Milrinone: basic and clinical pharmacology and acute and chronic management.

Milrinone (Inocor-Sanofi-Winthrop) represents a second generation phosphodiesterase inhibitor currently approved for intravenous administration in the treatment of decompensated congestive heart failure. By inhibiting Type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate. This results in a positive inotropic effect on the heart and vasodilatation in the periphery. The hemodynamic consequences of this action produce left ventricular afterload reduction, with an increase in cardiac output and a reduction in total peripheral resistance. Unlike the sympathomimetic amines, milrinone produces no tolerance and possesses the distinct advantage of directly decreasing pulmonary vascular resistance. Short-term intermittent infusion by peripheral administration, continuous infusion, long-term therapy, and intermittent outpatient therapy was demonstrated to be safe, efficacious, and cost effective. It is hypothesized that intravenous milrinone, by producing biventricular afterload reduction, offers an efficacious, cost-effective tool for the treatment of decompensated heart failure.

Cardiac transplantation with corticosteroid-free immunosuppression: long-term results.

To assess the long-term safety of an immunosuppressive regimen without corticosteroids, we retrospectively evaluated 42 long-term (greater than 1 year) survivors of orthotopic cardiac transplantation. We determined the incidence of (1) conversion of the immunosuppressive regimen from cyclosporine and azathioprine alone (group I) to cyclosporine, azathioprine, and prednisone (group II), (2) late acute graft rejection (defined as occurring at greater than 1 postoperative year), and (3) major postoperative complications related to corticosteroids. Of the 42 patients who were started on cyclosporine and azathioprine, 48% remained in group I, and 52% converted to group II. Forty-five percent of group II patients were able to taper and discontinue prednisone in 15.6 +/- 2.2 months. Among the patients on long-term corticosteroid-free immunosuppression, the incidence of late rejection was 2.1% per endomyocardial biopsy. The incidence of late infectious episodes was not significantly different between the two groups of patients, although diabetes mellitus and hypercholesterolemia were more prevalent in group II than in group I. These data suggest that cardiac transplant recipients who chronically remain on corticosteroid-free immunosuppression represent a select group of patients with an acceptably low risk of late graft rejection and associated reduction of potential risk factors of accelerated coronary artery disease.

The heart as a target organ of immune injury.

Over the last 10 years, our knowledge of immunologically mediated processes involving the myocardium appears to have made quantum leaps. New and important disease entities such as AIDS have appeared and the cardiologist now becomes an important member of the "AIDS team." Our understanding of "older diseases" such as sarcoidosis, Lyme disease, systemic lupus and other connective tissue syndromes has significantly increased. The concept of high-dose steroid therapy for these processes may, in fact, turn out to be futile and more selective, as less dangerous immunosuppression is being introduced. This concept has significantly advanced in the field of cardiac transplantation where immunosuppression has now been usurped by specific immunotherapy aimed at selective aspects of the immune sequence. New and exciting concepts will emerge from the molecular biology laboratory that will have direct bearing on the management of patients with cardiovascular disorders. This information explosion will force the cardiovascular physician to become more in tune with the world of immunology and molecular biology. Many obvious, significant problems remain, such as accelerated atherosclerosis in the transplant patient and the role of myocarditis in the patient with heart failure. However, it will truly be an exciting decade in which to work and watch the unraveling of these mysteries and hopefully, the study of today's problems will give way to solutions and a clearer understanding of the heart as a target of immune injury.

Hypercholesterolemia in long-term survivors of heart transplantation: an early marker of accelerated coronary artery disease.

Coronary artery disease remains a significant long-term problem for survival after heart transplantation. Hyperlipidemia is a known risk factor for coronary artery disease in the general population, but the role of hyperlipidemia in cardiac allograft recipients has not been elucidated. To study this problem, we retrospectively reviewed 38 heart transplant recipients who survived more than 3 years after surgery and looked at age, development of diabetes, drug protocol, and development of hypercholesterolemia for a possible correlative or predictive value to the development of early coronary artery disease after heart transplantation. Eleven patients were identified as having coronary disease by the third year after transplantation. High-risk cholesterol values (in milligrams per deciliter) at 6 months after heart transplantation were defined as follows: for ages 10 to 20, 190; 20 to 30, 220; 30 to 40, 240; 40+, 260. We found a strong predictive value with high-risk lipid profiles (p less than 0.01) for the development of coronary artery disease by the third year. No significance was found for a low-risk value, the development of diabetes, or hypertension. All patients below the age of 20 years had coronary artery disease by the third year after transplantation. We conclude that a high-risk cholesterol value at 6 months after transplantation is a strong predictor for development of accelerated coronary artery disease and early graft failure. This has major implications for management of hyperlipidemia in the cardiac allograft recipient.

