Nicorandil ameliorates posttransplant dysfunction in cardiac allografts harvested from non-heart-beating donors.

OBJECTIVE: Warm ischemia is a major cause of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). We evaluated the cardioprotective effects of nicorandil, an adenosine triphosphate-sensitive potassium channel opener, on the early posttransplant left ventricular (LV) function of hearts harvested from asphyxiated canine NHBDs. METHODS: Hypoxic cardiac arrest was induced in 12 donor dogs. In 6, nicorandil was administered intravenously at 100 micrograms/kg + 25 micrograms/kg/min after respiratory arrest and hearts were preserved with nicorandil-supplemented cardioplegic solution (nicorandil group). The remaining 6 did not receive nicorandil at any time during the experiment (control group). Hearts were orthotopically transplanted after a mean myocardial ischemic time of 4 hours. RESULTS: All 12 recipients were weaned from cardiopulmonary bypass without inotropic support. In the control group, posttransplant cardiac indices and left ventricular end-systolic pressure (LVESP) decreased significantly, while LV max-dP/dt and Tau increased over pretransplant values. No differences were seen in parameters between pretransplant and posttransplant values in the nicorandil group. Posttransplant cardiac indices, LVESP, and LV max + dP/dt were higher in the nicorandil group than in controls, while posttransplant LV max-dP/dt in the nicorandil group was lower. CONCLUSIONS: Our results indicate that pretreatment with nicorandil during hypoxic perfusion before cardiac arrest and subsequent preservation with nicorandil-supplemented cardioplegia ameliorates early posttransplant LV dysfunction of hearts harvested from asphyxiated NHBDs.     

Nicorandil ameliorates posttransplant dysfunction in cardiac allografts harvested from non-heart-beating donors

Objective: Warm ischemia is a major cause of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). We evaluated the cardioprotective effects of nicorandil, and adenosine triphosphate-sensitive potassium channel opener, on the early posttransplant left ventricular (LV) function of hearts harvested from asphyxiated canine NHBDs.Methods: Hypoxic cardiac arrest was induced in 12 donor dogs. In 6, nicorandil was administered intravenously at 100 μg/kg+25 μg/kg/min after respiratory arrest and hearts were preserved with nicorandil-supplemented cardioplegic solution (nicorandil group). The remaining 6 did not receive nicorandil at any time during the experiment (control group). Hearts were weaned from cardiopulmonary bypass without inotropic support. In the control group, posttransplant cardiac indices and left ventricular end-systolic pressure (LVESP) decreased significantly, while LV max-dP/dt and Tau increased over pretransplant values. No differences were seen in parameters between pretransplant and posttransplant values in the nicorandil group. Posttransplant cardiac indices, LVESP, and LV max+dP/dt were higher in the nicorandil group than in controls, while posttransplant LV max-dP/dt in the nicorandil group was lower.Conclusions: Our results indicate that pretreatment with nicorandil during hypoxic perfusion before cardiac arrest and subsequent preservation with nicorandil-supplemented cardioplegia ameliorates early posttransplant LV dysfunction of hearts harvested from asphyxiated NHBDs.     

Effects of adding P38 mitogen-activated protein-kinase inhibitor to celsior solution in canine heart transplantation from non-heart-beating donors

BACKGROUND: The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in ischemia-reperfusion injury. This study evaluated the effects of p38 MAPK inhibition using FR167653, a novel p38 MAPK inhibitor, as an additive to Celsior solution in canine heart transplantation from non-heart-beating donors (NHBDs). METHODS: Donor hearts were left in situ for 20 minutes after cardiac arrest, which was induced by rapid exsanguination. Twelve donor-recipient pairs of mongrel dogs were divided into two groups: the control and FR167653 (FR) groups (n=6 each). In both groups, the grafts were subjected to coronary flushing and immersed in Celsior solution for 4 hours with or without FR167653. Orthotopic heart transplantation was then performed. Cardiac output (CO), left ventricular pressure (LVP), and end-systolic maximal elastance (Emax) were measured 2 hours after weaning from cardiopulmonary bypass (CPB), and the hearts were then harvested for histopathologic study. The activation of p38 MAPK was evaluated in another 20 mongrel dogs. RESULTS: In the FR group, CO, LVP recovery rate, and Emax were significantly (P<0.05) higher 2 hours after weaning from CPB, histopathologic damage was attenuated, and the activation of p38 MAPK was significantly (P<0.05) inhibited 10 minutes after reperfusion compared with the control group. CONCLUSIONS: The addition of FR167653 to Celsior solution improved heart-graft viability, probably by way of the inhibition of p38 MAPK activation, which may attenuate ischemia-reperfusion injury in heart transplantation from NHBDs.     

