Noninvasive assessment of transplant-associated arteriosclerosis.

BACKGROUND: Transplant-associated arteriosclerosis is the major limitation to long-term survival in the cardiac transplant recipient, and annual surveillance angiography is used in many centers to monitor its progression. Noninvasive methods would be preferable because angiography is invasive, costly, and insensitive; however, the reliability of such methods has been questioned. METHODS: All publications relating to the assessment of the cardiac allograft by noninvasive testing were identified through MEDLINE and a review of references from the published literature on transplant-associated arteriosclerosis. RESULTS: Resting and stress ECG, radionuclide scintigraphy, echocardiography, and positron emission tomography have all been used in cardiac transplant recipients with variable results. Most techniques are insensitive, but this limitation may be improved with pharmacologic stress imaging like dobutamine echocardiography. Although insensitive, some methods have good specificity (i.e., radionuclide scintigraphy). The noninvasive measurement of absolute coronary blood flow is promising as a specific and sensitive technique but is limited by availability and cost. CONCLUSIONS: In general, noninvasive techniques to assess transplant-associated coronary arteriosclerosis are limited by variable sensitivity and specificity. However, certain methods, such as dobutamine echocardiography and radionuclide scintigraphy, can provide important adjunctive physiologic information to angiography. Such techniques can therefore help to guide the care and treatment of the cardiac transplant recipient with allograft coronary arteriosclerosis.

Hemostatic/fibrinolytic predictors of allograft coronary artery disease after cardiac transplantation.

Allograft coronary artery disease (CAD) remains the leading cause of morbidity and mortality affecting the long-term survival of patients after cardiac transplantation. Because there is increasing evidence that imbalances in hemostatic and fibrinolytic pathways are associated with graft failure, we hypothesized that atherothrombotic risk factors may contribute to allograft CAD. This study sought to determine if plasma hemostatic and fibrinolytic parameters are associated with the severity of allograft CAD. The extent of allograft CAD was investigated by angiography and intravascular ultrasound (IVUS) in 16 cardiac transplant recipients. Intimal thickening was quantified using IVUS by measuring the intimal index (li = intimal area/[intimal area + luminal area]) in two to five segments of the left anterior descending (LAD) coronary artery. The maximal li per patient was calculated and index to the time post-transplant (Mxli/Yr). Plasma fibrinogen (FGN), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), lipoprotein(a) (Lp(a)), and net fibrinolytic activity of plasma were assayed 6-24 months after transplant as indicators of the fibrinolytic system and then correlated with the IVUS measurements. The FGN level correlated with the severity of intimal thickening, Mxli/Yr (r2 = 0.41, p = 0.008), and was inversely correlated with angiographic tertiary vessel filling (r2 = 0.25, p = 0.051). In patients with lower plasma fibrinolytic activity (lytic zone less than 100 mm2), Mxli/Yr was increased eightfold (0.218 +/- 0.137 versus 0.025 +/- 0.021, p = 0.001). t-PA (r2 = 0.0004, p = 0.94), PAI-1 (r2 = 0.008, p = 0.75) and Lp(a) levels (r2 = 0.11, p = 0.21) did not predict Mxli/Yr. Thus, we demonstrate that plasma FGN and net fibrinolytic activity correlate with the degree of intimal thickening measured by IVUS after cardiac transplantation. These data suggest that fibrin deposition may play a role in allograft CAD after cardiac transplantation.

Changing patterns in donor and recipient risk: a 10-year evolution in one heart transplant center.

BACKGROUND: Expansion of the donor pool and liberalization of recipient criteria have occurred since the introduction of cyclosporine for heart transplantation. METHODS: We sought to evaluate the impact of these changes on outcome during a 10-year period in one program. A total of 251 transplantations were retrospectively reviewed and divided into two periods (1984 to 1989 and 1990 to 1994). RESULTS: In the latter period, there were increases in donor and recipient age, degree of weight mismatch, ischemic time, bypass time, and severity of illness in the recipient before transplantation as judged by status at the time of transplantation and preoperative requirements for pharmacologic or mechanical support. Despite these changes, time to hospital discharge decreased and a trend to improved survival was seen with the use of Kaplan-Meier analysis. CONCLUSIONS: These findings suggest that improvements in perioperative and posttransplantation care have permitted a safe expansion of both the donor pool and recipient criteria for transplantation.

