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Background: Right ventricular (RV) hypertrophy is an adaptive process that occurs in the setting of chronic pulmonary hypertension (CPH) and can lead to alterations in normal RV diastolic properties. This study was designed to investigate the effects of NO and milrinone on RV diastolic dysfunction in the setting of CPH and RV hypertrophy by use of a canine model of monocrotaline pyrrole (MCTP)-induced CPH., Methods and Results: Sixteen mongrel dogs (22 to 24 kg) were used. Animals underwent percutaneous pulmonary artery (PA) catheterization to measure pulmonary hemodynamics before and 8 weeks after injection of 3 mg/kg MCTP (n=8) or placebo (control, n=8). Eight weeks after injection, all hearts were instrumented with a PA flow probe, sonomicrometric dimension transducers, and micromanometers. Data were collected at baseline and after both NO and milrinone administration. Diastolic properties were quantified by use of the end-diastolic pressure-volume relationship and the time constant of ventricular isovolumic relaxation. Eight weeks after injection, significant increases in the PA pressure and pulmonary vascular resistance were observed in MCTP dogs. Significant worsening of RV diastolic function occurred in association with significant increases in the ratio of RV dry weight to LV+septal dry weight. NO and milrinone administration both led to significant improvements in RV diastolic properties., Conclusions: In the setting of MCTP-induced CPH, significant worsening of RV diastolic function was observed in association with significant increases in the ratio of RV dry weight to LV+septal dry weight, suggesting that these changes are partially due to RV hypertrophy. The significant improvement in RV diastolic properties after both NO and milrinone administration suggests that these agents may be effective forms of pharmacological therapy for improving RV diastolic dysfunction in the setting of CPH.

Background: Right ventricular (RV) failure remains an important risk factor for early morbidity and mortality after orthotopic cardiac transplantation and is most commonly related to preexistent chronic pulmonary hypertension (CPH) in the recipient, which occurs secondary to long-standing congestive heart failure. This study was designed to assess the compensatory mechanisms of the acutely transplanted RV in the setting of recipient CPH using a canine model of bicaval cardiac transplantation (TX) and monocrotaline pyrrole (MCTP)-induced CPH., Methods and Results: Twenty adult mongrel dogs were used for 10 successfully completed TX experiments. Recipients received an injection of 3 mg/kg MCTP 4 months before TX. RV function was assessed with load-insensitive means (preload recruitable stroke work), and Fourier analysis was used to calculate RV hydraulic power and transpulmonary efficiency. At the time of TX, significant increases in the mean pulmonary artery pressure, mean right ventricular pressure, and pulmonary vascular resistance were observed in recipients compared with donors and were further significantly increased after cardiopulmonary bypass. Significant increases in RV preload recruitable stroke work and RV hydraulic power were observed after TX compared with before TX and occurred in association with significant decreases in transpulmonary efficiency., Conclusions: Significant increases in pulmonary hemodynamic indexes occurred after MCTP injection and were further significantly increased after cardiopulmonary bypass. In the setting of recipient CPH, RV performance adapts acutely after bicaval TX with significant increases in power and contractility. However, a significant decrease in transpulmonary efficiency was also observed, which may improve over time as the RV adapts to the increased afterload.

This study was designed to examine the effects of both nitric oxide and milrinone on pulmonary hemodynamics and right ventricular function using a newly established model of monocrotaline pyrrole-induced chronic pulmonary hypertension. Sixteen mongrel dogs (23-25 kg) were used. All animals underwent percutanous pulmonary artery catheterization to measure right heart hemodynamics prior to and 8 weeks after a right atrial injection of either monocrotaline pyrrole (MCTP, n=8) or placebo (CTL, n=8). Eight weeks postinjection, all hearts were instrumented with a pulmonary artery flow probe and intracavitary micromanometers. Data were collected at baseline as well as following both nitric oxide and milrinone administration. There was no significant difference in the baseline hemodynamic measurements between the two groups. Eight weeks postinjection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed in MCTP compared with CTL. Both nitric oxide and milrinone resulted in significant improvements in pulmonary vascular resistance, pulmonary blood flow, and right ventricular contractility. In addition, nitric oxide caused a significant improvement in pulmonary artery pressure and transpulmonary efficiency, while milrinone led to a significant increase in right ventricular hydraulic power. This study demonstrates the well-known clinical effects of nitric oxide and milrinone in improving pulmonary hypertension, which were also associated with an increase in pulmonary blood flow, transpulmonary efficiency, and right ventricular hydraulic power in the setting of monocrotaline pyrrole-induced chronic pulmonary hypertension.

