Dale G. Renlund

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients : Mycophenolate Mofetil Investigators

BACKGROUND After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Ischemic Heart Disease Events Triggered by Short-Term Exposure to Fine Particulate Air Pollution

Background— Recent evidence suggests that long-term exposure to particulate air pollution contributes to pulmonary and systemic oxidative stress, inflammation, progression of atherosclerosis, and risk of ischemic heart disease and death. Short-term exposure may contribute to complications of atherosclerosis, such as plaque vulnerability, thrombosis, and acute ischemic events. These findings are inconclusive and controversial and require further study. This study evaluates the role of short-term particulate exposure in triggering acute ischemic heart disease events. Methods and Results— A case-crossover study design was used to analyze ischemic events in 12 865 patients who lived on the Wasatch Front in Utah. Patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a large, ongoing registry of patients who underwent coronary arteriography and were followed up longitudinally. Ambient fine particulate pollution (particles with an aerodynamic diameter ≤2.5 &mgr;m; PM2.5) elevated by 10 &mgr;g/m3 was associated with increased risk of acute ischemic coronary events (unstable angina and myocardial infarction) equal to 4.5% (95% confidence interval, 1.1 to 8.0). Effects were larger for those with angiographically demonstrated coronary artery disease. Conclusions— Short-term particulate exposures contributed to acute coronary events, especially among patients with underlying coronary artery disease. Individuals with stable presentation and those with angiographically demonstrated clean coronaries are not as susceptible to short-term particulate exposure.

Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study.

OBJECTIVES This study assessed the safety and efficacy of carvedilol in patients with heart failure caused by idiopathic or ischemic cardiomyopathy. BACKGROUND Carvedilol is a mildly beta 1-selective beta-adrenergic blocking agent with vasodilator properties. Beta-blockade may be beneficial in patients with heart failure, but the effects of carvedilol are not known. METHODS Sixty patients with heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction < or = 0.35 were enrolled in the study. All patients tolerated challenge with carvedilol, 3.125 mg twice a day, and were randomized to receive carvedilol (n = 36) versus placebo (n = 24). Study medication was titrated over 1 month from 6.25 to 25 mg twice a day (< 75 kg) or 50 mg twice a day (> 75 kg) and continued for 3 months. One placebo-treated and two carvedilol-treated patients did not complete the study. RESULTS Carvedilol therapy resulted in a significant reduction in heart rate and mean pulmonary artery and pulmonary capillary wedge pressures and a significant increase in stroke volume and left ventricular stroke work. Left ventricular ejection fraction increased 52% in the carvedilol group (from 0.21 to 0.32, p < 0.0001 vs. placebo group). Carvedilol-treated patients also reported a significant lessening of heart failure symptoms (p < 0.05 vs. placebo group). Submaximal exercise duration tended to increase with carvedilol therapy (from 688 +/- 31 s to 871 +/- 32 s), but this change was not significantly different from that with placebo therapy by between-group analysis. Peak oxygen consumption during maximal exercise did not change. CONCLUSIONS Long-term carvedilol therapy improves rest cardiac function and lessens symptoms in patients with heart failure.

A Controlled Trial of Ganciclovir to Prevent Cytomegalovirus Disease after Heart Transplantation

BACKGROUND Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. METHODS This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. RESULTS Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. CONCLUSIONS The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis A Post Hoc Analysis of a Randomized, Placebo-Controlled Study