Cardiomyopathy of limb-girdle muscular dystrophy.

OBJECTIVES: This study sought to find an association between dilated cardiomyopathy and limb-girdle muscular dystrophy. BACKGROUND: Cardiomyopathy has been seen in various neuromuscular disorders, but it has not been recognized to be associated with limb-girdle muscular dystrophy. METHODS: We investigated three sisters with well documented limb-girdle dystrophy and congestive heart failure by the 3rd decade of life. All underwent noninvasive evaluation of left ventricular systolic function by both echocardiography and radionuclide scanning, and one also had cardiac catheterization. Deoxyribonucleic acid (DNA) linkage analysis was performed in these affected subjects and in the unaffected family members, and DNA was extracted from mononuclear cells with primer sequences for three chromosome 13q microsatellite markers. RESULTS: The parents had no evidence of clinical disease, but all three sisters had echocardiographic evidence of dilated cardiomyopathy. The sister with additional evidence of left ventricular dysfunction of cardiac catheterization had no coronary artery disease. The affected subjects had the same paternal allele for three potential markers of limb-girdle muscular dystrophy but different maternal alleles. The very small family size did not permit statistical confirmation or refutation of linkage for chromosome 13q markers. CONCLUSIONS: Demonstrable cardiomyopathy accompanying limb-girdle muscular dystrophy and its probable genetic associations require continued investigation by anticipating the cardiomyopathy in limb-girdle muscular dystrophy.

Pericardial effusions after cardiac transplantation.

OBJECTIVES: The aim of this study was to determine the etiologic factors in the formation of significant pericardial effusion after orthotopic heart transplantation and to determine the association of pericardial effusion with survival. BACKGROUND: The formation of pericardial effusions has been well described after orthotopic heart transplantation, but the risk factors for development of effusions remain unclear. Rejection and cyclosporine have been cited as possible causes, but anatomic factors have not been studied. METHODS: We conducted a retrospective review of medical records and echocardiograms of 203 consecutive patients at one center, including ischemic time, incidence and severity of rejection, weight difference between donor and recipient and previous cardiac surgical history. Multivariate analysis was performed, and actuarial survival rate curves were calculated according to the Kaplan-Meier method. RESULTS: Eighteen (8.9%) of 203 transplant recipients developed moderate to large pericardial effusions. Forty-four percent of patients required pericardiocentesis, and 28% subsequently required pericardiectomy for management of the effusions. Multivariate analysis identified the presence of a positive weight difference between recipient and donor (recipient weight > donor weight) and the lack of previous median sternotomy as the most powerful predictors of effusion formation. No significant association was found with rejection. There was no difference in actuarial survival rate between patients with and without effusions. CONCLUSIONS: A positive mismatch in weight between recipient and donor and the absence of previous cardiac surgery are associated with the formation of significant pericardial effusions. Closer monitoring of these patients at risk may be warranted.

Role of panel-reactive antibody cross-reactivity in predicting survival after orthotopic heart transplantation.

