Alain Heroux

Increased Incidence of Lymphoproliferative Disorder after Immunosuppression with the Monoclonal Antibody OKT3 in Cardiac-Transplant Recipients

BACKGROUND A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. METHODS In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. RESULTS Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, 1.6 to 54.7). According to multivariate analysis, the only factor significantly associated with the development of post-transplantation lymphoproliferative disorder was the use of OKT3 (P = 0.001). A significant increase in risk with increasing doses was also apparent: 4 of 65 patients who received a cumulative dose of 75 mg of OKT3 or less (6.2 percent) had post-transplantation lymphoproliferative disorder, whereas 5 of 14 patients who received more than 75 mg had the disorder (35.7 percent; P less than 0.001). CONCLUSION The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg. We suggest that the risks and benefits of prophylactic OKT3 administration be reassessed in the light of these findings, particularly since the value of prophylactic immunotherapy in cardiac-transplant recipients remains to be clearly established.

Risk/benefit ratio of perioperative OKT3 in cardiac transplantation

This study shows that perioperative OKT3 provides no benefit in terms of the time of onset or frequency of rejection or patient survival. However, it does result in an increased incidence of infection, particularly CMV infection. Thus, the risk/benefit ratio of perioperative OKT3 does not appear favorable. However, a multicenter, randomized trial including a larger number of patients and longer patient follow-up will be required to definitively answer the question.

Intracoronary ultrasound assessment of morphological and functional abnormalities associated with cardiac allograft vasculopathy.

BACKGROUND The diffuse nature of cardiac allograft vasculopathy makes early detection of the disease by traditional noninvasive methods or coronary angiography difficult. The aim of this study was to determine if there is a relation between abnormalities in vessel wall morphology, as assessed by intracoronary ultrasound, and a decreased vasodilatory response to the endothelium-dependent vasodilator papaverine hydrochloride and if cardiac allograft vasculopathy detected by coronary angiography is associated with specific intracoronary ultrasound findings. METHODS AND RESULTS Twenty-three heart transplant recipients underwent 25 intracoronary ultrasound studies and 24 studies of coronary vasomotor tone 10 days to 8.3 years after surgery using a 20-mHz intracoronary ultrasound catheter. The studies were divided in two groups according to the presence (n = 7, group 1) or absence (n = 18, group 2) of angiographically evident cardiac allograft vasculopathy. Qualitative assessment of vessel wall morphology and quantitative analysis of the vasodilator response to the injection of papaverine hydrochloride into the coronary artery distal to the imaging site were performed off-line, and results for the two study groups were compared. A significantly higher percentage of patients with than without angiographic evidence of cardiac allograft vasculopathy had a three-interface vessel wall morphology by intracoronary ultrasound (100% versus 11%, P < .001). In two recipients who underwent two serial studies, the appearance of three interfaces in the vessel wall or a progressive thickening of the inner interface of the vessel wall occurred in conjunction with the appearance of angiographic cardiac allograft vasculopathy. The vasodilator response to papaverine was less in patients with than in those without angiographically evident cardiac allograft vasculopathy both in terms of absolute and relative increases in lumen diameter (+0.1 +/- 0.12 mm versus +0.3 +/- 0.17 mm, P < .05, and +5.1 +/- 5.3% versus +8.2 +/- 5.3%, P = NS) and lumen cross-sectional area (+0.5 +/- 0.6 mm2 versus +1.7 +/- 1.1 mm2, P < .02, and +7.1 +/- 8.8% versus 16.6 +/- 11.0%, P = .055), respectively. CONCLUSIONS Intracoronary ultrasound assessment of vessel wall morphology and evaluation of vascular response to endothelium-dependent vasodilators are useful techniques for detecting cardiac allograft vasculopathy.

Incidence, Risk Factors, and Clinical Outcomes of Atrial Fibrillation and Atrial Flutter After Heart Transplantation

Atrial fibrillation (AF) and atrial flutter (AFL) after heart transplantation (HT) has been associated with increased mortality. Diverse incidence rates have been reported to date, with no clear classification according to the time of onset of such arrhythmias. We determined the incidence of AF/AFL using the time of onset after HT and analyzed the associated risk factors and outcomes. We performed a retrospective study of 228 HT recipients (March 1996 to July 2007), including donor and recipient demographics, gender mismatch, ischemia time, surgical anastomosis, time of onset of AF/AFL, acute cellular rejection, left ventricular systolic function, and all-cause mortality. The mean age of the donors (81% men) was 30 +/- 12 years and of the recipients (78% men) was 53 +/- 11 years. AF/AFL occurred in 45 patients (20%): 24 (11%) in the first 30 days, 10 (4%) within the 31 days to 1 year, and 11 (5%) after 1 year. When the patients with AF/AFL were compared to those with sinus rhythm, the significant difference was the older mean age of the donors (p = 0.001) and the recipients (p = 0.02). The all-cause mortality rate was 43% for those with AF/AFL compared to 23% for those with sinus rhythm (hazard ratio 2.45; 95% confidence interval 1.2 to 4.8), mostly driven by the greater mortality in the later-onset AF/AFL group (>30 days after HT). In conclusion, AF and AFL have an incidence of 20% after HT and are associated with increased overall mortality compared to that in patients in sinus rhythm. AF/AFL is more common within the first 30 days of HT, with an overall incidence of 20%. Older donor and recipient age is a risk factor associated with AF/AFL.