Background: Total orthotopic heart transplantation was recently introduced into clinical practice as an alternative technique for orthotopic cardiac transplantation. Total cardiac transplantation uses separate bicaval and left and right pulmonary anastomoses, whereas the standard technique of cardiac transplantation uses atrioplasty. Because the anatomic differences between total and standard orthotopic heart transplantation occur at the atrial level, this study compares atrial systolic function and biventricular filling (dV/dt) between the standard and total transplantation techniques., Methods and Results: Forty-eight mongrel canines (23 to 31 kg) were used for 12 total and 12 standard orthotopic cardiac transplantations. Right and left ventricular (RV/LV) function and AV synchrony were analyzed with micromanometry, sonomicrometry, ultrasonic flow meters, and intraoperative echocardiography. Results are expressed as mean +/- SEM (ANOVA, paired and unpaired t tests, and chi 2 test). There were no significant differences in baseline function (pretransplantation), bypass times, and cardiac ischemic times between the two groups. Posttransplantation sinus rhythm was preserved in all total (P < 0025) and in only one standard transplantation recipient (all required atrial diastole pacing). Significant decreases in RV/LV dV/dt from 113 +/- 13 and 123 +/- 14 mL/s to 69 +/- 6 and 85 +/- 10 mL/s after transplantation were measured in the standard group. No significant changes occurred in the total group after transplantation with respect to RV/LV diastolic filling. After transplantation, left atrial contractility and relaxation (-dP/dt) decreased significantly in the standard group by 43% and 70%, respectively, whereas in the total transplantation group, there were no observed changes in left atrial contractility and-dP/dt. A significant increase in the septum to RV free wall dimension in the standard group suggests altered geometry., Conclusions: Total AV transplantation is a feasible alternative to standard cardiac transplantation and conserves both normal sinus rhythm and synchronized beating of the atria and ventricles. Ischemic and bypass times are comparable in patients undergoing either method. These data suggest that RV/LV diastolic function and geometry and atrial systole are better preserved in the total AV transplantation technique.

Background: Myocardial injury after ischemia and reperfusion may be mediated, at least in part, by oxygen-derived free radicals; this supposition is supported by the observation that significant quantities of these radicals are generated during reperfusion. To directly assess the protective effect of extracellular superoxide dismutase (EC-SOD), this study was designed to investigate the ability of EC-SOD overexpression in the hearts of transgenic mice to protect myocardial tissue against ischemiareperfusion injury by use of an isolated work performing murine heart preparation and functional analysis., Methods and Results: Ten transgenic mice (EC.SOD, 28 to 31 g) were studied and compared with 10 control mice (Ctl, 28 to 31 g) in terms of preischemic and postischemic myocardial function. All hearts underwent cardiac harvest and arrest, followed by instrumentation and subsequent reperfusion with warm Krebs-Henseleit solution. Preload-dependent functional analysis was then performed to evaluate cardiac output, contractility (dP/dt), heart rate, stroke work, and stroke volume before and after a 7-minute period of warm ischemia. Results are expressed as mean +/- SEM (ANOVA, paired unpaired t tests). There was no significant difference in preischemic myocardial performance for Ctl and EC-SOD mice. After warm ischemia, cardiac output in EC-SOD was significantly improved compared with Ctl (EC-SOD, 4.55 +/- 0.37 mL/min; Ctl, 2.55 +/- 0.28 mL/min; P < .05). Postischemic dP/dt, stroke work, and stroke volume were also significantly improved in EC-SOD compared with Ctl mice (EC-SOD, 1808 +/- 39 mm Hg/s, 745 +/- 67 dyne.cm, and 13.1 +/- 1.2 microL, respectively; Ctl, 1497 +/- 87 mm Hg/s, 472 +/- 83 dyne.cm, and 8.2 +/- 1.5 microL; P < .05)., Conclusions: EC-SOD overexpressed mice showed significant improvement in postischemic cardiac function compared with Ctl mice. Thus, EC-SOD overexpressed hearts are less susceptible to mild degrees of ischemia-reperfusion injury than normal hearts.