To test the hypothesis that elevated preformed circulating antibody levels, as measured by panel-reactive antibody levels, predict survival after orthotopic heart transplantation, we analyzed 120 consecutive patients undergoing heart transplantation at the Brigham and Women's Hospital in a retrospective, chart-review format. Prospective, donor-specific lymphocyte crossmatches were performed in all patients with a panel-reactive antibody level of 10% or greater. Both the peak pretransplantation panel-reactive antibody level and the panel-reactive antibody level obtained on the day of transplantation were analyzed with respect to the end points of the number of acute rejection episodes, presence of coronary artery disease, and overall survival after transplantation. Patients with a panel-reactive antibody level on the day of transplantation of 25% or greater, despite a negative prospective donor-specific lymphocyte crossmatch, demonstrated a trend toward reduced actuarial long-term survival compared with patients with panel-reactive antibody values less than 25% (p < 0.05). Panel-reactive antibody levels were not predictive of the number of acute rejection episodes, early (< 60 days) versus late (> or = 60 days) death, or the development of graft coronary artery disease. No episodes of hyperacute rejection were observed, even in six patients with a positive retrospective donor-specific lymphocyte crossmatch. In conclusion, an elevated panel-reactive antibody value of 25% or greater at the time of heart transplantation may be a risk factor for decreased long-term survival. A trend toward an increased risk of death caused by rejection was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Asymptomatic mitral regurgitation: when to operate?

The timing of surgical intervention in asymptomatic or mildly symptomatic patients with mitral regurgitation has always been a difficult clinical dilemma, especially with current options of valve replacement or valve repair. Symptomatic status should be carefully assessed and may depend upon either atrial fibrillation or progressive left ventricular dysfunction. Many patients may claim to be asymptomatic, but have profound limitations to their functional capacity and impairment of contraction indices. Because of this, every effort should be made to objectively follow the asymptomatic patient and schedule surgical intervention before irreversible left ventricular dysfunction. Left ventricular ejection fraction continues to be an inappropriate parameter, for the regurgitant fraction increases the preload to the left ventricle, and the regurgitant orifice reduces left ventricular afterload with increase to the left ventricle, and the regurgitant orifice reduces left ventricular afterload with increase in ejection fraction. End-diastolic dimension of volume is dependent upon such preload, and hence not accurate. End-systolic diameter is a better prognostic index; an end-systolic dimension of 4.5 cm (2.6 cm/m2) and a calculated end-systolic volume of 50 mL/m2 seem to be reasonable discriminators of outcome following surgery. More recent investigations suggest that left ventricular dP/dt, measured from a Doppler profile of mitral regurgitation, is perhaps a better predictor. In the asymptomatic patient, it is difficult to justify a role for intense medical therapy. The patient who develops atrial fibrillation does require a long-term anticoagulation therapy, and valve repair might be considered in this patient. Sinus rhythm may be restored with early surgical intervention, thereby reducing complications of thromboembolism or anticoagulant therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Early cardiac allograft failure after orthotopic heart transplantation.

Early cardiac graft failure has been reported to occur in 4-25% of patients undergoing orthotopic heart transplantation. To further elucidate the characteristics and prognosis of patients with graft failure, we retrospectively identified 10 patients from a series of 212 consecutive recipients with catastrophic graft dysfunction in the absence of acute cellular rejection, right ventricular failure secondary to pulmonary hypertension and technical factors. We present a case report and the experience from one transplant center, a review of the literature and possible strategies for the management of early graft failure. Mean onset of graft failure was 6.5 days (range intraoperative to 23 days). Multivariable analysis revealed a longer total ischemic time in patients with early graft dysfunction (200 +/- 14 vs. 166 +/- 4 min). No episodes of hyperacute rejection were observed. Pathologic changes noted on biopsy or autopsy included ischemia in 9 and vascular rejection in 1. The mortality at 60 days was 50%. Early use of aggressive mechanical and pharmacological support is described and appears to be important for graft salvage.

Functional significance of intimal thickening as detected by intravascular ultrasound early and late after cardiac transplantation.