The effect of short-term coronary perfusion using a perfusion apparatus on canine heart transplantation from non-heart-beating donors.

BACKGROUND: We investigated the effects of briefly perfusing hearts from non-heart-beating donors (NHBDs) with a Celsior solution before cardiac transplantation. METHODS: Donor hearts were left in situ for 20 minutes after cardiac arrest was induced by rapid exsanguination. Twelve donor-recipient pairs of mongrel dogs were divided into 2 groups, the simple immersion (SI, n = 6) group and the coronary perfusion (CP, n = 6) group. Both groups underwent coronary flushing with Celsior, after which hearts from the SI group were stored using simple immersion for 4 hours and hearts from the CP group underwent 1 hour of further perfusion followed by storage for 3 hours. Orthotopic transplantation was then performed. We measured cardiac output, end-systolic maximal elastance (E(max)), left ventricular pressure, and rate pressure product 1 and 2 hours after weaning from cardiopulmonary bypass (CPB). Two hours after weaning from CPB, the hearts were harvested for histopathologic study and to determine the percentage of water content. RESULTS: The cardiac output (CO) recovery rate was significantly higher in the CP group than in the SI Group 1 hour after weaning from CPB (p < 0.05). The CO recovery rate, E(max), and rate pressure product were significantly higher and the percentage of water content was significantly lower in the CP group than in the SI Group 2 hours after weaning from CPB (p < 0.05). Histopathologic damage was more severe in the SI group. CONCLUSIONS: The results of this study suggest that short-term coronary perfusion with a Celsior solution may be useful for heart transplantation from NHBDs.     

The Harmful Effects of Ventricular Distention during Postischemic Reperfusion

To assess the effects of left ventricular distention during the early reperfusion period following ischemic arrest, 16 canine heart preparations were subjected to 45 minutes of hypothermic (27°C) cardioplegic arrest and normothermic reperfusion. Isovolumic left ventricular developed pressure and rate of rise of left ventricular pressure (dP/dt) were measured with an intraventricular balloon; endocardial/epicardial flow ratios were determined with microspheres; and myocardial gas tensions were monitored with mass spectrometry.During early reperfusion, Group 1 hearts (n = 8) were not distended (end-diastolic pressure = 0). Group 2 hearts (n = 8) were subjected to an end-diastolic pressure of 20 mm Hg for the initial 15 minutes of reperfusion. Group 2 hearts demonstrated impaired subendocardial blood flow after 5 minutes of reflow (0.75 ± 0.06 vs 0.96 ± 0.04, endocardial/epicardial flow rates, Group 2 vs Group 1) and persistent elevation of intramyocardial carbon dioxide (CO₂) tension (68 ± 4 vs 51 ± 4 mm Hg, Group 2 vs Group 1). In addition, postischemic ventricular function was significantly worse in Group 2 hearts (60 ± 7 vs 79 ± 3% of control dP/dt, Group 2 vs Group 1, and 53 ± 6 vs 81 ± 5% of control left ventricular developed pressure, Group 2 vs Group 1).These data demonstrate that even mild distention during early reperfusion can result in reduced subendocardial perfusion and delayed washout of tissue CO₂. Although myocardial blood flow and CO₂ tension subsequently returned to normal in the distended hearts, left ventricular performance remained significantly depressed. This injury can occur clinically in nonvented hearts prior to the resumption of effective ventricular contraction.     

