Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations.

Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.

Insensitivity of noninvasive tests to detect coronary artery vasculopathy after heart transplant.

Obstructive coronary artery vasculopathy can be a major problem after cardiac transplant. The use of noninvasive tests to detect coronary artery vasculopathy was studied in 73 consecutive patients after heart transplant. Angiographically or autopsy-proved coronary artery disease was noted in 19 consecutive patients (26%) followed prospectively for 2.5 +/- 1.3 years (mean +/- standard deviation). Patients underwent yearly surveillance echocardiographic, rest/exercise-gated wall motion, oral dipyridamole thallium, ambulatory electrocardiographic monitor and angiographic studies. Positive test results were defined by decrease in ejection fraction, wall motion abnormality, failure to increase ejection fraction, lack of systolic blood pressure increase, and ischemic ST changes at maximal exercise (or on ambulatory monitor). Wall motion abnormalities and depressed ejection fraction on echocardiography were also abnormal studies as were fixed or reversible perfusion defects on thallium scan. Angiograms were considered positive when 50% luminal narrowing was observed and autopsy coronary artery vasculopathy was defined as cross-sectional coronary obstruction greater than or equal to 70%. No procedure that was examined proved to be a sensitive noninvasive detector of heart transplant coronary artery vasculopathy. All except ambulatory electrocardiographic monitoring had positive predictive values less than 50%. Interestingly, of the techniques evaluated, echocardiography was most sensitive (53%). The poor predictive ability of noninvasive testing in this population may be due to the fact that these tests are designed to detect effects of ischemia rather than coronary obstruction alone. Use of these particular noninvasive modalities routinely after heart transplant to detect coronary artery vasculopathy should be reconsidered because of their low sensitivity and predictive value when used as a surveillance screen.

The relationship of soluble interleukin-2 receptor levels to allograft arteriopathy after heart transplantation.

Certain dynamics of rejection after heart transplantation can be characterized by measuring soluble interleukin-2 receptor levels. To determine whether elevated levels could predict development of coronary artery disease, the mean of three weekly determinations the first month after heart transplantation, as well as values obtained at 6 months, 12 months, 18 months, and 24 months after the procedure, were evaluated. Comparison was made between the groups in whom allograft arteriopathy did or did not develop. Concomitant endomyocardial biopsy scores also were evaluated. Fifty-five patients surviving the initial 30 days after heart transplantation were prospectively followed up. Eighty-five percent were male, and the median age was 51 years. Coronary arteriopathy developed in 15 patients (27%) during a mean follow-up period of 26 months (range, 1 to 54 months). For the early follow-up point, mean (+/- standard deviation) receptor levels for those patients without allograft arteriopathy were 880 +/- 846 U/ml and for those with arteriopathy, 1410 +/- 590 U/ml (p = 0.001). At each follow-up point thereafter, soluble interleukin-2 receptor levels were greater in the group with allograft arteriopathy. Indeed, at all observation points, the group in whom disease developed had levels greater than 1000 U/ml, and these values were, from a statistical standpoint, always greater than the group without detectable arteriopathy. In contradistinction, endomyocardial biopsy scores were no different at either early or late follow-up periods. Allograft arteriopathy after heart transplantation seems predicted by early elevation of plasma soluble interleukin-2 receptor levels, and patients with this difficulty generally have elevated levels during long-term follow-up.

Long-term follow-up of heart transplant recipients requiring permanent pacemakers.

BACKGROUND: Permanent pacemaker implantation after heart transplantation is contentious. Indications for these devices in this population are uncertain. The goals of this project were to (1) analyze the time course of donor sinus node dysfunction and atrioventricular block after heart transplantation; (2) evaluate which selected parameters (donor age, ischemic time, heart rate before pacer insertion, and number of rejection episodes) might relate to persistent permanent pacing need, and (3) assess pacemaker complications during follow-up. METHODS: A retrospective analysis of pacemaker implantations (22 cases) was performed in 286 consecutive heart transplantations performed between February 1984 and April 1994 at The Methodist Hospital and Baylor College of Medicine, Houston, Texas. RESULTS: Permanent pacemakers were inserted early after transplantation in 19 patients (mean 24 days); 14 pacemakers were for sinus node dysfunction (bradycardia in five, sinus arrest with junctional escape in eight, and optimization of hemodynamics in one). Symptomatic complete heart block prompted insertion late in two patients (3 and 47 months), and symptomatic sinus pause was the indication for late insertion in one. Recipient mean age was 52.4 years, with mean donor age 29.7 years in patients with pacemakers. By 3 months, 13 of 19 patients receiving pacemakers early (mean preinsertion heart rate 58.3 beats/min) became pacer independent with subsequent mean intrinsic heart rate of 97 beats/min. Recipient or donor age, ischemic time, and rejection episodes did not appear related to long-term pacing need early or late after transplantation. CONCLUSIONS: Inferences from these observations include the fact that many patients with early sinus node dysfunction and bradycardia are not pacer dependent at 3 months. However, those with atrioventricular block early appear to require long-term pacing support. However, the possibility that more aggressive and long-term oral chronotropic medication use after transplantation would obviate early permanent pacemaker need is not addressed. Finally, prospective clinical trials are necessary to precisely characterize benefit of permanent pacemakers and define optimal pacing modes after heart transplantation.

