Eugenia Raichlin

Conversion to Sirolimus as Primary Immunosuppression Attenuates the Progression of Allograft Vasculopathy After Cardiac Transplantation

Background— We investigated the potential of conversion to sirolimus (SRL) as a primary immunosuppressant in attenuating cardiac allograft vasculopathy progression. Methods and Results— Twenty-nine cardiac transplant recipients were converted to SRL 3.8±3.4 years after transplantation with complete calcineurin inhibitor (CNI) withdrawal. Secondary immunosuppressants (azathioprine or mycophenolate) and steroids remained unchanged. Forty patients (controls) 4.8±4.0 years from transplantation were maintained on CNIs. Three-dimensional intravascular ultrasound studies were performed at baseline and 12.1±2.6 months later. Mean plaque (media and intima) volume (PV) and plaque index (PI) (PV/vessel volume percent) increased significantly in the CNI group (1.28±2.86 mm3/mm, P=0.004; and 6±8%, P=0.0001) but not in the SRL group (0.1±1.13 mm3/mm, P=0.63; and 0.1±8%, P=0.94). In patients enrolled within 2 years after transplantation, the increases in PV (0.06±1.06 versus 1.77±1.65 mm3/mm; P=0.0081) and PI (0±9% versus 10±8%; P=0.0145) were smaller in the SRL group (n=11) than in the CNI (n=12) group. In patients enrolled ≥2 years after transplantation, the increase in PI was less in the SRL group compared with the CNI group (0.1±6.5% versus 5±8%; P=0.033), but changes in PV did not differ significantly. Treatment with azathioprine or mycophenolate did not affect PV or PI in either the SRL group (PV: 0.22±0.66 versus 0.05±1.45 mm3/mm, P=0.46; PI: 1.5±6% versus −1.6±8.5%, P=0.29) or the CNI group (PV: 1.42±1.39 versus 1.06±2.28 mm3/mm, P=0.49; PI: 7.8±8.7% versus 4.8±7.3%, P=0.23). Conclusions— Substituting CNI with SRL as primary immunosuppression attenuates cardiac allograft vasculopathy progression.

Long-Term Administration of Endothelin Receptor Antagonist Improves Coronary Endothelial Function in Patients With Early Atherosclerosis

Background— Endothelin (ET-1) is one of the most potent vasoconstrictors and plays a seminal role in the pathogenesis of atherosclerosis. The present study was designed to test the hypothesis that long-term treatment with an endothelin-A (ETA) receptor antagonist improves coronary endothelial function in patients with early coronary atherosclerosis. Methods and Results— Forty-seven patients with multiple cardiovascular risk factors, nonobstructive coronary artery disease, and coronary endothelial dysfunction were randomized in a double-blind manner to either the ETA receptor antagonist atrasentan (10 mg) or placebo for 6 months. Coronary endothelium-dependent vasodilation was examined by infusing acetylcholine (10−6 to 10−4 mol/L) in the left anterior descending coronary artery. NG-monomethyl-l-arginine was administered to a subgroup of patients. Endothelium-independent coronary flow reserve was examined by use of intracoronary adenosine and nitroglycerin. Baseline characteristics and incidence of adverse effects were similar between the 2 groups. There was a significant improvement in percent change of coronary blood flow in response to acetylcholine at 6 months from baseline in the atrasentan group compared with the placebo group (39.67%, 95% confidence interval 23.23% to 68.21%, versus −2.22%, 95% confidence interval −27.37% to 15.28%; P<0.001). No significant difference in the percent change of coronary artery diameter or change in coronary flow reserve was demonstrated. Coronary blood flow, coronary artery diameter, and the effect of NG-monomethyl-l-arginine were similar between the groups at baseline and at 6 months. Conclusions— This study demonstrates that 6-month treatment with atrasentan improves coronary microvascular endothelial function and supports the role of the endogenous endothelin system in the regulation of endothelial function in early atherosclerosis in humans. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271492.

Combined heart and liver transplantation: A single-center experience

Background. Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx. Methods. Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1). Results. Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT ≥grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6±53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity. Conclusion. Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.

Acute Cellular Rejection and the Subsequent Development of Allograft Vasculopathy After Cardiac Transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development. METHODS The study comprised 252 cardiac transplant recipients (mean age, 49.02 +/- 17.05 years; mean follow-up, 7.61 +/- 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R = 1, 2R = 2, 3R = 3) and any rejection score (ARS; calculated as 0R = 0, 1R = 1, 2R = 1; 3R = 1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months. RESULTS In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99-3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01-4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44-6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset (p = 0.018). There was direct correlation (r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months. CONCLUSION Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.

Sirolimus as Primary Immunosuppression Attenuates Allograft Vasculopathy With Improved Late Survival and Decreased Cardiac Events After Cardiac Transplantation

Background— We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. Methods and Results— Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). Conclusions— Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Replacement of calcineurin-inhibitors with sirolimus as primary immunosuppression in stable cardiac transplant recipients