The effects of ropivacaine at clinically relevant doses on myocardial ischemia in pigs

A major risk associated with bupivacaine during myocardial ischemia is ventricular fibrillation. We investigated the influence of ropivacaine on cardiac contractility and the propensity to ventricular fibrillation before and after myocardial ischemia in a placebo-controlled pig study. Anesthetized domestic pigs were administered 1 mg·kg⁻¹ of ropivacaine intravenously over 1 min and then 0.03 mg·kg⁻¹·min⁻¹ as a 30-min infusion, or saline. The following endpoints were measured before and after ropivacaine administration: (1) the ventricular fibrillation threshold (VFT) before and during myocardial ischemia induced by total transient ligation of the anterior interventricular artery and (2) electrophysiological (sinus heart rate, duration of QRS and QT intervals) and hemodynamic (blood pressure, the time derivative of left ventricular pressure [peak LV dP/dt]) parameters. Ropivacaine induced no changes in sinus heart rate, QRS, and or QT before or during ischemia. In contrast, there was a mild increase in the VFT before ischemia, which was drastically and significantly reduced during ischemia. The reduction of peak LV dP/dt during ischemia was further increased by ropivacaine. We also found that the effect of ropivacaine on the VFT was coronary blood flow-dependent, with a markedly decreased threshold in the presence of ischemia. Similar effects have been observed in humans with several other local anesthetics, as well as with class I antiarrhythmic drugs. The results of this study should be taken into account by anesthesiologists when administering ropivacaine to coronary patients.     

Heterotopic transplantation as a model to study functional recovery of unloaded failing hearts

OBJECTIVES: Recent studies have demonstrated cardiac improvement in patients supported with a ventricular assist device, suggesting that reverse remodeling and myocardial recovery are possible. We developed an animal model of cardiac unloading by adapting a heterotopic transplantation technique and used it to examine the pattern of functional recovery in the left ventricle of the failing heart. METHODS: Heart failure was induced in adult New Zealand rabbits by coronary artery ligation with subsequent myocardial infarction. Animals undergoing sham operation served as a control group. After 4 weeks or 3 months, failing hearts were transplanted into the necks of recipient rabbits. A left ventricular latex balloon connected to subcutaneous tubing allowed repeated physiologic analysis on days 1 and after transplantation and then every 5 days until day 30. RESULTS: Contractility (left ventricular dP/dt(max)) and relaxation (left ventricular dP/dt(min)) were significantly lower in transplanted postinfarction hearts as compared to control hearts immediately after transplantation. Both left ventricular dP/dt(max) and left ventricular dP/dt(min) responses to increased preload and to beta-adrenergic stimulation progressively improved to a significantly higher level after 30 days of left ventricular unloading for the hearts that were transplanted 4 weeks after myocardial infarction. However, this functional improvement was not detected in failing hearts transplanted 3 months after infarction. CONCLUSIONS: This model of cardiac unloading appears at least partially to mimic conditions of ventricular assist devices. If performed early in the development of heart failure, it permits improvement of contractile dysfunction and restoration of cardiac responsiveness to mechanical and beta-adrenergic stimulation. Therefore this model may constitute a novel alternative in the study of reverse remodeling in unloaded failing hearts.     

Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2

BACKGROUND: This study investigated the changes of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during acute cardiac transplant rejection. METHODS: Isogeneic Lewis to Lewis and allogeneic Dark Agouti (DA) to Lewis rat cardiac transplants were studied 3 and 5 days after heterotopic intraabdominal transplantation (n=6/group). Myocardial blood flow (MBF), left ventricular systolic pressure (LVSP), maximum pressure development (+dP/dt), and end-diastolic pressure (LVEDP) were measured using an intraventricular balloon. Contractile response to dobutamine (5 microg/kg/min) was also assessed. In separate groups beta-adrenergic receptor density and adenylyl cyclase activity were measured in the grafts, in the recipients' native hearts and in native hearts of sham-operated controls. RESULTS: During mild to moderate rejection cardiac function indices remained unchanged, although MBF and contractile response to dobutamine decreased significantly (P<0.05) in the allogeneic group. The beta-adrenergic receptor density was significantly (P<0.05) increased in both isografts and allografts and in the native hearts of allografted recipients in comparison to native hearts of controls. Adenylyl cyclase activity showed a significant decrease (P<0.05) only in allografts. During severe rejection, LVSP and +dP/dt decreased and LVEDP increased in allografts in comparison to isografts (P<0.05). This was accompanied by a significant decrease in MBF, contractile response to dobutamine, beta-adrenergic receptor density, and adenylyl cyclase activity (P<0.05). CONCLUSIONS: Both microcirculatory disturbances and primary alteration in adenylyl cyclase activity may contribute to decreased contractile reserve in mild to moderate cardiac allograft rejection, whereas beta-adrenergic receptor density seems to be also influenced by cardiac denervation. Severe rejection leads to systolic and diastolic heart failure with complex dysregulation of the beta-adrenergic receptor/adenylyl cyclase pathway and impaired microcirculation.     