Comparison of atrial contribution to cardiac hemodynamics in patients with normal and severely compromised cardiac function.

The importance of atrial contribution to cardiac function in patients with congestive heart failure is controversial. Ten patients with severe congestive failure (Group A) and 10 patients with normal ventricular function (Group B) were studied during atrial and ventricular pacing. Left ventricular ejection fraction, baseline pulmonary capillary wedge pressure, and baseline cardiac index were different between Group A and Group B patients: 22 +/- 10 vs. 65 +/- 11 (p less than 0.01); 21 +/- 5 vs. 8 +/- 4, (p less than 0.01); and 2.8 +/- 0.5 vs. 3.5 +/- 1.0 (p = 0.05). Compared with atrial pacing, cardiac index decreased from 2.8 +/- 0.6 to 2.2 +/- 0.5 (p less than 0.01) in Group A and from 3.6 +/- 0.7 to 2.9 +/- 0.5 (p less than 0.01) in Group B, during ventricular pacing. Pulmonary capillary wedge pressure increased by similar amounts in both groups during ventricular pacing. The change in cardiac index, % change in cardiac index, and change in pulmonary capillary wedge pressure from atrial to ventricular pacing, were not different between Group A and Group B patients. By logistic regression analysis, no association was found between the % change in cardiac index and the following variables: left ventricular ejection fraction, left ventricular end-diastolic volume, baseline pulmonary capillary wedge pressure, change in pulmonary capillary wedge pressure, and baseline cardiac index. The atrial contribution to resting steady-state cardiac function is similar between patients with severe congestive failure and those with preserved ventricular function.

Accelerated coronary atherosclerosis in cardiac transplantation.

The implications of this new aggressive form of coronary disease for the transplant population are obvious. It appears that for the majority of transplant patients we have simply bought some time. We have given them a temporary respite from congestive failure and cardiomyopathy while they surmount the daily challenges imposed by immunosuppression. Clearly, this issue now looms as a major stumbling block toward improving long-term survival. It is no longer enough to simply perform the procedure and submit the patient to the rigors of transplantation, only to obtain 50 percent 5-year survival. We must pay particular attention to the patient postoperatively and make those modifications necessary to improve the individual's risk profile. Moreover, we must continue to concentrate our research efforts on interventions in accelerated coronary disease.

Management and long-term followup of outpatient care in the cardiac transplant recipient.

Successful long-term management of the cardiac transplant patient requires the concerted effort of the patient, the cardiac transplant team, and the primary care physician. The long-term management of these patients will continue to evolve as new immunosuppressive agents are used and new methods of surveillance for rejection are found. The long-term management is indeed one of the most exciting parts of the care of the transplant patient, especially when all those involved can watch the patient enter into a normal lifestyle.

Hyperlipidemia after clinical heart transplantation.

Accelerated coronary atherosclerosis is a major cause of morbidity and death in the cardiac transplant recipient. Hypercholesterolemia has been implicated as a contributing risk factor. Because of this we reviewed lipoprotein profiles from transplant recipients from 1968 to 1986 in an attempt to identify the risk factors for the development of lipid disorders after transplantation. Patients were divided into three groups based on their immunosuppressive protocols. Group 1 consisted of 10 patients receiving azathioprine and prednisone. Group 2 consisted of 24 patients receiving cyclosporine and prednisone with or without azathioprine. Group 3 consisted of 18 patients receiving cyclosporine and azathioprine without prednisone. Total cholesterol levels at 1 year were highest in group 2 (266 mg/dl versus 236 mg/dl for group 1 [p = 0.16] and 223 mg/dl for group 3 [p = 0.005]). High-density lipoprotein cholesterol levels were lowest in group 3 (38 mg/dl versus 51 mg/dl for group 1 [p = 0.025] and 54 mg/dl for group 2 [p = 0.0001]). Subgroup analysis with multivariate and univariate analysis found that prednisone and preoperative coronary artery disease are the major contributors to the posttransplant lipid abnormalities.

Denial and medical outcome in unstable angina.

Denial may be adaptive during hospitalization for acute coronary disease. We studied the impact of denial in 48 patients referred to a tertiary care center for treatment of unstable angina. Using the Hackett-Cassem Denial Scale, we divided the group into 25 high deniers and 23 low deniers. The two groups were comparable in baseline demographic and social data, coronary risk factors, cardiac history, medical treatment, vital signs, and cardiac catheterization results (number of diseased vessels and ejection fraction). Compared to low deniers, high deniers had half as many episodes of angina during hospitalization (1.3 vs. 2.5; p less than 0.03, t = 2.2, df = 46) and were more likely to reach medical stabilization, i.e., pain free for 36 hr (92% vs. 65%, p less than 0.03, Fisher exact probability test). Intravenous nitroglycerin drips were also required less often in high deniers (32% vs. 78%, p = 0.002, Fisher exact). Two myocardial infarctions and one death occurred, all in low deniers. We conclude that denial independently predicts better medical outcome during acute hospitalization for unstable angina.