Emotional adjustment 5 years after heart transplant: A multisite study

Objective: To assess levels of and factors associated with depression and negative affect 5 years after heart transplant (HT). Participants: 370 adults 5 years post-HT. Outcome Measures: Cardiac Depression Scale and the Positive and Negative Affect Schedule (PANAS). Research Method: Stepwise multiple regression analyses were used to test 32 potential demographic, medical, functional, and psychosocial factors in adjustment. Results: Predictor variables accounted for 53% of the variance of depression scores and 45% of the variance of PANAS negative affect scores. The best predictors (p .001) for depression were neurological symptoms, younger age, lower recreational functioning, and lower satisfaction with emotional support, and the best predictors for negative affect were neurological symptoms, lower mobility functioning, and perceived uncertainty about health. Depression scores were lower than norms for nontransplanted heart failure patients, and negative affect levels were comparable to those of the general population. Conclusions: The findings indicate normal long-term adjustment among HT recipients. Several factors associated with negative emotions, including younger age, have not been identified in previous research.

Outcomes of Bare Metal versus Drug-eluting Stents in Allograft Vasculopathy

BACKGROUND Because of improved outcomes with drug-eluting stents (DES), we examined angiographic and clinical outcomes of bare metal stents (BMS) vs DES for discrete lesions in chronic allograft vasculopathy. METHODS Heart transplant patients who underwent percutaneous coronary intervention were divided into one of two groups: BMS or DES. Baseline clinical characteristics, rejection episodes and procedural details were compared. Distal arteriopathy was qualitatively compared using the Gao score. End-points included angiographic in-stent restenosis, acute coronary syndrome (ACS), ST-elevation myocardial infarction, heart failure admissions and cardiac death at 1 year. Students t-test, chi-square test and the Mann-Whitney U-test were utilized to assess the results. Correlations were assessed using Pearsons correlation coefficient. RESULTS Forty-two patients with 80 stents (56 DES, 24 BMS) were identified. Baseline clinical characteristics, immunosuppression regimen, cardiac risk factors, frequency of rejection and procedural details were similar. Distal arteriopathy was similar (p = 0.374), suggesting equally advanced vasculopathy. Twenty-nine patients (69%) and 46 lesions (58%) were available at 1 year for clinical and angiographic follow-up. One-year diameter stenosis (26.1 +/- 21.3% vs 31.7 +/- 38.3%; p = 0.602) and binary restenosis (22.6% vs 22.7%; p = 0.774) rates were similar for DES and BMS, respectively. There were no ST-elevation infarctions; ACS [9 (16%) vs 5 (21%) p = 0.638] and cardiac death (2 in both groups) were similar for DES and BMS, respectively. Heart failure admissions were more frequent in the DES group [18 (32%) vs 5 (21%); p = 0.016]. No clinical predictors were identified. CONCLUSIONS In-stent stenosis, ACS and cardiac death at 1 year were similar for DES and BMS. The milieu of systemic immunosuppression in heart transplant decreases the advantages of DES in allograft vasculopathy.

Factors associated with stress and coping at 5 and 10 years after heart transplantation.

BACKGROUND Heart transplant-related stressors and coping are related to poor outcomes early after transplant. The purposes of our study were to (1) identify the most frequent and bothersome stressors and most used and effective coping strategies and (2) compare the most frequent and bothersome stresses and most used and effective coping styles between patients at 5 and 10 years after heart transplantation. We also examined differences in coping styles by patient characteristics and factors associated with frequency and intensity of stress at 5 and 10 years after heart transplantation. METHODS This report is a secondary analysis of data from a prospective, multisite study of quality of life outcomes. Data are from separate cohorts of 199 patients at 5 years after transplant and 98 patients at 10 years. Patients completed the Heart Transplant Stressor Scale and Jalowiec Coping Scale. Statistical analyses included frequencies, measures of central tendency, t-tests, chi-square, and generalized linear models. RESULTS At 5 and 10 years after heart transplantation, the most bothersome stressors were regarding work, school, and financial issues. Patients who were 10 years after transplant reported less stress, similar stress intensity, and less use and perceived effectiveness of negative coping than patients who were 5 years after transplant. Long-term after transplant, demographic characteristics, psychologic problems, negative coping, and clinical factors were related to stress frequency and/or intensity. CONCLUSIONS Heart transplant-related stress occurs long-term after surgery. Types of transplant-related stress and factors related to stress confirm the importance of ongoing psychologic and clinical support after heart transplantation.

