Biomedical subjects

Mark Hicks

Publications and source records attributed to Mark Hicks.

11 recordsLinked to original sources

PubMed2006

Organ preservation.

The success of organ transplantation is critically dependent on the quality of the donor organ. Donor organ quality, in turn, is determined by a variety of factors including donor age and preexisting disease, the mechanism of brain death, donor management prior to organ procurement, the duration of hypothermic storage, and the circumstances of reperfusion. It has been recognized for some time that both the short- and long-term outcomes after cadaveric organ transplantation are significantly inferior to those obtained when the transplanted organ is obtained from a living donor, regardless of whether the donor is related or unrelated to the recipient. Brain death results in a series of hemodynamic, neurohormonal, and pro-inflammatory perturbations, all of which are thought to contribute to donor organ dysfunction. The process of transplantation exposes the donor organ to an obligatory period of ischemia and reperfusion. Traditionally, hypothermic storage of the donor organ has been used to protect it from ischemic injury, but donor organs differ markedly in their capacity to withstand hypothermic ischemia. Data from the Registry of the International Society for Heart and Lung Transplantation indicate that the risk of primary graft failure and death rises dramatically for both the heart and lung as ischemic time increases. Based on these data, maximum recommended ischemic times for the donor heart and lung are 6 and 8 h, respectively. In this chapter, strategies aimed at minimizing the adverse consequences of brain death and ischemia/reperfusion injury to the donor heart and lung are discussed. These strategies are likely to become increasingly important as the reliance on marginal donors increases to meet the growing demand for organ transplantation.

Brain Death↗

PubMed2005

Improved preservation of the rat heart with celsior solution supplemented with cariporide plus glyceryl trinitrate.

Our aim was to investigate whether the addition of glyceryl trinitrate (GTN), a source of nitric oxide, and/or cariporide, a Na/H exchange inhibitor, to a commercial preservation solution (Celsior) improved and extended cardiac preservation. After baseline indices of cardiac function (aortic flow, coronary flow, heart rate, cardiac output) were measured in an isolated working rat heart model, hearts were arrested and stored at 2-3 degrees C for 6 or 10 h in Celsior solution alone, Celsior supplemented with either 0.1 mg/mL GTN or 10 microM cariporide or both. After storage, functional measurements were repeated and recovery of each parameter was expressed as a percentage of its pre-storage baseline. After 6 h storage, recovery of cardiac function was significantly better in hearts stored in GTN- or cariporide-supplemented Celsior solution compared with Celsior solution alone. The beneficial effect of GTN was significantly abrogated in hearts perfused with glibenclamide prior to storage. Significant recovery of cardiac function after 10 h storage was only observed in hearts stored in Celsior solution supplemented with both GTN and cariporide. Combined supplementation with GTN and cariporide extends the safe period of storage of the rat heart and may be a useful approach to enhancing preservation of the donor heart.

Animals↗

PubMed2004

Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease.

Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (GJA5) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (ACPL1 and Cx50 gene, GJA8) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5- to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.

Acid Phosphatase↗

PubMed2003

Sodium-hydrogen exchanger inhibition, pharmacologic ischemic preconditioning, or both for extended cardiac allograft preservation.

BACKGROUND: The aim of this study was to determine the efficacy of cariporide (a sodium-hydrogen exchanger inhibitor), BMS180448 (a pharmacologic ischemic preconditioning agent), and the combination thereof, as adjuvant therapies for extended cardiac allograft preservation. METHODS: A porcine model of donor brain death and orthotopic heart transplantation was used. All hearts were arrested and stored for 14 hr in an extracellular preservation solution. Control hearts (CON; n=3) did not receive any additional treatment. Treated hearts received BMS180448 alone (BMS; n=3), cariporide alone (CAR; n=6), or both BMS180448 and cariporide (B+C; n=6). Donors of BMS180448-treated hearts received 2 mg/kg, 15 min before explantation. Donors and recipients of cariporide-treated hearts received 2 mg/kg, 15 min before explantation and reperfusion, respectively. RESULTS: The CON and BMS arms of the study were terminated after three transplantations because initial results in these groups were poor. Significantly, none of the control hearts could be weaned successfully from bypass, whereas all of the treated hearts were weaned successfully (CAR vs. CON and B+C vs. CON: P=0.012). The rate of troponin I release during the first 3 hr after reperfusion was significantly lower in CAR (P=0.0180) and B+C (P=0.0154) recipients than in CON recipients. Mean plasma troponin I levels (microg/mL) 3 hr after reperfusion were as follows: CON 633+/-177, BMS 576+/-110, CAR 346+/-93, and B+C 296+/-97. CONCLUSION: In this porcine model of extended cardiac allograft preservation, cariporide was more effective than BMS180448 as an adjuvant to our usual preservation solution. There was no additional benefit from the combination of the two therapies.

Animals↗

PubMed2003

Cariporide (HOE-642) improves cardiac allograft preservation in a porcine model of orthotopic heart transplantation.

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.

Animals↗

PubMed2003

The initial rate of troponin I release post-reperfusion reflects the effectiveness of myocardial protection during cardiac allograft preservation.

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.

Animals↗

PubMed2003

Lazaroid (U74389G)-supplemented cardioplegia: results of a double-blind, randomized, controlled trial in a porcine model of orthotopic heart transplantation.

