Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis.

BACKGROUND: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation. METHODS: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function. RESULTS: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006). CONCLUSIONS: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy?

BACKGROUND: Induction immunosuppression utilizing lymphocytolytic agents in the early peri-operative period has a number of theoretical and practical advantages and disadvantages. However, the efficacy of cytolytic agents as induction therapy remains unproven. METHODS: To assess the current impact of induction therapy in heart transplantation, we queried a multi-institutional database regarding the frequency of use, type of agent, duration of therapy and outcomes of 6,553 patients transplanted from 1990 to 2001. A study group of 5,897 patients were identified who survived the first 48 hours post-transplant and received either no induction therapy (n = 4,161) or induction with OKT3 or anti-thymocyte preparations (n = 1,736). RESULTS: By multivariate analysis, risk factors for rejection death were identified and then applied to a model of overall mortality. Among patients with a 1-year risk of rejection death at >5%, induction therapy provided a survival advantage, but survival with induction was decreased when the risk of rejection death was <2%. Specific patient sub-sets that received a survival benefit in the current era with induction included younger patients of black race with >/=4 HLA mismatches and long-term (>6 months) support on a ventricular assist device (VAD). CONCLUSIONS: Use and application of induction therapy continues to be controversial in heart transplantation. At present, this approach appears to be beneficial in selected patients who are at high risk for rejection death, but likely detrimental in patients who are at low risk for rejection death. Those with a combination of longer term VAD support, of black ethnicity, and having extensive HLA mismatching are most likely to benefit from cytolytic induction therapy.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Nesiritide: a unique therapeutic cardiac peptide.

Nesiritide is the generic name for recombinant human B-type natriuretic peptide. This drug represents the first of a new class of agents for the treatment of decompensated congestive heart failure. The properties of B-type natriuretic peptide include a balanced arterial and venous vasodilatation and a marked natriuresis and diuresis, making it an excellent drug for the management of heart failure. We review the physiology and pathophysiology of the natriuretic peptides and the clinical data for nesiritide. In addition, the hemodynamic effects of the drug as well as its efficacy and safety in the treatment of heart failure are critiqued. Nesiritide is a new class of therapeutic peptide for the treatment of heart failure that appears to offer unique and safe hemodynamic properties.

Management of wound and left ventricular assist device pocket infection.

Our patient developed a wound infection that involved an implanted left ventricular assist device. At surgery, the pump was washed with a detergent-containing bacteriocidal solution, then antibiotic-impregnated polymethylmethacrylate beads were placed around the pump. The wound was revised using rectus muscle to cover the pump. The incisions have healed and the patient is now at home. She is on no systemic antibiotics and has no evidence of infection 11 months postoperatively.

Are efforts at expanding the donor pool misdirected?

BACKGROUND: The number of patients potentially benefiting from heart transplantation far exceeds the number of hearts available. This has led to an increasing interest in use of hearts from previously unacceptable donors. However, the long-term outcome of such hearts is largely unknown. Research on other parts of the donor process may provide a greater number of additional hearts of high quality. METHODS: Journal reviews were conducted to identify proposed methods for use of previously unacceptable donor hearts, as well as research regarding the consent process. Data from the United Network for Organ Sharing were obtained to identify the reason consented heart referrals were not recovered. Data from the Association of Organ Procurement Organizations were obtained for consent rates in the United States. Calculated estimates were made for the number of excess hearts potentially available by use of extended donor criteria versus increasing the consent rate. RESULTS: More than 40 articles proposing extended donor criteria were identified versus only 12 articles about consent. Of the 2199 consented heart referrals not recovered in 1995, more than 1300 fit into a category amenable to a proposed strategy for use of extended donors. If these strategies were used aggressively (50% of the time), 701 additional hearts would have been available. Alternatively, if the consent rate were increased a comparable amount, 1260 excess hearts of high quality would have been available. CONCLUSION: Although research into extended donor criteria is probably justified, transplantation programs should direct research efforts into the consent process as a potential source of additional hearts.

The relationship between cardiac function and neuropsychological status among heart transplant candidates.