Relationship of increased levels of circulating intercellular adhesion molecule 1 after heart transplantation to rejection: human leukocyte antigen mismatch and survival.

Noninvasive methods to assess immune activation would be helpful in optimizing therapy after heart transplantation to reduce rejection (acute and chronic) and complications caused by excessive immunosuppressive therapy. Intercellular adhesion molecule 1 has been shown to play an important role in T-cell activation and allograft rejection. A soluble form of intercellular adhesion molecule 1 has been discovered to be circulating in plasma. To test the hypothesis that increased levels of circulating intercellular adhesion molecule 1 may have prognostic value as a marker of immune activation, we examined whether levels of circulating intercellular adhesion molecule 1 during the early postoperative period correlated with endomyocardial biopsy scores, soluble interleukin-2 receptor levels, human leukocyte antigen mismatch, and survival. For the first 3 weeks after surgery, serum was obtained once weekly on the same day as endomyocardial biopsy samples from 52 patients who survived more than 30 days after heart transplantation. A sandwich enzyme-linked immunosorbent assay was used to measure circulating intercellular adhesion molecule 1 and soluble interleukin-2 receptor. Increased circulating intercellular adhesion molecule 1 levels did not correlate with endomyocardial biopsy scores but were associated with greater mismatch at the human leukocyte antigen-B and -DR loci (p = 0.02). A significant correlation was found (p = 0.002) between circulating intercellular adhesion molecule 1 levels and soluble interleukin-2 receptor, albeit with a low r value of 0.27. Survival was reduced in patients with high levels of circulating intercellular adhesion molecule 1 (p = 0.006) or soluble interleukin-2 receptor (p = 0.001) with the greatest reduction in survival when both were elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

What are the implications of cardiac infection with cytomegalovirus before heart transplantation?

To elucidate prognostic implications of recipient cytomegalovirus infection before heart transplantation, we prospectively followed the clinical outcome of 21 transplant recipients whose explanted hearts (myocardium and coronary arteries) were first examined for the presence of cytomegalovirus DNA with polymerase chain reaction. Subsequently, serial endomyocardial biopsy tissue samples obtained from the allograft during routine evaluation for rejection were analyzed by polymerase chain reaction for both an immediate early and late cytomegalovirus gene region of cytomegalovirus DNA. Humoral cytomegalovirus immunoglobulin G antibodies were also measured by radioimmunoassay. Both early and late antigens were present in 14 of 21 (67%) explants from patients with (12 of 15 explants) and without (2 of 6 explants) pretransplant cytomegalovirus antibodies. Although the presence of both early and late antigens was uncommon in allografts the first week after transplantation (5 of 20 allografts, 25%), their presence significantly increased at 1 month (14 of 21 allografts, 67%) and 2 to 3 months (13 of 17 allografts, 77%) regardless of pretransplantation cytomegalovirus antibody status. The presence of both early and late antigens in explant tissue strongly predicted allograft virus status during the follow-up periods. Of five patients in whom clinical cytomegalovirus disease subsequently developed, all had explants positive for both early and late antigens, and all allografts were positive for early and late antigens within 1 month after transplantation. These are the first prospective data to correlate pretransplantation serum antibodies and explant polymerase chain reaction status with the development of future allograft infections and overall clinical outcome.

Elevated soluble interleukin-2 receptor levels early after heart transplantation and long-term survival and development of coronary arteriopathy.