Background: Acute graft failure is an important cause of morbidity and mortality in cardiac transplantation, and it may be associated with myocardial changes that occur during brain death (BD). This study investigates the changes in biventricular systolic and diastolic function that occur after BD in a validated canine model., Methods and Results: The hearts of 20 mongrel canines (23 to 31 kg) were instrumented with micromanometers, flow probes, and dimension transducers to measure minor/major axes as well as left and right ventricular (LV/RV) septum-to-free wall distances. LV/RV volumes were measured according to the shell subtraction method. LV/RV systolic function was analyzed by ventricular stroke work plotted versus end-diastolic volume during a caval occlusion (preload-independent recruitable systolic work, PRSW). The nonlinear relationships between diastatic pressure (stress) and LV/RV septum-to-free wall distances and volumes (strain) from successive diastoles during caval occlusion were used to evaluate LV/RV diastolic mechanics. The Cushing phenomenon, hyperdynamic response, and diabetes insipidus were observed in each animal after BD. Results are expressed as mean +/- SEM (P < .05 versus baseline, ANOVA, paired two-tailed Student's t test). Biventricular systolic function deteriorated significantly from baseline PRSW 6 to 7 hours after BD. The diastatic LV/RV pressure dimension relationships were significantly different after BD, indicating a decrease in ventricular chamber compliance during diastole., Conclusions: BD causes a significant loss of systolic and diastolic LV/RV function in the brain-dead, heart-beating cadaver, which may contribute to early postoperative cardiac graft failure in the recipient. These findings have significant clinical applications and may help to avoid suboptimal donor/recipient matches.

Objective: To examine the hormonal and hemodynamic changes in a validated animal model of brain death., Design: Prospective, controlled study., Setting: Experimental research laboratory., Subjects: Adult male mongrel dogs (n = 10)., Interventions: Brain death was induced by inflation of a subdural balloon in ten mongrel dogs weighing 23 to 30 kg and validated neuropathologically. The hearts were instrumented with micromanometers and ultrasonic flow probes to measure cardiovascular changes. No inotropic or vasoactive support was given. Hemodynamic stability was maintained with intravenous fluids. Blood samples and hemodynamic readings were collected before and after the induction of brain death., Measurements and Main Results: A Cushing reflex, followed by a hyperdynamic response and diabetes insipidus, occurred in every animal following brain death. Mean arterial pressure, heart rate, contractility, and cardiac output increased to > 350 mm Hg, 230 beats/min, 4200 mm Hg/sec, and 2.8 L/min, respectively, at the peak of this phenomenon before returning to baseline. A plasma catecholamine surge was observed in every animal 15 mins after brain death, while the circulating concentrations of the pituitary gland hormones vasopressin and adrenocorticotrophic hormone decreased significantly after 15 and 45 mins of brain death, respectively, and continued to decrease throughout the experiments. Circulating triiodothyronine, thyroxine, and glucagon concentrations decreased significantly (p < .01) from 0.58 +/- 0.05 ng/mL, 2.20 +/- 0.15 micrograms/dL, and 49.7 +/- 9.1 pg/mL, respectively, to 0.34 +/- 0.03 ng/mL, 1.14 +/- 1.14 micrograms/dL, and 6.9 +/- 1.4 pg/mL, respectively, 420 mins after brain death. The hematocrit increased significantly 15 mins after brain death and then gradually decreased throughout the duration of the experiments., Conclusions: In a validated animal model of brain death, significant decreases in the circulating concentrations of stress hormones, as well as hemodynamic instability, occurred after brain death. Measurements of plasma adrenocorticotrophic hormone and vasopressin values may be useful as diagnostic predictors of brain death. Furthermore, the observed changes may contribute to organ dysfunction after brain death and may necessitate hormonal as well as inotropic and vasoactive support to maintain donor organ function in the clinical setting.