BACKGROUND: Cognitive deficits among heart transplant candidates have been well documented. This study was designed to examine the hypothesis that impaired cognitive test performance among heart transplant candidates may be attributed, in part, to decreased cerebral perfusion secondary to poor cardiac function. METHODS AND RESULTS: Sixty-two patients participated in the study who underwent heart catheterization within 1 day of completing a battery of cognitive tests. Multiple demographic and patient characteristics were examined for their potential moderating role in the relationship between measures of cardiac function and cognitive performance including age, education, race, gender, psychiatric history, medication usage, cardiac surgical history, and self-reported symptoms of depression and anxiety. Only age and education were significantly related to cognitive performance (P < .01). Thus, partial correlation analyses controlling for age and education were used to examine the relationship between cardiac function and cognitive performance. In general, increasing hemodynamic pressure variables (ie, pulmonary artery pressure and right atrial pressure), and to a lesser extent cardiac output and cardiac index, were related (r = - .32 to - .43; P < .01) to decreased performance on cognitive tasks that assessed simple attention, speed of mental processing, and mental flexibility (Digit Span-Forward, Trail Making Test-Part B, Symbol Digits Modalities Test, and Stroop Neuropsychological Screening Test). Left ventricular ejection fraction, systemic and pulmonary vascular resistance, and mean arterial pressure were largely unrelated to cognitive performance in this sample of patients with end stage cardiac disease. CONCLUSIONS: Hemodynamic pressure variables seem to be most consistently related (ie, inversely) to cognitive functioning among heart transplant candidates.

Electroconvulsive therapy in patients with heart failure or valvular heart disease.

As the use of electroconvulsive therapy (ECT) increases, the chance of a practitioner's encountering a patient with significant heart failure, ventricular dysfunction, or valvular heart disease also increases. This article reviews the epidemiology, pathophysiology, and available data on the risk of ECT in these patients. Recommendations are made regarding evaluation and treatment of such patients. Some special situations are identified that may require a modification of routine procedures. Overall, ECT can be performed safely in most patients with underlying cardiac conditions, as long as appropriate precautions are taken to identify these patients ahead of time.

Severely symptomatic mitral stenosis with a low gradient: a case for low-technology medicine.

We have observed a group of patients with mitral valve disease and severe symptoms but also with low transmitral gradients and normal cardiac outputs who defy the traditional hemodynamic explanation of mitral stenosis. We performed a 10-year retrospective chart review of all mitral valve replacements at our institution to further characterize this population. The study group consisted of 16 of 132 patients (12%) with symptomatically severe (New York Heart Association [NYHA] class 3.3 +/- 0.5) mitral stenosis but a low (< 10 mm Hg) transmitral gradient, a normal cardiac output (4.8 +/- 1.2 L/min), and a preserved valve area (1.6 +/- 0.4 cm2). Sixteen patients were randomly chosen from the remaining group to serve as a comparison population. Study patients were noted to have less atrial fibrillation, lower wedge and mean pulmonary artery pressures, and a higher incidence of subvalvular disease identified at the time of surgery than did the comparison population. Left ventricular end-diastolic pressure and cardiac output did not differ. Study patients did well with surgery and reported an excellent functional benefit. We believe that this subgroup of patients with mitral valve disease is important, may be missed by using conventional criteria of valve area to determine timing of surgical intervention, and may have their symptoms primarily because of subvalvular disease. Further and perhaps most important, this group illustrates the ongoing need for careful clinical assessment skills and judgement in the face of ever-increasing technology.

Acquired cor triatriatum after orthotopic cardiac transplantation.

Orthotopic cardiac transplantation was performed in a 42-year-old woman with idiopathic cardiomyopathy. Postoperative right ventricular failure developed and a transesophageal echocardiogram demonstrated acquired cor triatriatum with marked obstruction to mitral valve inflow and severe right ventricular dilatation. At reexploration, redundant donor atrial tissue was excised correcting the cor triatriatum. She was alive and well with normal hemodynamic parameters 12 months after transplantation.

Peritransplant injury to the myocardium associated with the development of accelerated arteriosclerosis in heart transplant recipients.

Accelerated arteriosclerosis is now the major long-term complication of heart transplantation. Defining the risk factors associated with the development of accelerated arteriosclerosis will provide not only a means of identifying patients at risk for this complication but also clues to the etiology of accelerated arteriosclerosis. The purpose of this study was to examine the relationship between peritransplant myocardial ischemic injury and the development of accelerated arteriosclerosis. In a case-control study we examined the first three endomyocardial biopsies from 50 heart transplant recipients and graded the degree of ischemic injury present in these biopsies. The histologic changes graded in the biopsies included contraction band necrosis, coagulative necrosis, and macrophagic removal of ischemically injured myocytes. Of the 50 recipients included in the study, 25 had angiographic evidence of accelerated arteriosclerosis and 25 did not. In multivariate analysis, which included the number of class I major histocompatibility (MHC) antigen mismatches between the donor and the recipient, the recipient's post-transplant cytomegalovirus status, the donor's age, and the number of rejection episodes, the histologic degree of ischemic injury present in the biopsies emerged as the strongest predictor of the development of accelerated arteriosclerosis (RR 2.6, 95% CI 1.2-5.8, p = 0.02). These results suggest that ischemic injury to the heart during the peritransplant period significantly contributes to the development of accelerated arteriosclerosis in heart transplant recipients and that histologic changes in early posttransplant biopsies can be used to identify recipients at risk of developing accelerated arteriosclerosis.