Applications of percutaneous transluminal coronary angioplasty in cardiac transplantation. Preliminary results in five patients.

Atherosclerotic coronary artery disease is the major cause of late cardiac transplant failure secondary to silent ischemia and infarction. To increase the longevity of cardiac homografts, we performed percutaneous transluminal coronary angioplasty (PTCA) in five male patients (aged 45 +/- 7 years, mean +/- SEM); 17 lesions were dilated during eight procedures 83 +/- 11 months after cardiac transplant. PTCA was successful (greater than or equal to 20% change in vessel diameter) in 13 of 17 (76%) lesions (the degree of prePTCA stenosis was 84% +/- 3% vs. 40% +/- 4% postPTCA; p less than or equal to 0.01). Multiple PTCA procedures were performed for progressive coronary artery disease in two patients; in one patient, two procedures were 13 months apart, and, in the second patient, another three procedures were 2 and 6 months apart. Indications for PTCA included reversible thallium perfusion defects, segmental left ventricular wall-motion abnormalities, or both in the distribution of proximal coronary artery stenoses. No deterioration occurred in the four unsuccessful PTCA attempts (two patients with initial total occlusion, and two patients in whom the lesion could not be crossed with a guidewire). Noninvasive evidence of ischemia was improved immediately after PTCA in all cases. Three patients remain alive 5, 7, and 11 months, respectively, after PTCA without evidence of new ischemia. One patient died 39 months after his first PTCA, while another patient was retransplanted 8 months after the first PTCA. Thus, PTCA can be performed in cardiac transplant patients with proximal major vessel coronary artery disease and may prolong cardiac homograft function.(ABSTRACT TRUNCATED AT 250 WORDS)

Are steroids essential for successful maintenance of immunosuppression in heart transplantation?

To determine the necessity for maintenance dosages of prednisone in the management of heart transplant patients, a retrospective study was made of 86 patients undergoing orthotopic heart transplantation and two patients having heart-lung transplantation from June 1985 through October 1986. Group 1 (n = 52) had maintenance immunosuppressive therapy that included cyclosporine, azathioprine, and prednisone. Group 2 (n = 36) received only cyclosporine and azathioprine with no maintenance dosage of steroids. Data were analyzed for frequency of rejections, infections, noninfectious complications, and mortality. The rate of rejection was 1.44 episodes per patient in group 1 and 1.58 episodes per patient in group 2. Twenty of 52 patients (38%) in group 1 had no rejection compared with 12 of 36 patients (33%) in group 2 (p = not significant [NS]). One or more infections occurred in 30 patients (58%) in group 1, whereas only 12 patients (33%) in group 2 had infections (p less than 0.05). Noninfectious complication rates were noted to be similar in both groups (27% versus 25%, p = not significant). There were five deaths in group 1: three from infections, one from rejection, and one from trauma. There were three deaths in group 2: two from infection and one from rejection. Although 14 patients in group 2 eventually were placed on low-dosage steroid maintenance, the remaining 22 patients (61%) never received maintenance dosages of steroids. We conclude that some patients can be successfully managed without maintenance dosages of steroids after heart transplantation. Such patients do not appear to have an increased risk of rejection and may have a reduced rate of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Pretransplant transfusions in cardiac allograft recipients.

The role of pretransplant transfusion in cardiac allograft recipients was determined retrospectively in 68 patients. Three groups were studied: group 1 (n = 29) received no pretransplant transfusion, group 2 (n = 15) received transfusion over one year prior to transplantation, and Group 3 (n = 24) received 5 or 10 50-100 ml units of random donor red blood cells or buffy coat 2-4 weeks prior to transplantation. Data were analyzed for survival, number of rejection episodes, and number of infections. Immunosuppression included azathioprine, prednisone, and antithymocyte globulin. Survival in transfused patients (groups 2 and 3) was 68% and 51% at 1 and 5 years, respectively, while in the nontransfused population (group 1) it was 35% and 16%. The incidence of rejection episodes per year of survival was similar in the three groups (group 1: 1.3, group 2: 1.1, group 3: 1.3; P greater than 0.05). The number of infections per year of survival were greater in the transfused patients but this did not achieve statistical significance (group 1: 1.0, group 2: 1.2, group 3: 1.7; P greater than 0.05). Thus, we conclude that cardiac transplant recipients who have received blood transfusions prior to transplantation may have enhanced survival over patients who have not received preoperative transfusions.