Objective: Heart and lung transplantation has gained acceptance as therapy for end-stage cardiac and pulmonary failure. The early and intermediate survival benefits of one center's 10-year experience with 177 patients undergoing thoracic transplantation were examined., Summary Background Data: As experience in cardiac and pulmonary transplantation has increased, improvements in patient selection, organ preservation, preoperative support, and perioperative care have significantly reduced the early threats to patient survival. Graft dysfunction due to chronic rejection appears to be the main risk for longer-term survival, and data compiled by the United Network for Organ Sharing (UNOS) indicate a 70% 5-year survival for heart transplants and a 50% 5-year survival for lung transplant recipients., Methods: The medical records of 120 heart recipients, 52 lung transplant recipients, and 5 heart-lung recipients were reviewed. Cumulative survival estimates were made using Kaplan-Meier analysis. The etiologies of operative and long-term mortality in each transplant population were identified. A comparison of long-term survival after heart transplantation versus coronary revascularization in a group of patients with ischemic cardiomyopathy was performed., Results: Operative mortality in both the cardiac and pulmonary transplant recipients was 8%. From 1990 to 1995, 70 consecutive adult cardiac transplant procedures were performed without an operative mortality. Three of five patients survived heart-lung transplantation. The extended actuarial survival rate at 5 years was 80% for the cardiac transplant recipients. The 2-year actuarial survival rate for the lung transplant recipients was 88%. Graft dysfunction was the most common cause of operative mortality in the heart transplant group whereas infection was responsible for most of the operative mortality after lung transplantation., Conclusions: Cardiac and pulmonary transplantation can be applied to morbidly ill patients with excellent operative and intermediate-term survival.

Background: The incidence of lymphoproliferative disease, including B-cell lymphomas (BCL) in patients who have undergone heart or combined heart-lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo., Methods and Results: An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor cells in low-dose interleukin-2. Autologous BCL, HLA-mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using 51CrO4 after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at an effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells., Conclusions: The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV-associated lymphomas.

Background: Cardiac failure remains an important problem after heart transplantation and may be associated with events that occur during brain death (BD) before transplantation. In this study, cardiac function is studied after BD, and biochemical evaluation of myocardial high-energy phosphates and the beta-adrenergic receptor system is presented., Methods and Results: The hearts of 17 mongrel dogs (23 to 31 kg) were instrumented with flow probes, micromanometers, and ultrasonic dimension transducers to measure ventricular pressure and volume relationships. In a validated canine BD model, systolic right and left ventricular (RV/LV) function was analyzed by load-insensitive measurements during caval occlusion (preload-recruitable stroke work, PRSW). The beta-adrenergic receptor (BAR) density, adenylate cyclase (AC) activity, and myocardial ATP and creatine phosphate (CP) were measured before and 6 to 7 hours after BD. Results are expressed as mean +/- SEM (*P < .05 versus baseline, paired two-tailed Student's t test). Myocardial function deteriorated significantly from baseline PRSW (RV, 22 +/- 1 erg x 10(3); LV, 75 +/- 4 erg x 10(3)) by 37 +/- 10% for the RV (P < .001) and 22 +/- 7% for the LV (P < .001). BAR density increased from 282 +/- 42 to 568 +/- 173 fmol/mg for the RV and from 291 +/- 64 to 353 +/- 56 fmol/mg for the LV. Isoproterenol-stimulated AC activity was also significantly enhanced after BD. ATP and CP, however, remained unchanged after BD compared with baseline values before BD., Conclusions: BD causes significant systolic biventricular dysfunction. The loss of ventricular function after BD was more prominent in the right ventricle and may contribute to early postoperative RV failure in the recipient. These injuries occurred despite BAR system upregulation after BD. Global myocardial ischemia is unlikely, since ATP and CP remained normal before and after BD.

Objective: Right ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. The effect of brain death and subsequent hypothermic cardioplegic arrest and storage on subsequent post-transplant right ventricular function was examined., Summary Background Data: Right ventricular dysfunction in the donor heart usually is attributed to failure of the donor right ventricle to adapt to the sudden increase in afterload (pulmonary vascular resistance) in the recipient. Strategies to improve ventricular mechanics in the postoperative period are aimed at reducing pulmonary vascular resistance with vasodilators or augmenting right ventricular contractility with inotropic agents. Events occurring in the donor heart (brain death, hypothermic cardioplegic arrest, and storage) also may be directly related to post-transplant RV dysfunction., Methods: A canine model of brain death and orthotopic cardiac transplantation was used. A dynamic pressure-volume analysis of RV mechanics was performed using micromanometers and sonomicrometric dimension transducers. Systolic function was assessed by measurement of preload recruitable stroke work (PRSW). Brain death was induced in 17 dogs by inflation of an intracranial balloon. Right ventricular function then was assessed serially to 6 hours (PRSW). Right ventricular adrenergic beta receptor density and function was sampled at control and after 6 hours of brain death. The effect of cardioplegic arrest and hypothermic storage was assessed in a second group of 17 dogs, using the same instrumentation and method of RV analysis., Results: A significant decrease in right ventricular PRSW occurred after brain death, with the average decrease being 37% +/- 10.4% from the control. The RV myocardial beta adrenergic receptor density did not significantly change (253 +/- 34 fmol/ng control vs. 336 +/- 54 fmol/ng after brain death). The adenylyl cyclase activity of the RV beta receptor was assessed and was not altered by brain death. Orthotopic transplantation after cardioplegic arrest and hypothermic storage significantly decreased RV PRSW from 23.6 +/- 2.0 x 10(3) erg to 13.5 +/- 1.4 x 10(3) erg., Conclusions: These data indicate that the donor right ventricle is exposed to factors significantly detrimental to its mechanical performance well before facing an increased afterload in the recipient. Strategies to reduce RV dysfunction associated with brain death and hypothermic storage could positively impact post-transplant survival.