Myocardial contractility and relaxation after deep hypothermic circulatory arrest in a neonatal piglet model

Cooling before circulatory arrest or ischemic arrest has been reported to influence myocardial performance in isolated neonatal hearts. The aim of the present study was to analyze indices of myocardial contractility and relaxation in an in vivo neonatal model after deep hypothermic circulatory arrest (DHCA). DHCA (18°C; DHCA group; n = 8) or mild hypothermic cardiopulmonary bypass ([MH-CPB] 32°C; MH-CPB group; n = 10) was applied in newborn piglets. After reperfusion (60 and 120 min), left ventricular dP/dt(max) increased in DHCA and MH-CPB, while-dP/dt(max) decreased slightly in DHCA and increased in MH-CPB. Nevertheless, the differences between the two groups did not reach statistical significance. In conclusion, left ventricular contractility remained stable after reperfusion following DHCA, to some degree at the expense of the diastolic function.     

Comparative analysis of the performance of various crystalloid cardioplegic solutions on myocardial protection after prolonged cold ischemia

Introduction

The quality and effectiveness of myocardial protection are fundamental problems to expand the use of and consequently good outcomes of donated hearts for transplantation.

Objective

The purpose of this investigation was to compare the cardioprotective effects of Krebs-Henseleit, Bretschneider-HTK, St Thomas, and Celsior solutions using a modified nonrecirculating Langendorff column model of isolated perfused rat heart during prolonged cold storage.

Materials and Methods

After removal 36 rat hearts underwent isolated perfusion into a Langendorff apparatus using Krebs-Henseleit solution for a 15-minute period of recovery; we excluded organs that did not maintain an aortic pressure above 100 m Hg. Subsequently, we equally distributed the hearts into four groups according to the cardioprotection solution; group 1, Krebs-Henseleit (control); group II, Bretschneider-HTK; group III, St Thomas; and group IV, Celsior. Each heart received the specific cardioplegic solution at 10°C for 2-hour storage at 20°C, before a 15 minutes perfusion with Krebs-Henseleit solution for recovery and stabilization. After 60 additional minutes of perfusion, every 5 minutes we determined heart rate (HR), coronary flow (CF), left ventricular systolic pressure (LVSP), and positive and negative peak of the first derivative of left ventricular pressure (+dP/dt and −dP/dt, respectively).

Results

Comparative analysis by Turkey's test showed the following performances among the groups at 60 minutes of reperfusion: HR: II = IV > III > I; CF: II = IV > I = III; LVSP: IV > I = II = III; +dP/dt: IV > I = II = III; and −dP/dt: IV = II > I = II.

Conclusion

Cardioprotective solutions generally used in clinical practice are not able to avoid hemodynamic alterations in hearts exposed to prolonged ischemia. Celsior solution showed better performance than Bretschneider-HTK, St Thomas, and Krebs-Henseleit.     

Hypertonic saline dextran resuscitation of thermal injury.