BACKGROUND Coronary artery disease occurs in an accelerated fashion in the donor heart after heart transplantation (TxCAD), but the cause is poorly understood. The risk of developing TxCAD is increased by cytomegalovirus (CMV) infection and decreased by use of calcium blockers. Our group observed that prophylactic administration of ganciclovir early after heart transplantation inhibited CMV illness, and we now propose to determine whether this therapy also prevents TxCAD. METHODS AND RESULTS One hundred forty-nine consecutive patients (131 men and 18 women aged 48+/-13 years) were randomized to receive either ganciclovir or placebo during the initial 28 days after heart transplantation. Immunosuppression consisted of muromonab-CD3 (OKT-3) prophylaxis and maintenance with cyclosporine, prednisone, and azathioprine. Mean follow-up time was 4.7+/-1.3 years. In a post hoc analysis of this trial designed to assess efficacy of ganciclovir for prevention of CMV disease, we compared the actuarial incidence of TxCAD, defined by annual angiography as the presence of any stenosis. Because calcium blockers have been shown to prevent TxCAD, we analyzed the results by stratifying patients according to use of calcium blockers. TxCAD could not be evaluated in 28 patients because of early death or limited follow-up. Among the evaluable patients, actuarial incidence of TxCAD at follow-up (mean, 4.7 years) in ganciclovir-treated patients (n=62) compared with placebo (n=59) was 43+/-8% versus 60+/-10% (P<0.1). By Cox multivariate analysis, independent predictors of TxCAD were donor age >40 years (relative risk, 2.7; CI, 1.3 to 5.5; P<0.01) and no ganciclovir (relative risk, 2.1; CI, 1.1 to 5.3; P=0.04). Stratification on the basis of calcium blocker use revealed differences in TxCAD incidence when ganciclovir and placebo were compared: no calcium blockers (n=53), 32+/-11% (n=28) for ganciclovir versus 62+/-16% (n=25) for placebo (P<0.03); calcium blockers (n=68), 50+/-14% (n=33) for ganciclovir versus 45+/-12% (n=35) for placebo (P=NS). CONCLUSIONS TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Risk factors predictive of right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation appears to be associated with increased mortality. However, the determination of which patients are at greater risk of developing postoperative RVF remains controversial and relatively unknown. We sought to determine the preoperative risk factors for the development of RVF after LVAD implantation. The data were obtained for 175 consecutive patients who had received an LVAD. RVF was defined by the need for inhaled nitric oxide for >/=48 hours or intravenous inotropes for >14 days and/or right ventricular assist device implantation. An RVF risk score was developed from the beta coefficients of the independent variables from a multivariate logistic regression model predicting RVF. Destination therapy (DT) was identified as the indication for LVAD implantation in 42% of our patients. RVF after LVAD occurred in 44% of patients (n = 77). The mortality rates for patients with RVF were significantly greater at 30, 180, and 365 days after implantation compared to patients with no RVF. By multivariate logistic regression analysis, 3 preoperative factors were significantly associated with RVF after LVAD implantation: (1) a preoperative need for intra-aortic balloon counterpulsation, (2) increased pulmonary vascular resistance, and (3) DT. The developed RVF risk score effectively stratified the risk of RV failure and death after LVAD implantation. In conclusion, given the progressively growing need for DT, the developed RVF risk score, derived from a population with a large percentage of DT patients, might lead to improved patient selection and help stratify patients who could potentially benefit from early right ventricular assist device implantation.

Long-term β-Blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind, randomized study of bucindolol versus placebo☆

PURPOSE Bucindolol is a potent nonselective beta-blocking agent with vasodilatory properties. In this study, we evaluated the effects of long-term bucindolol therapy in the treatment of heart failure from idiopathic dilated cardiomyopathy. PATIENTS AND METHODS Patients were eligible for enrollment if they had symptomatic heart failure, idiopathic dilated cardiomyopathy, and left ventricular ejection fraction less than 0.40. All patients received an initial test dose of 12.5 mg bucindolol orally every 12 hours for two or three doses. Patients tolerating the test dose were randomly assigned (double-blind) to receive bucindolol or placebo in a 3:2 ratio. Study medication was begun at a dose of 12.5 mg orally every 12 hours and gradually increased over a 1-month period until either a maximum tolerated dose or a target dose of 100 mg every 12 hours was reached. Study medication was then continued for an additional 2 months. RESULTS A total of 24 patients were enrolled into the study. Twenty-three patients tolerated bucindolol test challenge; 14 were randomized to receive bucindolol, and nine were randomly assigned to receive placebo. The placebo group (age 56 +/- 2 years) was significantly older than the bucindolol group (46 +/- 3 years), but by all other clinical and hemodynamic parameters the two groups were comparable. Twenty-two of 23 patients completed the study. Patients treated with bucindolol had significant improvements in clinical heart failure symptoms and in resting hemodynamic function, including an increase of left ventricular ejection fraction (0.26 +/- 0.02 to 0.35 +/- 0.09, p = 0.003), cardiac index (2.2 +/- 0.1 to 2.5 +/- 0.4 L/minute/m2, p = 0.014), and left ventricular stroke work index (25 +/- 3 to 35 +/- 7 g.m/m2, p = 0.002) and a decrease in pulmonary artery wedge pressure (17 +/- 3 to 10 +/- 5 mm Hg, p = 0.005) and heart rate (86 +/- 3 to 75 +/- 9 beats/minute, p = 0.012). Patients treated with bucindolol also had a significant increase in exercise left ventricular ejection fraction (0.26 +/- 0.03 to 0.32 +/- 0.14, p = 0.015) and reduction in questionnaire-measured symptoms (p = 0.007) and New York Heart Association functional class (p less than 0.001). However, total treadmill exercise duration and maximal oxygen consumption with exercise did not change. No changes in rest or exercise parameters were observed in the placebo-treated group. Central venous plasma norepinephrine concentration decreased significantly in the bucindolol-treated group (423 +/- 79 to 212 +/- 101 pg/mL, p = 0.010), but was unchanged in the placebo-treated group. CONCLUSION Bucindolol is well tolerated in patients with idiopathic dilated cardiomyopathy and congestive heart failure, and therapy for 3 months is associated with improved resting cardiac function, improved heart failure symptoms, and a reduction in venous norepinephrine concentration.