Background: Percutaneous balloon aortic valvuloplasty is limited by a high risk of procedural morbidity, transient clinical benefit, and a high restenosis rate. The management of patients with symptomatic aortic valve restenosis after percutaneous balloon aortic valvuloplasty is unclear. We hypothesized that aortic valve replacement would produce superior midterm survival compared with repeat balloon aortic valvuloplasty or medication alone in patients with symptomatic aortic valve restenosis after prior balloon aortic valvuloplasty., Methods and Results: Baseline clinical, echocardiographic, and hemodynamic data were collected on 165 patients who underwent percutaneous balloon aortic valvuloplasty as treatment for symptomatic degenerative calcific aortic stenosis. In 144 of these patients (87%), aortic valve replacement was originally considered to carry excessive risk. The survival of three subgroups was calculated during a median follow-up period of 3.9 years (range, 1 to 6 years). Ninety-four patients (57%) had no further mechanical intervention (subgroup 1-BAV), 31 patients (19%) developed symptomatic aortic valve restenosis and underwent a repeat balloon aortic valvuloplasty (subgroup 2-BAV), and 40 patients (24%) subsequently underwent aortic valve replacement (subgroup BAV+AVR). Follow-up was 99% complete. Patients in subgroup BAV+AVR tended to be younger and have a lower prevalence of coronary artery disease or mitral regurgitation. Only 1 patient (2.5%) suffered a perioperative death during aortic valve replacement. The probability of survival 3 years from the date of the last mechanical intervention was 13% for subgroup 1-BAV, 20% for subgroup 2-BAV, and 75% for subgroup BAV+AVR. At the conclusion of follow-up, only 2 patients had symptoms of congestive heart failure or angina after aortic valve replacement., Conclusions: Aortic valve replacement may be performed with a low mortality rate, excellent palliation of symptoms, and prolongation of survival in selected high-risk patients with a history of previous balloon aortic valvuloplasty.

Background: Functional capacity and quality of life are subjectively improved after cardiac transplantation. However, the objective improvement in exercise tolerance after transplantation has been disappointing. The extent to which allograft diastolic dysfunction contributes to this exercise intolerance has not been defined., Methods and Results: Thirty cardiac transplant recipients between 3 and 16 months after transplantation and 30 age-matched normal control subjects underwent maximal symptom-limited graded upright bicycle exercise testing with simultaneous radionuclide angiography, invasive hemodynamic monitoring, and breath-by-breath gas analysis. Mean blood pressure was higher in the transplant group at supine rest (112.1 versus 97.7 mm Hg), normalized with upright posture, and became lower than normal at peak exercise (121.1 versus 133.2 mm Hg). Systolic function as measured by ejection fraction was normal in both groups. However, the cardiac transplant recipients had significantly lower exercise tolerance, achieving a mean maximal work rate of 390 kilopond-meters per minute (kpm/min), compared with 825 kpm/min in the normal subjects. Peak oxygen consumption was 12.3 mL.min-1.kg-1 in the transplant group, 46% lower than the normal group's value of 22.9 mL.min-1.kg-1. The transplant patients had a resting tachycardia (94 beats per minute) and a 79% reduction in exercise heart rate reserve compared with normal. Despite this chronotropic incompetence, stroke index response to exercise was consistently lower after transplantation, accounting for a 41% reduction in cardiac index at maximal exercise. The lower stroke index was accompanied by a 32% lower end-diastolic volume index at rest and a 14% lower end-diastolic volume index at peak exercise. Despite the smaller ventricular volumes after transplantation, pulmonary capillary wedge pressure was 35% higher than normal at supine rest and 50% higher at maximal exercise. Right atrial and mean pulmonary arterial pressures were similarly elevated. The ratio of pulmonary capillary wedge pressure to end-diastolic volume index was significantly higher during the postural change and exercise, suggesting allograft diastolic dysfunction. Arteriovenous oxygen difference was similar between groups at rest and with submaximal exercise but was 24% lower at maximal exercise in the transplant group, suggesting an abnormality in peripheral oxygen uptake or utilization., Conclusions: Exercise tolerance is severely limited during the first 16 months after cardiac transplantation despite preservation of allograft left ventricular systolic function. This intolerance is due to an inadequate cardiac index response from a combination of chronotropic incompetence and diastolic dysfunction limiting the appropriate compensatory use of the Starling mechanism. In addition, there is a peripheral abnormality in oxygen transport or utilization that may partially reflect the effects of deconditioning.