Burn treatment requires large volumes of crystalloid, which may exacerbate burn-induced cardiopulmonary dysfunction. Small-volume hypertonic saline dextran (HSD) resuscitation has been used for effective treatment of several types of shock. In this study isolated coronary perfused guinea pig hearts were used to determine if HSD improved left ventricular contractile response to burn injuries. Parameters measured included left ventricular pressure (LVP) and maximal rate of LVP rise (+dP/dt max) and fall (-dP/dt max) at a constant preload. Third-degree scald burns comprising 45% of total body surface area (burn groups, N = 75), or 0% for controls (group 1, N = 25) were produced using a template device. In group 2, 25 burned guinea pigs were not fluid resuscitated and served as untreated burns; 20 burns were resuscitated with 4 mL lactated Ringer's (LR) solution/kg/% burn for 24 hours (group 3); additional burn groups were treated with an initial bolus of HSD (4 mL/kg, 2400 mOsm, sodium chloride, 6% dextran 70) followed by either 1, 2, or 4 mL LR/kg/% burn over 24 hours (groups 4, 5, and 6, respectively). Untreated burn injury significantly impaired cardiac function, as indicated by a fall in LVP (from 88 +/- 3 to 68 +/- 4 mmHg; p = 0.01) and +/- dP/dt max (from 1352 +/- 50 to 1261 +/- 90 and from 1150 +/- 35 to 993 +/- 59; p = 0.01, respectively) and a downward shift of LV function curves from those obtained from control hearts. Compared to untreated burns, hearts from burned animals treated with LR alone showed no significant improvement in cardiac function. However hearts from burned animals treated with HSD + 1 mL LR/kg/% burn had significantly higher LVP (79 +/- 4 vs. 68 +/- 4 mmHg, p = 0.01) and +/- dP/dt max (+dP/dt: 1387 +/- 60 vs. 1261 +/- 90 mmHg/sc, p = 0.01; -dP/dt: 1079 +/- 50 vs. 993 +/- 59 mmHg/sc, p = 0.01) than hearts from untreated burned animals and generated left ventricular function curves comparable to those calculated for hearts from control animals. Mortality 24 hours after burn was 29% for untreated burns was 0% for control animals, as well as for groups treated with the Parkland formula or HSD plus 1 or 2 mL/kg/% burn lactated Ringer's. The only deaths after treatment occurred in those animals given HSD plus 4 mL/kg/% burn, Parkland formula (17% mortality).(ABSTRACT TRUNCATED AT 400 WORDS)     

FK409 ameliorates ischemia-reperfusion injury in heart transplantation following 12-hour cold preservation.

OBJECTIVE: FK409 is the first spontaneous nitric oxide donor to increase plasma guanosine 3':5'-cyclic monophosphate. We designed this study to investigate whether the administration of FK409 during reperfusion ameliorated ischemia-reperfusion injury and enhanced post-transplant graft function in orthotopic heart transplantation following 12-hour cold preservation in a canine model. METHODS: We used 10 pairs of adult mongrel dogs, weighing 9.5 to 13.5 kg. Following cardiac arrest using cardioplegia, we washed out the coronary vascular beds with cold University of Wisconsin solution followed by 12-hour preservation. After preservation, we performed orthotopic transplantation. The experimental animals were divided into 2 groups. In the FK group (n = 5), FK409 (5 microg/kg/min) was administered intravenously, beginning 15 minutes before the onset of reperfusion and continuing for 45 minutes after reperfusion. In the control group (n = 5), saline vehicle was administered in the same manner. Two hours after transplantation, we assessed cardiac function, including cardiac output, left ventricular systolic pressure (LVP), and the maximum rates of positive and negative increase of LVP (+/-LV dP/dt) by comparing the recovery rate (%) of the cardiac function of the donor animal. We measured endothelin-1 levels in blood obtained from a catheter inserted into the coronary sinus 30, 60, and 120 minutes after reperfusion. RESULTS: Cardiac output was higher in the FK group than in the control group, but the difference was not significant (p = 0.08). Left ventricular systolic pressure and +/-LV dP/dt were significantly (p < 0.05) higher in the FK group than in the control group. Endothelin-1 levels were significantly (p < 0.05) lower in the FK group than in the control group 30 minutes after reperfusion. Transmission electron microscopy showed that the basal lamina of capillary vessels, glycogen granules, and mitochondrial structure were well-preserved in the FK group. CONCLUSIONS: In orthotopic transplantation models, FK409 is effective in ameliorating ischemia-reperfusion injury following preservation and in enhancing post-transplant cardiac function.     