Rejection dynamics after heart transplantation might be characterized by soluble interleukin-2 receptor levels. To determine whether elevated levels early (measured by enzyme-linked immunosorbent assay once weekly the first 3 weeks at time of heart biopsy) after transplantation predict mortality and development of coronary disease, the means of these three determinations and the endomyocardial biopsy scores (McAllister scale 0-10) were compared for survivors and nonsurvivors and patients who had coronary arteriopathy develop and those who did not. Fifty-five patients alive 30 days after heart transplantation were prospectively followed up. Overall, 47 patients were male (85%), and the median age was 51 years. Mean +/- SD follow-up was 26 +/- 15 months (range, 1 to 54 months). There were 38 survivors (69%), and coronary arteriopathy developed in 15 patients (27%). Whereas mean +/- SD heart biopsy scores for the early weeks were similar between survivors and nonsurvivors (3.6 +/- 1.4 vs 4.4 +/- 1.6; p greater than 0.05), the difference in soluble interleukin-2 receptor levels was significant (703 +/- 362 U/ml vs 1793 +/- 1070 U/ml; p less than 0.001). A mean level less than 1000 U/ml in any given patient predicted long-term survival with a 76% sensitivity, 79% specificity, and 88% negative predictive value. Mean receptor levels for those patients in whom coronary arteriopathy did not develop were 880 +/- 846 U/ml and for those with this difficulty, 1410 +/- 590 U/ml (p = 0.001). Late morbidity and mortality after heart transplantation seem predicted by early elevation of plasma soluble interleukin-2 receptor levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular function in patients with centrifugal left ventricular assist device.

We used blood pool radionuclide angiography to study the left ventricular (LV) ejection fraction (EF) in 17 patients with a centrifugal assist device (AD) placed because of severe postoperative LV dysfunction. During maximal LVAD flow, the 12 patients who could be weaned had a higher LV-EF than the 5 who could not be weaned (18 +/- 12% vs. 9 +/- 2%, p = 0.04). Sequential studies during variable AD flows in 12 patients revealed an increase in LV-EF from 15 +/- 7% at maximal flows to 33 +/- 8% during minimal flows (p less than 0.005) in the 10 patients who could be weaned and no change in LV-EF in 2 patients who could not be weaned. The LV-EF during maximal LVAD flow rates was similar in the 10 patients with long-term survival (192 +/- 129 days) and in the 7 patients with only short-term (9 +/- 6 days) survival (LV-EF 17 +/- 12% vs. 12 +/- 6%, p = ns). The long-term survivors, however, had a substantial increase in LV-EF from 20 +/- 13% to 34 +/- 9% (p less than 0.01), as the LVAD flow was decreased from maximal to minimal, whereas the short-term survivors had an insignificant increase in LV-EF from 12 +/- 7% to 21 +/- 12% (p = ns). The long-term survivors increased the LV-EF from maximal to minimal LVAD flows by 182%, in contrast with the short-term survivors, who increased the LV-EF by only 44%.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterotopic heart transplantation: catheterization, endomyocardial biopsy, and coronary angiography of the donor heart.

UNLABELLED: Follow-up after heart transplantation presently requires invasive techniques to assess graft viability and function. As the heterotopic transplant technique assumes a more important therapeutic role for patients not eligible for an orthotopic allograft, an understanding of the inherent challenges associated with management of these patients is mandatory to optimize patient care. Heterotopic transplant technique was used in 19 of 135 (14%) consecutive heart transplant procedures over a 41 month period. Invasive diagnostic procedures performed in follow-up revealed 1) adequate tissue for histologic evaluation in 140/158 (89%) biopsy procedures, 2) successful pulmonary wedge pressure measurements in 142/158 (90%) right heart catheterizations, and 3) successful coronary arteriography in 18 patients undergoing angiography (both vessels in 12 and one vessel in six patients). Thus, biopsy and surveillance procedures are feasible and productive in patients who have undergone heterotopic heart transplantation. BACKGROUND: Although heterotopic heart transplantation has become an increasingly utilized therapy for some patients with heart failure, there are no guidelines for routine biopsy and angiographic techniques in these patients. The objective of this study was to determine the feasibility of angiographic and endomyocardial biopsy procedures in heterotopic heart transplant recipients. METHODS: The complete experience with heterotopic heart transplant recipients at Baylor College of Medicine and The Methodist Hospital over a 41 month period including endomyocardial biopsy, right heart catheterization, and selective coronary arteriography results were analyzed. RESULTS: Eighteen patients underwent 310 procedures without significant complications. Of 158 biopsy procedures, 140 (89%) yielded tissue adequate for histologic evaluation. Right heart pressures were obtained in almost all patients undergoing right heart catheterization. Pulmonary wedge pressures were obtained in 137 (90%). A rapid decrease in right heart pressures was noted following transplant; however, a gradual but significant rise in mean arterial pressure occurred. Eighteen selective coronary arteriogram procedures were performed; 12 (66%) resulted in successful cannulation of both coronary arteries. Of 12 patients followed for at least 1 year, five (40%) have developed evidence of allograft arteriopathy. The 1 and 2 year survival rates were 67% and 53%, respectively. CONCLUSIONS: Invasive diagnostic techniques can be performed safely and reliably and should not preclude the use of heterotopic heart transplantation in selected patients who are otherwise unsuitable for orthotopic transplantation.