A preliminary study of cardiopulmonary resuscitation by circumferential compression of the chest with use of a pneumatic vest.

BACKGROUND: More than 300,000 people die each year of cardiac arrest. Studies have shown that raising vascular pressures during cardiopulmonary resuscitation (CPR) can improve survival and that vascular pressures can be raised by increasing intrathoracic pressure. METHODS: To produce periodic increases in intrathoracic pressure, we developed a pneumatically cycled circumferential thoracic vest system and compared the results of the use of this system in CPR (vest CPR) with those of manual CPR. In phase 1 of the study, aortic and right-atrial pressures were measured during both vest CPR (60 inflations per minute) and manual CPR in 15 patients in whom a mean (+/- SD) of 42 +/- 16 minutes of initial manual CPR had been unsuccessful. Vest CPR was also carried out on 14 other patients in whom pressure measurements were not made. In phase 2 of the study, short-term survival was assessed in 34 additional patients randomly assigned to undergo vest CPR (17 patients) or continued manual CPR (17 patients) after initial manual CPR (duration, 11 +/- 4 minutes) had been unsuccessful. RESULTS: In phase 1 of the study, vest CPR increased the peak aortic pressure from 78 +/- 26 mm Hg to 138 +/- 28 mm Hg (P < 0.001) and the coronary perfusion pressure from 15 +/- 8 mm Hg to 23 +/- 11 mm Hg (P < 0.003). Despite prolonged unsuccessful manual CPR, spontaneous circulation returned with vest CPR in 4 of the 29 patients. In phase 2 of the study, spontaneous circulation returned in 8 of the 17 patients who underwent vest CPR as compared with only 3 of the 17 patients who received continued manual CPR (P = 0.14). More patients in the vest-CPR group than in the manual-CPR group were alive 6 hours after attempted resuscitation (6 of 17 vs. 1 of 17) and 24 hours after attempted resuscitation (3 of 17 vs. 1 of 17), but none survived to leave the hospital. CONCLUSIONS: In this preliminary study, vest CPR, despite its late application, successfully increased aortic pressure and coronary perfusion pressure, and there was an insignificant trend toward a greater likelihood of the return of spontaneous circulation with vest CPR than with continued manual CPR. The effect of vest CPR on survival, however, is currently unknown and will require further study.

Complications of endomyocardial biopsy in heart transplant patients.

Despite the increasing use of alternative techniques, endomyocardial biopsy remains the primary method for diagnosing cardiac allograft rejection. Improved patient longevity and an increasing number of transplantation centers are resulting in an increase in the number of biopsies performed. Although endomyocardial biopsy is usually considered a safe procedure, no large studies of the risks of endomyocardial biopsy specifically in the transplant population have been undertaken. To determine the risk of endomyocardial biopsy in these patients, we reviewed 2454 endomyocardial biopsies performed from January 1983 to December 1990 in 133 cardiac allograft patients at our institution. At the time of each endomyocardial biopsy, a worksheet was completed detailing the patient's interval history, the site of vascular introduction, the number of attempts, the number of specimens, and any complications encountered. A total of 74 (3.0%) complications occurred. Fifty-six (2.3%) complications were associated with catheter insertion, including carotid puncture (1.8%), vasovagal reaction (0.1%), and prolonged bleeding (0.4%). Complications during biopsy included arrhythmias (0.25%) and conduction abnormalities (0.2%). In addition, we observed five episodes (three patients) of allergic reaction to a reusable bioptome and one case of pacemaker dislodgement. All complications were without significant long-term sequelae. In contrast to the cardiomyopathy population, no ventricular perforations or deaths occurred. Thus although endomyocardial biopsy has some risk, it continues to be a safe and effective way of monitoring rejection.

Estimation of myocardial mechanical properties with dynamic transverse stiffness.