Does heart transplantation confer additional benefit over medical therapy to patients who have waited >6 months for heart transplantation?

OBJECTIVES This study compared the survival of patients with heart failure who have waited > 6 months for heart transplantation with that patients who undergo heart transplantation after a similarly prolonged waiting period. BACKGROUND There are little data describing outcome in patients with severe heart failure who have waited for extended periods of time on the heart transplant waiting list. METHODS Sixty-three consecutive patients who spent > 6 months on the heart transplant waiting list were examined. Mean (+/- SD) age was 53 +/- 9 years, mean left ventricular ejection fraction was 19 +/- 6%, and all were taking digoxin and diuretic and vasodilator agents. Patients who underwent transplantation during the follow-up period were censored from the pretransplantation analysis, and their survival was examined as part of the posttransplantation phase of the study. RESULTS Of the 63 original patients examined, 25 underwent transplantation, 10 during inotropic or mechanical circulatory support. The pretransplantation mortality rate was 6% at 6 months after the 6-month milestone on the waiting list, 12% at 12 months and 22% at 18 months. The posttransplantation mortality rate was 5% at 6 months, 10% at 12 months and 24% at 18 months. There were no differences in survival at any time between the two phases of the study. CONCLUSIONS Survival of patients who have survived > 6 months on the heart transplant waiting list is generally good. Although heart transplantation did not appear to confer additional survival advantage over medical therapy, a large proportion of the patients who underwent transplantation were critically ill at the time of transplantation and would undoubtedly have died of progressive heart failure had they not undergone transplantation. We conclude that heart transplantation should still be considered a therapeutic alternative in patients with heart failure even after a prolonged waiting period on the heart transplant waiting list.

Serine 910 Phosphorylation of Focal Adhesion Kinase is Critical for Sarcomere Reorganization In Cardiomyocyte Hypertrophy

AIMS Tyrosine-phosphorylated focal adhesion kinase (FAK) is required for the hypertrophic response of cardiomyocytes to growth factors and mechanical load, but the role of FAK serine phosphorylation in this process is unknown. The aims of the present study were to characterize FAK serine phosphorylation in cultured neonatal rat ventricular myocytes (NRVM), analyse its functional significance during hypertrophic signalling, and examine its potential role in the pathogenesis of human dilated cardiomyopathy (DCM). METHODS AND RESULTS Endothelin-1 (ET-1) and other hypertrophic factors induced a time- and dose-dependent increase in FAK-S910 phosphorylation. ET-1-induced FAK-S910 phosphorylation required ET(A)R-dependent activation of PKCδ and Src via parallel Raf-1 → MEK1/2 → ERK1/2 and MEK5 → ERK5 signalling pathways. Replication-deficient adenoviruses expressing wild-type (WT) FAK and a non-phosphorylatable, S910A-FAK mutant were then used to examine the functional significance of FAK-S910 phosphorylation. Unlike WT-FAK, S910A-FAK increased the half-life of GFP-tagged paxillin within costameres (as determined by total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching) and increased the steady-state FAK-paxillin interaction (as determined by co-immunoprecipitation and western blotting). These alterations resulted in reduced NRVM sarcomere reorganization and cell spreading. Finally, we found that FAK was serine-phosphorylated at multiple sites in non-failing, human left ventricular tissue. FAK-S910 phosphorylation and ERK5 expression were dramatically reduced in patients undergoing heart transplantation for end-stage DCM. CONCLUSION FAK undergoes S910 phosphorylation via PKCδ and Src-dependent pathways that are important for cell spreading and sarcomere reorganization. Reduced FAK-S910 phosphorylation may contribute to sarcomere disorganization in DCM.

The Value of Psychosocial Factors in Patient Selection and Outcomes after Heart Transplantation

Heart transplantation remains the gold standard treatment for advanced heart failure, although its use is limited by donor organ availability. To ensure that the rare resource of a donor heart is allocated appropriately, the evaluation of the heart transplant candidates includes extensive medical and psychosocial assessments. These psychosocial factors are critically important to understand pre-heart transplant because it is known that psychosocial evaluation and psychosocial comorbidities have a strong association with post-heart transplant outcomes. The critical factors to assess are psychological functioning, adherence to medical recommendations, and social support. These factors are likely inter-related and have been shown to have an effect on the health-related quality of life and overall survival. Recently, new tools have been developed to standardize the evaluation process. In this review, we will discuss the tools available to assess psychosocial factors in the transplant candidate and discuss the role these factors have on post-heart transplant outcomes.