BACKGROUND: Detection of transplant coronary disease remains difficult. Both intravascular ultrasound (IVUS) imaging and functional coronary vasomotion studies have been used to evaluate this process. However, the time course of intimal thickening as assessed by IVUS and the relation between structure and function have not been explored. METHODS AND RESULTS: In 40 patients 1 to 8 years after transplantation, 108 coronary artery segments were analyzed by IVUS. Intimal index [% intimal area (lumen+intimal area)] and maximal thickness were used to quantify intimal thickening. Abnormal IVUS was present in 53 of 108 segments (49%) (mean intimal index of diseased segments, 23 +/- 2%; maximal thickness, 530 +/- 47 microns). For those patients with intimal thickening in all segments of the analyzed artery, more time had elapsed since transplantation (4.3 +/- 0.6 years) than for those whose arteries contained some normal (2.6 +/- 0.3 years) or all normal segments (2.2 +/- 0.6 years, P < .05). Both the proportion of segments with intimal thickening and the degree of thickening increased as a function of time after transplantation (P < .5). By multivariate analysis, the independent predictors of intimal thickening were increasing time after transplantation and pretransplantation hypercholesterolemia (P = .02). Within the cohort of 40 patients, endothelium-dependent vasomotor function was evaluated in 26 matched segments from 11 patients studied 1 year after transplantation and in 15 matched segments from 8 patients studied > or = 5 years after transplantation by serial infusions of acetylcholine (10(-8) to 10(-6) mol/L). Of the 26 segments assessed for structure/function correlation at 1 year after transplantation, 22 had no intimal thickening by IVUS. However, endothelial dysfunction was present in 13 of these normal segments (mean diameter constriction, 18.8 +/- 2.3%). Of the 15 segments studied > or = 5 years after transplantation, 11 had intimal thickening. Nine of these 11 segments had preserved endothelial function (mean diameter dilation, 8.6 +/- 2.9%). There was no relation between the degree of intimal thickening and the magnitude of the endothelium-dependent response to acetylcholine. CONCLUSIONS: This study has shown that intimal thickening after transplantation begins as a heterogeneous process and increases in extent and magnitude over time. Also, endothelial dysfunction occurs early before the intimal thickening; yet in those patients surviving > or = 5 years, endothelial function may recover even in the presence of moderate intimal pathology. The variable relation between intimal pathology and endothelial function is probably a result of the episodic nature of immune injury.

Sinoatrial and atrioventricular block caused by intracoronary infusion of adenosine early after heart transplantation.

Intracoronary adenosine was infused in 22 patients early (less than 2 months) after heart transplantation to study coronary flow reserve in the left anterior descending artery. Potentially serious bradycardia requiring discontinuation of the infusion occurred in three patients. This complication had not been noted when adenosine was given to 84 patients with at least 1 year after transplantation. Newly transplanted hearts may therefore have increased susceptibility to the bradycardic action of adenosine, which should be used with caution in this population.

Loss of the coronary microvascular response to acetylcholine in cardiac transplant patients.

BACKGROUND: The coronary arteries of transplanted hearts frequently develop accelerated diffuse arteriosclerosis. The effects of this disease on resistance vessel function are unknown. METHODS AND RESULTS: To investigate the integrity of endothelium-dependent small-vessel vasodilation in transplanted hearts, coronary blood flow (CBF) responses to the endothelium-dependent dilator acetylcholine (10(-8) to 10(-6) M) and the essentially endothelium-independent dilator adenosine (10(-6) to 10(-4) M) were assessed in 40 studies of 29 transplant patients 1-3 years after transplantation and in seven nontransplanted controls. CBF was measured at constant arterial pressure with a Doppler catheter in the left anterior descending coronary artery. Controls, year 1 transplant patients, and year 2 transplant patients had similar increases in CBF in response to acetylcholine (232 +/- 40%, 200 +/- 41%, and 201 +/- 54%, respectively; p = NS), whereas year 3 transplant patients had increased CBF of only 100 +/- 39% (p less than 0.05 versus controls). An index of the proportion of CBF reserve attributable to endothelium-dependent dilation was obtained by normalizing each patient's peak acetylcholine flow response by the peak adenosine flow response. In patients receiving both acetylcholine and adenosine, endothelium-dependent flow responses declined over time [57 +/- 9% in controls, 56 +/- 10% for year 1, 47 +/- 12% for year 2, and 29 +/- 9% for year 3 (p less than 0.05 versus controls)]. An increased mean cyclosporine level (range, 99-261 ng/ml) (r = 0.67, p = 0.004) and increased transplant recipient age (range, 20-63 years) (r = 0.51, p = 0.004) predicted a preserved endothelium-dependent microvascular response. CONCLUSIONS: Thus, microvascular endothelium-dependent dilation deteriorates over time in the transplanted heart, which may reflect underlying graft arteriosclerosis and contribute to ischemic damage of the myocardium.