Left Ventricular Assist Device as Destination for Patients Undergoing Intravenous Inotropic Therapy: A Subset Analysis From REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure)

Background—Left ventricular assist devices (LVADs) have improved survival in patients with end-stage heart failure. Compared with previous trials, the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH) trial enrolled patients with more advanced heart failure and high prevalence of intravenous inotropic therapy. This study analyzes, on a post hoc basis, outcomes in patients undergoing inotropic infusions at randomization. Methods and Results—Of 129 patients randomized, 91 were receiving intravenous inotropic therapy at randomization to LVAD or optimal medical management (OMM). Mean systolic pressure was 100 versus 107 mm Hg in those not receiving inotropes, serum sodium was 134 versus 137 mEq/L, and left ventricular ejection fraction was 17% for both groups. LVADs improved survival throughout follow-up for patients undergoing baseline inotropic infusions (P=0.0014); for the LVAD group versus the OMM group, respectively, 6-month survival was 60% versus 39%, 1-year survival rates were 49% versus 24%, and 2-year survival rates were 28% versus 11%. For 38 patients not undergoing inotropic infusions, 6-month survival was 61% for those with LVADs and 67% for those with OMM, whereas 1-year rates were 57% and 40%, respectively (P=0.55). Quality-of-life scores for survivors improved. Median days out of hospital for patients on inotropic therapy at randomization were 255 with LVAD and 105 with OMM. Conclusions—Despite severe compromise, patients undergoing inotropic infusions at randomization derived major LVAD survival benefit with improved quality of life. Patients not undergoing inotropic infusions had higher survival rates both with and without LVAD, but differences did not reach significance. Future studies should prespecify analyses of inotropic and other therapies to determine how disease severity and parallel medical treatment influence the benefits offered by mechanical circulatory support.

Allograft coronary artery disease: clinical correlations with circulating anti-HLA antibodies and the immunohistopathologic pattern of vascular rejection ☆

Despite advances in immunosuppression over the past ten years, the overall longevity of the cardiac allograft has only minimally increased. The average allograft half-life has increased only 6 months (8.8 years to 9.4 years) between the time periods of 1986–1990 and 1991–1997.1 The single major cause of allograft loss after one year remains allograft coronary artery disease (ACAD).1 This entire issue of the Journal of Heart and Lung Transplantation is devoted to the potential etiologic factors as well as the clinical manifestations of ACAD. Traditionally, the immune response to allotransplantation has been divided into the cellular (T-cell) and humoral (B-cell) processes. While it is likely that both processes are activated and ongoing simultaneously in most allograft recipients, patients who appear to have a predominately humoral process have been reported to have worse long-term outcomes.2–10 Patients developing circulating anti-HLA antibodies or the immunohistopathologic pattern of vascular rejection early after cardiac transplantation have demonstrated poorer survival and increased risk for the development of ACAD.4–10

Relation of Heart Failure Hospitalization to Exposure to Fine Particulate Air Pollution

Cardiopulmonary disease has been associated with particulate matter (PM) air pollution. There is evidence that exposure to elevated PM concentrations increases risk of acute ischemic heart disease events, alters cardiac autonomic function, and increases risk of arrhythmias. It is plausible, therefore, that PM exposure may exacerbate heart failure (HF). A case-crossover study design was used to explore associations between fine PM (PM(2.5): particles with an aerodynamic diameter < or =2.5 microm) and 2,628 HF hospitalizations. Patients lived on Utahs Wasatch Front and were drawn from those hospitalized at Intermountain Healthcare facilities with a primary diagnosis of HF. A 14-day lagged cumulative moving average of 10 microg/m(3) PM(2.5) was associated with a 13.1% (95% confidence interval 1.3 to 26.2) increase in HF admissions. The strongest PM(2.5)-HF associations were for elderly patients who had previously been admitted for HF and who required only a short period of hospitalization. HF hospitalizations are associated with lagged cumulative exposure to PM(2.5) of approximately 2 weeks. In conclusion, particulate air pollution may play a role in precipitating acute cardiac decompensation in otherwise well-managed patients with HF, perhaps through effects of PM on myocardial ischemia, cardiac autonomic function, and/or arrhythmic effects.