There are currently no validated methods for accurately estimating regional ventricular mechanical properties. We recently developed a dynamic indentation system that can determine dynamic transverse stiffness (the slope of the relation between the indentation stress and indentation strain during high frequency indentations) in as little as 10 msec. The apparatus consists of an indentation probe coupled to a linear-motor and a computerized control system. This indentation system was tested on beating, canine ventricular septa that were mounted in a biaxial system that could apply strains in the plane of the septum and measure the resulting in-plane stresses. The probe indented the septa with peak displacements of 0.1-0.5 mm at frequencies of 20 and 50 Hz. The transverse stiffness was shown to be related to the in-plane stress and stiffness in the isolated septa. Dynamic transverse stiffness was then used to study the effects of myocardial perfusion on passive tissue stiffness and on contractility. In addition, the transverse stiffness was studied in intact canine hearts during diastole, where it was related to the chamber stiffness. Thus, dynamic transverse stiffness appears to allow estimation of myocardial mechanical properties.

Measurement and characterization of postischemic free radical generation in the isolated perfused heart.

Electron paramagnetic resonance spectroscopy has been applied to measure radical generation in the postischemic heart; however, there is controversy regarding the methods used and the conclusion as to whether radicals are generated. In order to resolve this controversy, direct and spin trapping measurements of the time course and mechanisms of radical generation were performed in isolated perfused rabbit hearts. In reperfused tissue, 3 prominent radical signals are observed: A, isotropic g = 2.004 suggestive of a semiquinone; B, anisotropic g parallel = 2.033 and g perpendicular = 2.005 suggestive of ROO.; and C, a triplet g = 2.000 and aN = 24 G suggestive of a nitrogen centered radical. B and C, however, are highly labile and disappear at temperatures probably encountered in some previous studies. In normally perfused hearts, A is observed with only small amounts of B and C. During ischemia, B and C increase reaching a maximum after 45 min while A decreases. On reflow with oxygenated perfusate all 3 signals increase. With varying duration of ischemia and reflow, peak signal intensities occurred after 15 s of reflow following 30 min of ischemia. Reperfusion with superoxide dismutase, deferoxamine, or mannitol abolished the reperfusion increase of B. Measurements performed with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) demonstrated a similar time course of radical generation with prominent DMPO-OH and DMPO-R signals peaking between 10 and 20 s of reflow. Superoxide dismutase and deferoxamine also quenched these signals. Thus, .O2- derived .OH, R., and ROO. radicals are generated in postischemic myocardium. While the experimental techniques used can result in loss of intrinsic radicals and generation of extraneous radicals, with proper care and controls valid measurements of free radicals in biological tissues can be performed.

Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium.

It has been proposed that oxygen free radicals mediate damage that occurs during postischemic reperfusion. Recombinant human superoxide dismutase (r-h-SOD) has been shown to be effective at reducing reperfusion injury, but it is not known if this infused enzyme actually reduces oxygen free radical concentrations in the myocardial tissue. Electron paramagnetic resonance spectroscopy was used to directly measure the effect of r-h-SOD on free radical concentrations in the postischemic heart. Hearts were freeze clamped at 77 degrees K after 10 min of normothermic global ischemia followed by 10 s of reflow with control perfusate (n = 7) or perfusate containing 60,000 U r-h-SOD (n = 7). The spectra of these hearts exhibited three different signals: signal A isotropic, g = 2.004, identical to the carbon-centered ubiquinone free radical; signal B anisotropic with axial symmetry, g parallel = 2.033, g perpendicular = 2.005, identical to the oxygen-centered alkyl peroxyl free radical; and the signal C an isotropic triplet, g parallel = 2.000, an = 24 G, similar to a nitrogen-centered free radical such as a peroxyl amine. With r-h-SOD administration the concentration of the oxygen free radical, signal B, was reduced 49% from 6.8 +/- 0.3 microM to 3.5 +/- 0.3 microM (P less than 0.01) and the concentration of the nitrogen free radical, signal C, was reduced 38% from 3.4 +/- 0.3 to 2.1 +/- 0.3 microM (P less than 0.01). The concentration of the carbon-centered free radical, signal A, however, was increased 51% from 3.3 +/- 0.2 to 5.0 +/- 0.2 microM (P less than 0.01). Identical reperfusion with peroxide-inactivated r-h-SOD did not alter the concentrations of free radicals indicating that the specific enzymatic activity of r-h-SOD is required to decrease the concentrations of reactive oxygen free radicals. Additional measurements performed varying the duration of reflow demonstrate a burst of oxygen free radical generation peaking at 10 s of reperfusion. r-h-SOD entirely abolished this burst. These studies demonstrate that superoxide-derived free radicals are generated during postischemic reperfusion and suggest that the beneficial effect of r-h-SOD is due to its specific enzymatic scavenging of superoxide free radicals.