Cyclosporine A and prednisone-associated osteoporosis in heart transplant recipients.

Immunosuppressive therapy with cyclosporine A or prednisone produces bone loss in some animal models. Although we have clinically observed osteoporotic fractures in our heart recipients, the effects of cyclosporine and prednisone on bone density in transplant populations has not been fully elucidated. This study was undertaken to examine indexes of mineral metabolism and bone mineral density (BMD) in heart transplant recipients referred for evaluation of possible bone disease. Twenty of 93 patients who underwent heart transplantation at our institution were evaluated for osteoporosis. Sixteen of these patients (eight men; eight women) were included in this cross-sectional study (two patients were excluded because of hyperparathyroidism, and two patients were excluded because severe fractures prevented BMD from being measured). The mean age of the heart transplant recipients was 52.4 +/- 2.2 years, and the study was conducted a mean of 33.4 +/- 4.6 (men) and 19.0 +/- 7.0 (women) months after heart transplantation. Forty-four percent of these heart transplant recipients were seen clinically with fractures. Biochemical tests of skeletal homeostasis and BMD measurements with dual energy x-ray absorptiometry were performed. In male and female patients, the indexes of mineral metabolism showed (mean +/- sem) osteocalcin levels of 9.60 +/- 2.3 micrograms/L and 9.46 +/- 1.9 micrograms/L (normal: men, 6.39 +/- 0.69 micrograms/L; women, 5.87 +/- 0.71 micrograms/L) and intact parathyroid hormone levels of 48.8 +/- 10.3 ng/L and 63.4 +/- 10.7 ng/L (normal: men, 26.8 +/- 3.3 ng/L; women, 30.7 +/- 2.1 ng/L), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Strategies to manage the heart failure patient after transplantation.

Cardiac transplantation has emerged as an effective form of therapy for end-stage congestive heart failure (CHF), but patients are predisposed to both dilated and restrictive congestive physiology. The etiologies of post-transplant CHF are unique and complicated, most certainly reflecting a chronic rejection process that has yet to be elucidated. Successful identification of underlying pathophysiologic mechanisms and subsequent therapeutic approaches will require close coordination among cardiologists, cardiac surgeons, and immunobiologists.

Serial assessment of left ventricular function and mass after orthotopic heart transplantation: a 4-year longitudinal study.

Long-term changes in left ventricular performance and geometry in the transplanted human heart have been incompletely described. Therefore, two-dimensional echocardiograms were performed on 22 recipients of an orthotopic heart transplant at 1 month (32 +/- 20 days), 1 year (11 +/- 3 months) and 4 years (54 +/- 9 months) after transplantation. All studies were performed at a time when the patient had no pathologic evidence of rejection. Ten healthy men served as a normal control group. Over 4 years of follow-up, mean systolic blood pressure in the study patients increased from 121 +/- 12 (p = NS vs. values in the control group) to 139 +/- 11 mm Hg (p less than 0.05 vs. both control values and values at 1 month); mean diastolic blood pressure increased from 72 +/- 7 (p = NS vs. normal values in the control group) to 93 +/- 8 mm Hg (p less than 0.05 vs. both control values and values at 1 month). Left ventricular end-systolic volume increased from 42 +/- 10 (p = NS vs. control values) to 51 +/- 14 ml (p less than 0.05 vs. both control values and values at 1 month) and end-diastolic volume increased from 103 +/- 28 (p = NS vs. control values) to 112 +/- 27 ml (p less than 0.05 vs. control values) over 4 years. Left ventricular mass and ejection fraction did not change significantly within the patient cohort and remained similar to that found in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)