Heparin and phentolamine combined, rather than heparin alone, improves hepatic microvascular procurement in a non-heart-beating donor rat-model

Improvement of organ procurement from non-heart-beating donors (NHBDs) could increase the donor organ pool for liver transplantation. Whether anti-coagulative and anti-vasospastic substances can improve hepatic microvascular preservation from NHBDs is unknown. In donor rats which were pretreated with either heparin (n = 6) or heparin combined with phentolamine (n = 7) 10 min prior to cardiac arrest, the extent and homogeneity of hepatic microvascular reperfusion was assessed at the end of a 60-min period of cardiac arrest using in situ fluorescence microscopy. Non-pretreated animals with cardiac arrest for 60 min served as controls (n = 6). In the non-treated NHBDs, arterial gravity perfusion of 100 cm H₂O with HTK-solution led to a hepatic acinar reperfusion of only ∼ 22 % with a remarkably diminished sinusoidal density. Application of heparin prior to cardiac arrest resulted in a two-fold, but insignificant increase of acinar perfusion and sinusoidal density with a still considerable heterogeneity of both parameters. Livers of NHBDs that additionally received phentolamine exhibited significantly increased values of both acinar perfusion and sinusoidal density. Phentolamine was found to reduce heterogeneity of organ microperfusion. Thus, our results indicate that the combined application of heparin and phentolamine is a useful additive for optimizing the quality of organs harvested from NHBDs. Received: 8 June 1999 Revised: 27 December 2000 Accepted: 5 April 2000     

Acute orthotopic transplantation of hearts stored for 72 hours

Using a storage method based on hypothermic (4° C) perfusion with a water-based asanguinous solution the dog heart has been preserved for up to 72 hours in a viable condition. The ultimate functional test of the viability of such hearts is orthotopic transplantation. Seven of eight dog hearts stored for 72 hours were able to support the recipient circulation in a stable manner after acute orthotopic transplantation. The donor hearts maintained a mean arterial pressure of 70-100 mmHg, left atrial pressure 5-12 cm H₂O, and maximum dp/dt of the left ventricular pressure was 1,200-2,400 mmHg/second. No myocardial stimulants were used. The results of 72 hours' hypothermic perfusion storage were superior to those of previously reported six hours' non-perfusion storage. A comment is made on the empirical nature of this field.     

Cardiac function and myocardial performance of 24-hour-preserved asphyxiated canine hearts.

A method of 24-hour storage of asphyxiated canine hearts for orthotopic cardiac transplantation was studied to expand the geographical size of the donor pool. Left ventricular function of asphyxiated hearts preserved for 24 hours (group 1, n = 8) was compared with that of hearts donated on-site (group 2, n = 5). Group 1 donors were pretreated with verapamil hydrochloride, propranolol hydrochloride, and prostacyclin. The donor hearts were perfused with warm blood cardioplegia in situ after 10 minutes of asphyxiation and then perfused with cold crystalloid cardioplegia for 2 hours. The hearts were excised and stored in ice-cold University of Wisconsin solution for 22 hours. At orthotopic transplantation, coronary perfusion with warm blood cardioplegia was performed before the graft aorta was unclamped. Conventional cardiac variables (eg, cardiac output and maximum rate of rise of left ventricular pressure), myocardial performance, and diastolic compliance of grafted hearts were assessed 1 hour after weaning from bypass. All recipients in both groups were easily weaned from cardiopulmonary bypass without inotropic agents, and there were no significant differences in cardiac variables between the two groups. These results strongly suggest that cadaver hearts can be preserved for 24 hours with satisfactory cardiac function.     