Background. Calcineurin-inhibitor (CNI) nephrotoxicity is a major cause of morbidity and mortality after cardiac transplantation. The aim of this study was to assess over 2 years the safety and effect on renal function of withdrawal of CNI immunosuppression and replacement with sirolimus (SRL) in stable cardiac transplant recipients. Methods. CNI was substituted with SRL in 78 cardiac transplant recipients (SRL group) of whom 58 (group A) had CNI-induced renal impairment (glomerular filtration rate [GFR] <50 mL/min) and 20 (group B) had preserved renal function (GFR >50 mL/min). Fifty-one patients (CNI group) with renal impairment (GFR ≤50 mL/min) maintained on CNI served as controls. Secondary immunosuppressants were unchanged. Results. In the SRL group, GFR increased from 47.0±18.0 to 61.2±22.2 ml/min (P=0.0001) 24 months after SRL initiation. In Group A, GFR increased from 40.5±12.7 to 53.9±19.8 mL/min (P<0.0001). In Group B, GFR increased marginally from 67.2±15.8 to 83.5±27.8 mL/min (P=0.10). In the CNI group, GFR declined from 40.5±14.0 mL/min to 36.4±12.5 mL/min (P=0.23) after 24 months of follow up. There was no significant difference in cardiac rejection or cardiac allograft function. In SRL group, proteinuria increased from 299±622 mg/day to 517±795 mg/day (P=0.0002) 12 months after SRL initiation and then stabilized; it did not differ from CNI group at 24 months (637±806 vs. 514±744 mg/day, P=0.39). Uric acid decreased from 7.6±2.4 to 6.2±1.9 mg/dL (P=0.0007) in the SRL group. Conclusions. Graduated substitution of CNI with SRL in cardiac transplant recipients is safe and improves renal function, without cardiac compromise.

Diastolic dysfunction in patients with end-stage liver disease is associated with development of heart failure early after liver transplantation.

Background Liver transplantation (LTx) is a life-saving treatment of end-stage liver disease. Cardiac complications including heart failure (HF) are among the leading causes of death after LTx. The Aim The aim is to identify clinical and echocardiographic predictors of developing HF after LTx. Methods Patients who underwent LTx at the University of Nebraska Medical Center (UNMC) between January 2001 and January 2009 and had echocardiographic study before and within 6 months after transplantation were identified. Patients with coronary artery disease (>70% lesion) were excluded. HF after LTx was defined by clinical signs, symptoms, radiographic evidence of pulmonary congestion, and echocardiographic evidence of left ventricular dysfunction (left ventricle ejection fraction <50%). Results Among 107 patients (presented as mean age [SD], 55 [10] years; male, 70%) who met the inclusion criteria, 26 (24%) patients developed HF after LTx. The pre-LTx left ventricle ejection fraction did not differ between the HF (69 [7]) and the control groups (69 [7] vs. 67 [6], P=0.30). However, pre-LTx elevation of early mitral inflow velocity/mitral annular velocity (P=0.02), increased left atrial volume index (P=0.05), and lower mean arterial pressure (P=0.03) were predictors of HF after LTx in multivariate analysis. Early mitral inflow velocity/mitral annular velocity greater than 10 and left atrial volume index 40 mL/m2 or more were associated with a 3.4-fold (confidence interval, 1.2–9.4; P=0.017) and 2.9-fold (confidence interval, 1.1–7.5; P=0.03) increase in risk of development of HF after LTx, respectively. Conclusions This study suggests that elevated markers of diastolic dysfunction during pre-LTx echocardiographic evaluation are associated with an excess risk of HF and may predict post-LTx survival.

Normal left ventricular mechanical function and synchrony values by speckle-tracking echocardiography in the transplanted heart with normal ejection fraction.

BACKGROUND The purpose of this study was to describe the normal values for strain (S), systolic strain rate (SRs) and synchrony by speckle-tracking echocardiography (STE) in heart transplant (HTx) recipients who had normal left ventricular ejection fraction (LVEF) and no clinically significant complications. METHODS We evaluated S and SRs in 40 HTx patients at 1 year after transplant and 82 healthy controls with STE using velocity vector imaging. RESULTS Mean (SD) global longitudinal S and SRs, respectively, were lower in the transplant group compared with controls [-13.43% (2.39%) vs -17.28% (2.30%), p < 0.001; -0.83 (0.15) s(-1) vs -0.96 (0.13) s(-1), p < 0.001]. These variables were good for differentiating between groups: area under the curve was 0.88 for S and 0.73 for SRs. The differences remained significant after adjustment for other clinical variables. Global circumferential S and SRs were similar between groups. The standard deviation of the global longitudinal S time to peak of the 16 segments for HTx and control groups, respectively, was 41.67 (13.53) milliseconds vs 32.57 (12.81) milliseconds (p < 0.001). With 58.2 milliseconds as a cutoff value to define left ventricular synchrony, only 3 (8%) of the HTx patients and 4 (5%) of the control subjects were above that value (p = 0.6). CONCLUSION To our knowledge, this is the first study describing normal values for S and SRs and synchrony by STE in a HTx population with normal LVEF: longitudinal S and SRs were reduced; circumferential deformation indexes were normal; and left ventricular synchrony was preserved.

Efficacy and Safety of Atrasentan in Patients With Cardiovascular Risk and Early Atherosclerosis

Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92±10 to 80±10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93±10 and 92±11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.

Device Therapy and Cardiac Transplantation for End-Stage Heart Failure

The prevalence of heart failure is increasing, and the prognosis of end-stage heart failure remains dismal. The gold-standard therapy in end-stage heart failure remains cardiac transplantation at the present time, but there is a great excess of eligible candidates compared with the number of donor organs. Advances in mechanical support, the development of the left ventricular assist device (LVAD), and the total artificial heart has reduced mortality and morbidity in patients awaiting transplantation, and LVADs are now approved as an strategy for destination therapy. Miniaturization, increased device durability, and complete implantability may render LVADs an option in earlier stages of heart failure, as a bridge to myocardial recovery or even as a viable alternative to transplantation. Alternative strategies under investigation are cell therapy and xenotransplantation. In the present article, current and potential future therapeutic options in end-stage heart failure are reviewed.