a balance of its advantages and disadvantages, and these must be discussed with the patient. It appears, however, that the trend towards reducing the age at which tissue valve implantation is performed may be justified.