Superiority of substrate enhancement over oxygen free-radical scavengers during extended periods of cold storage for cardiac transplantation

When cold storage techniques used in cardiac transplantation are extended beyond 3 hours, there is significant depression in ventricular function. This study was undertaken to determine whether the addition of the amino acid L-glutamate or the oxygen free-radical scavengers superoxide dismutase (SOD) and catalase (CAT) during extended periods of cold storage would improve ventricular function. Fifteen rabbit hearts were placed on a Langendorff apparatus, arrested with crystalloid potassium cardioplegia, stored in iced saline solution (3 degrees C) for 5 hours, and then reperfused at 37 degrees C for 1 hour. In five hearts L-glutamate (4 mmol/L) was added to the cardioplegic and reperfusate solutions, and five hearts received SOD (1500 units/kg/L) and CAT (3500 units/kg/L), whereas in five others the cardioplegic and reperfusate solutions were unmodified. Hearts treated with L-glutamate had the best recovery of positive dP/dt (79%* glutamate vs 49%* SOD and CAT vs 36% unmodified), negative dP/dt (76%* glutamate vs 53% SOD and CAT vs 45% unmodified), developed pressure (67%* glutamate vs 51% SOD and CAT vs 45% unmodified), and coronary flow (81%* glutamate vs 79%* SOD and CAT vs 62% unmodified). We conclude that substrate enhancement with L-glutamate provides superior myocardial protection than is possible with the oxygen free-radical scavengers SOD and CAT during extended periods of cold storage for cardiac transplantation.     

Dynamic right ventricular dimension. Relation to chamber volume during the cardiac cycle

Whereas the left ventricle has been analyzed extensively, the apparent complexity of right ventricular geometry and contraction has hindered analysis of right ventricular performance by an assessment of instantaneous ventricular dimensions and volume during the cardiac cycle. To address this issue, we examined the temporal and quantitative relation between dynamic right ventricular free wall dimension, rate of pressure development (dP/dt), and pulmonary artery flow in the open-chest dog. Right ventricular free wall chord dimension was recorded by sonomicrometry, right ventricular pressure by micromanometer-tipped catheter, and pulmonary flow by electromagnetic probe. The point of peak positive right ventricular dP/dt closely correlated with the end of isovolumic contraction and initiation of ejection, occurring within 10 +/- 25 msec of initiation of pulmonary flow. Right ventricular dimension at peak positive dP/dt differed from dimension at initiation of chord shortening by less than 3%. Peak negative dP/dt correlated with end ejection, occurring within 10 +/- 25 msec of cessation of pulmonary flow. Right ventricular dimension at peak negative dP/dt differed from minimal dimension by less than 1%. In all dogs, volume ejected from the right ventricular chamber during each cardiac cycle was directly related to the change in right ventricular dimension during the same period (mean r = 0.969). This relationship between right ventricular stroke volume and dimensional change remained linear and was not changed (p = NS) by increases in right or left ventricular afterload induced by constricting the pulmonary artery or descending aorta. Right ventricular stroke work, calculated as the integral of instantaneous right ventricular pressure and dimension, correlated well (mean r = 0.980) with directly measured global right ventricular stroke work over a wide range; it was also not changed (p = NS) by changes in afterload. Accurate assessments of beat-to-beat right ventricular chamber volume and stroke work can be obtained by analysis of dynamic right ventricular chord dimension.     

Myocardial Protection Through Cold Cardioplegia Using Diltiazem,a Calcium Channel Blocker

During two hours of aortic clamping, two groups of 10 dogs each were given an intermittent infusion of a cold solution in the aortic root. In one group, the solution contained 20 mEq per liter of potassium chloride (KCl) and in the other, a calcium channel blocker (diltiazem). Left ventricular (LV) performance was measured by calculation of LV pressure, left ventricular end-diastolic pressure (LVEDP), cardiac index (CI), and stroke-work index (SWI). Regional myocardial function was assessed through ultrasonic crystals implanted in the subendocardial areas of both the left anterior descending (LAD) and circumflex coronary arteries.Dogs receiving KCl displayed deterioration of LV performance as evidenced by a return of maximal LV pressure, maximal rate of rise of LV pressure (dP/dt_max), CI, and SWI to 74 ± 4%, 87 ± 5%, 74 ± 6%, and 59 ± 6%, respectively, of the initial (before clamping) values. Animals that received diltiazem, on the other hand, had for the same variables a return to 85 ± 4%, 99 ± 7%, 129 ± 8%, and 111 ± 10% of the initial values. The rate of relaxation (peak negative dP/dt) decreased in both groups but less in dogs receiving diltiazem. Regional function in the area of the LAD and circumflex arteries showed little change in either group.We conclude that cold cardioplegia with a solution containing KCl or diltiazem protects the myocardium during prolonged ischemic cardiac arrest. Return of LV function on the whole is superior when diltiazem is used.     