Objective: This study was designed to determine the cause of large pericardial effusions and evaluate the efficacy of subxiphoid pericardiotomy., Summary Background Data: Despite great advances in the techniques used to diagnose pericardial effusions, much controversy remains concerning their cause and the optimal treatment of these effusions., Methods: In a prospective consecutive case series, 57 patients underwent a thorough preoperative evaluation followed by a subxiphoid pericardiotomy. All tissue and fluid was exhaustively evaluated. Postoperatively, all patients were followed for a least 1 year., Results: Surgery was performed under local anesthesia in 77% of patients, and the complications of surgery were minimal. Pericardial tissue and fluid established or aided in establishing a diagnosis in 81% of patients. Infection and malignancy were the leading causes; the condition in only 4 patients remained undiagnosed. Follow-up revealed recurrent effusion in nine (16%) patients, but only five (9%) required further surgery. The mortality rate at 30 days was 12%, and at 1 year, it was 37%. Fourteen of the 21 deaths occurred in patients with malignancies., Conclusions: These data show that the cause of most large pericardial effusions can be determined by a thorough evaluation accompanied by subxiphoid pericardiotomy. In addition, subxiphoid pericardial biopsy and window creation is safe and effective in the treatment of these effusions.

When surgeons consider ventricular assist devices (VADs) for post-cardiotomy support, unnecessary delays and early use can have detrimental effects on patient outcome. The authors analyzed the timing of intraoperative events in all patients receiving post-cardiotomy VAD support at their institution during a 2-1/2 year period (N = 17). They used ability to wean patients from VAD support as a measure of outcome. Neither preoperative risk factors nor the timing of distinct intraoperative events (e.g., cross-clamp time, total bypass time, delay to VAD) significantly differed between those patients able (Group I, n = 9) and those unable (Group II, n = 8) to be weaned from VAD support. The authors did find, however, that the time intervals from completion of the cardiac procedure to insertion of either an intra-aortic balloon pump (time to IABP) or VAD (time to VAD) were predictive of outcome when normalized to the duration of the cardiac procedure (DCP). [Time to IABP]/DCP ratios of < 1.0 versus > 1.0 (p = 0.02) and [time to VAD]/DCP ratios of < 2.5 versus > 2.5 (p = 0.10) each segregated Group I and II patients, respectively. Appropriate timing criteria for VAD insertion may be predicted during surgery by consideration of the duration of the cardiac procedure. This approach may attenuate tendencies to delay VAD use without leading to premature VAD insertion in the post-cardiotomy setting.

Org 10172 provided adequate anticoagulation for this patient. An excellent correlation between anti-factor Xa activity and ACT was observed at the doses used for CPB. If high-dose Org 10172 is used, these data suggest that it may be possible to circumvent the measurement of anti-factor Xa activity by using the ACT as an index of this heparinoid's anticoagulant effect. Because postoperative bleeding may be excessive, however, development of a method of reversal of Org 10172 is desirable. Although the optimal ACT, dose, plasma concentration, and means of reversal (e.g., protamine vs. heparinase) remains to be determined, heparinoids provide an alternate means of anticoagulation for CPB in patients unable to receive standard heparin.