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.

Animals↗

PubMed2003

Functional evidence of reversible ischemic injury immediately after the sympathetic storm associated with experimental brain death.

BACKGROUND: Acute brain death from increased intracranial pressure results in a transient increase in myocardial adenosine and lactate, which indicates that oxygen demand exceeds oxygen delivery during the sympathetic "storm". The aim of this study was to determine the functional significance of this period of ischemia. METHODS: Brain death was inflicted on 40 Westran pigs (36.5-68.0 kg) by inflating a 21-ml subdural balloon over 3 minutes. In 38 animals, micromanometry and sonomicrometry were used to obtain left ventricular pressure-volume loops to determine the preload recruitable stroke work (PRSW) relationship. Data files were recorded before and at 15-minute intervals after beginning balloon inflation. Plasma troponin I was measured before and 60 minutes after beginning balloon inflation in the 38 instrumented and 2 non-instrumented animals. RESULTS: All animals experienced the classical sympathetic storm. The slope of the PRSW relationship decreased, and the volume-axis intercept shifted to the right 15 minutes after beginning balloon inflation (p < 0.0001). Progressive incremental recovery (leftward shift) occurred between subsequent time points (p < or = 0.0018). In the instrumented animals, the mean plasma troponin I level increased from 1.4 +/- 1.6 microg/liter to 2.8 +/- 2.3 microg/liter (p < 0.001). However, troponin I was not detected before or after induction of brain death in the plasma of either non-instrumented animal (p = 0.001). CONCLUSIONS: The sympathetic storm produced transient contractile dysfunction, consistent with ischemic injury. However, troponin I release reflected surgical instrumentation and not brain death.

Animals↗

PubMed2003

Cardioprotection by cariporide after prolonged hypothermic storage of the isolated working rat heart.

BACKGROUND: Inhibition of the sodium-hydrogen (Na(+)-H(+)) exchanger decreases the extent of ischemia-reperfusion injury in the myocardium. Inhibition may also improve preservation of hearts stored for transplantation. Our aim was to characterize the dose response and to determine optimal timing for administering cariporide, an Na(+)-H(+) exchange inhibitor, during prolonged hypothermic storage. METHODS: We used the rat isolated working-heart model to measure cardiac function. To determine the optimal dose of cariporide, hearts received either no treatment (control) or incremental doses of cariporide (1, 3.2, 10, or 30 micromol/liter) before storage and during reperfusion. Hearts were arrested with and stored in an extracellular-based cardioplegic solution at 2 to 3 degrees C for 6 hours. To determine optimal timing, we arrested a group of hearts with and stored them in a cariporide-supplemented (10 micromol/liter) cardioplegic solution but did not pre-treat them with cariporide. Finally, we treated a separate group of hearts with 10 micromol/liter cariporide before, during, and after storage. RESULTS: Recovery of cardiac function in control hearts was poor. The cardioprotective effect of cariporide was dose dependent, with maximal protection observed at a concentration of 10 micromol/liter. Storing hearts in a cariporide-supplemented cardioplegic solution did not result in better recovery of cardiac function compared with cariporide given before storage and during reperfusion. Moreover, recovery of cardiac function was significantly worse in hearts that had not been pre-treated with cariporide. CONCLUSIONS: Sodium-hydrogen-exchange inhibition with cariporide significantly protects the hypothermic ischemic rat heart, increasing cardiac function after reperfusion. The timing of cariporide administration is an important determinant of this cardioprotection.

Animals↗

PubMed2003

Enhanced cardioprotection of the rat heart during hypothermic storage with combined Na+ - H+ exchange inhibition and ATP-dependent potassium channel activation.

BACKGROUND: We investigated the ability of mitochondrial adenosine triphosphate-dependent potassium-channel activation to augment the protection of Na(+)-H(+) exchanger inhibition in isolated working rat hearts after 6 hours of hypothermic storage in an extracellular-based cardioplegic solution. METHODS: We treated hearts with the potassium-channel openers diazoxide (100 micromol/liter) or BMS-180448 (10 micromol/liter) or with the Na(+)-H(+) exchanger inhibitor cariporide (10 micromol/liter). Cariporide also was administered in combination with either diazoxide or BMS-180448 in 2 other treatment groups. All hearts were arrested and stored at 2 to 3 degrees C. After storage, we reperfused hearts for 10 minutes before performing work for a further 15 minutes, and then we measured and assessed cardiac function using a 2-way analysis of variance model. RESULTS: Neither diazoxide nor BMS-180448 significantly improved recovery of cardiac output. Cariporide therapy significantly improved cardiac output compared with control. However, we obtained the greatest recovery of cardiac output when we combined cariporide with either diazoxide or BMS-180448. CONCLUSIONS: Cariporide is more cardioprotective than the potassium-channel openers diazoxide and BMS-180448 after prolonged hypothermic storage. Co-administration of diazoxide or BMS-180448 with cariporide results in additive cardioprotection, with significantly improved cardiac function when compared with either treatment given alone. Such a combination could be used to improve the functional recovery of hearts stored for cardiac transplantation.

Animals↗

PubMed2002

The preload recruitable stroke work relationship as a measure of left ventricular contractile dysfunction in porcine cardiac allografts.

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.

Animals↗