Myocardial Stunning and Reperfusion Injury in Cardiac Surgery

Abstract This article reviews the evidence that myocardial stunning during surgical reperfusion after coronary revascularization or heart transplantation is not strictly due to myocardial injury sustained during ischemia, but results from pathophysiological events triggered by reperfusion (reperfusion injury). In sheep, left ventricular (LV) dP/dt and stroke work were reduced up to 50%, and 60% to 70% necrosis was observed in the area at risk during 3 hours reperfusion following coronary occlusion and cardioplegic arrest on bypass. Reperfusion with leukocyte depleted blood, or pharmacological blockade of either thromboxane or leukotriene receptors, provided significant improvements in LV function and myocardial blood flow, with a 40% to 50% reduction in necrosis. Similar results have been obtained using animal hearts subjected to 2 to 3 hours arrest at either 4 °C or 15°C, simulating cardiac preservation and reperfusion after transplantation. Diastolic pressure was significantly elevated, and increases in the time constant for relaxation of LV pressure and coronary vascular resistance were noted. These indices of myocardial stunning were reversed after blocking neutrophil-endothelial cell interaction with monoclonal antibodies against CD18 or ICAM-1 receptors, and significant improvements were also obtained after either thromboxane or leukotriene receptor blockade. We conclude that immediate postoperative myocardial stunning results largely from reperfusion injury that occurs due to an acute inflammatory response to ischemia and reperfusion, and that stunning can be largely reversed with appropriate pharmacological intervention.     

Single fibers of skeletal muscle as a novel graft for cell transplantation to the heart

OBJECTIVE: Skeletal myoblast transplantation is a promising alternative to treat heart failure. A single fiber, the minimal functional unit of skeletal muscle, retains skeletal myoblasts beneath the basal lamina. When surrounding muscle is injured, myoblasts migrate from the fiber into the damaged area to regenerate muscle. We hypothesized that such isolated fibers could be used as an efficient vehicle to deliver myoblasts into damaged myocardium, resulting in improved cardiac function. METHODS: Living single fibers of rat skeletal muscle were isolated, and their behavior was characterized in vitro. Single fibers were injected into the myocardium (at 4 sites, each receiving a single fiber) of rats in 2 models of heart failure induced either by means of doxorubicin administration or left coronary artery occlusion. RESULTS: Skeletal myoblasts dissociated from an isolated single fiber, proliferated, and differentiated into multinucleated myotubes in vitro. Within 3 days after grafting in vivo, original fibers provided putative myoblasts and disappeared. At 4 weeks, discrete loci consisting of several multinucleated myotubes were observed. Furthermore, single-fiber transplantation significantly improved cardiac function compared with the control treatment in either doxorubicin-treated hearts (maximum dP/dt, 4013.9 +/- 96.1 vs 3603.1 +/- 102.3 mm Hg/s; minimum dP/dt, -2313.7 +/- 75.1 vs. -2057.1 +/- 52.4 mm Hg/s) or ischemic hearts (maximum dP/dt, 3905.6 +/- 103.0 vs 3572.6 +/- 109.7 mm Hg/s; minimum dP/dt, -2336.1 +/- 69.7 vs -2106.4 +/- 74.2 mm Hg/s). CONCLUSION: Single-fiber transplantation acts as a vehicle for delivering putative skeletal myoblasts that appear to differentiate into myotubes within the myocardium. This was associated with improved function of failing hearts, suggesting its efficacy as a novel graft for cellular cardiomyoplasty.