The effect of sepsis on the intrinsic contractile status of the myocardium is best examined in the awake, closed-chest animal with intact circulation because anesthesia, open thoracotomy, and circulatory support are all known to affect hemodynamics. To fulfill these criteria, 18 adult dogs were chronically studied in the awake state after instrumentation with left ventricular high-fidelity pressure catheters and ultrasonic dimension transducers to measure left ventricular transmural pressure and minor axis dimension. This allowed computer assessment of the left ventricular end-systolic pressure-dimension relationship in the control state and at intervals following cecal ligation in one group of dogs. A second group of control animals was studied over variable time intervals without cecal ligation to evaluate the temporal stability and reproducibility of the animal model and the end-systolic pressure-dimension relationship. Evaluation of contractility by use of the end-systolic pressure-dimension relationship was essential because this relationship is a sensitive indicator of the intrinsic myocardial contractile state while remaining insensitive to the wide swings in preload and after load that are commonly seen in sepsis. In the control group of dogs, the temporal consistency and stability of the end-systolic pressure-dimension relationship in this model was confirmed; no significant changes in the slope and dimension-axis intercept were demonstrated over the study interval. In the septic group of dogs, however, the intrinsic myocardial contractility significantly deteriorated as the mean slope of the end-systolic pressure-dimension relationship (mmHg/mm) decreased from 16.87 +/- 0.85 to 12.79 +/- 1.67 over 120 hours following cecal ligation. Intrinsic contractility of the heart during sepsis was therefore isolated for the first time from the widely variant loading conditions seen during sepsis by pressure-dimension analyses in the chronically instrumented, awake, closed-chest canine with intact circulation.

It is frequently stated that hypertrophied ventricles tolerate ischemia less well than nonhypertrophied ventricles. The authors' earlier studies in a rat supravalvular aortic stenosis model and canine valvular aortic stenosis model, both with concentric left ventricular hypertrophy, disclosed accelerated rates of ischemic contracture and diminished basal myocardial high energy phosphate stores. These studies have been extended to ten patients with severe left ventricular hypertrophy caused by valvular aortic stenosis and normal coronary arteries. ATP (endocardial and epicardial) from transmural left ventricular biopsies taken at operation before aorta cross-clamping, and frozen immediately in liquid nitrogen, were compared with similar biopsies from patients with nonhypertrophied myocardium supplied by normal coronary arteries. The subendocardial high energy phosphate levels in the nonhypertrophied myocardium was greater than high energy phosphate levels in the subepicardium of nonhypertrophied ventricles (ATP-micromoles/gram-protein, epi = 36.8 +/- 3.3, endo = 37.7 +/- 3.3) (p = NS). However, in the hypertrophied myocardium the subendocardium consistently showed significantly depressed high-energy phosphate levels when compared with subepicardial levels (ATP-hypertrophied myocardium, epi = 31.5 +/- 1.6, endo = 25.9 +/- 1.7) (p less than 0.05). This uniform depression of ATP stores, greatest in the subendocardium, in left ventricular hypertrophy suggests a common biologic mechanism for the enhanced sensitivity to ischemia. Of importance for patients may be the prior observation in rats that repletion of ATP( stores before ischemia eliminates the accelerated rate to ischemic contracture. Diminished subendocardial ATP stores appear to be an intrinsic property of severely hypertrophied myocardium and probably contribute to its enhanced sensitivity to ischemia.

To compare the contractile response to dopamine and dobutamine after coronary artery bypass grafting, 20 patients were instrumented with ultrasonic dimension transducers to measure left ventricular anterior/posterior minor-axis diameter and equatorial wall thickness. Micromanometers were placed to measure left ventricular transmural pressure. Pressure-dimension data were recorded and computer analyzed during dopamine and dobutamine infusions in each patient at 0, 2.5, 5.0, and 10.0 micrograms/kg/min 16 to 20 hr after surgery. Contractility was measured by determination of maximal velocity of shortening of the ventricular diameter (mm/sec) and wall excursion (mm). Preload was assessed with end-diastolic diameter and peak left ventricular wall stress (dynes-cm-2) was calculated at each dose. End-diastolic diameter was unchanged at equal doses of dopamine and dobutamine. However, ejection phase indexes of contractility were significantly higher with dobutamine than dopamine, and were associated with lower levels of peak wall stress and peripheral vascular resistance. These data indicate that use of dobutamine results in greater enhancement of left ventricular contractility without the disadvantage of excess demand on myocardial oxygen reserve produced by higher levels of myocardial wall tension. Furthermore, the decreased peripheral vascular resistance induced by dobutamine accounts for some of the differences in drug response, and is beneficial in optimizing myocardial oxygen balance during pharmacologic inotropic support of the bypass graft patient or other patients in whom there is a potential for development of myocardial ischemia.