I. Vallejos

Initial experience with bosentan therapy in patients considered ineligible for heart transplantation because of severe pulmonary hypertension

Abstract: Background: Pre‐operative elevated pulmonary vascular resistance (PVR) has been associated with increased right ventricular failure and mortality after heart transplantation. The aim of this study was to assess the efficacy of bosentan, an oral endothelin‐receptor antagonist, to reduce PVR in patients considered ineligible for heart transplantation because of severe pulmonary hypertension.

Long-term prognostic value of elevated heart rate one year after heart transplantation.

BACKGROUND Elevated heart rate (HR) is associated with adverse cardiovascular outcome in the general population and in patients with cardiovascular disease. Elevated HR due to graft denervation is often found in heart transplantation (HTx) patients; the effect on graft survival and vasculopathy is unclear. Thus, the aim of this study was to evaluate the role of elevated HR at 12 months post-HTx and its power to predict HTx long-term outcome. METHODS We evaluated retrospectively a prospective database of 312 patients undergoing HTx at two centers. HR was registered at 12 months post-HTx. The median HR was used as a cutoff point. Cox regression analysis was performed with variables known to be clinically relevant to mortality and those selected from the univariate analysis. RESULTS During a mean follow-up of 5.5 ± 2.8 years there were 58 deaths (19%). Patients with a HR ≥ 90 bpm (median HR) at 12 months had an increased risk for all-cause mortality (Hazard Ratio=2.4, 95% CI 1.2 to 4.5, p=0.009) and mortality related to coronary allograft vasculopathy (CAV) (Hazard Ratio=3.0, 95% CI 1.25-7.14, p=0.01). Multivariate analysis showed that a HR ≥ 90 bpm independently predicted mortality (HR 3.2, 95% CI 1.4-7.1, p=0.004). CONCLUSIONS Elevated HR measured at 12 months after HTx is an independent predictor of all-cause mortality in HTx recipients. A HR ≥ 90 bpm identifies a group of patients at high risk of death and CAV-related mortality at mid- to long-term.

Decreased Expression of Thrombospondin-1 in Failing Hearts May Favor Ventricular Remodeling

BACKGROUND Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis and an activator of tissue transforming growth factor-beta1 (TGF-beta1). Analyses using genetically modified mice suggested that TSP-1 may play a protective role to prevent infiltration and tissue remodeling responses after myocardial infarction. The expression levels of TSP-1 and their putative role in ventricular remodeling have not been determined in patients with heart failure (HF). MATERIALS AND METHODS We analyzed the expression of TSP-1 and TGF-beta1 mRNA in myocardial biopsies from 34 subjects with end-stage HF undergoing heart transplantation and 13 healthy controls from heart donors. Among total RNA extracted from the left ventricle, 1 microg was retrotranscribed and mRNA expression levels were quantified by real-time polymerase chain reaction (PCR). RESULTS The mean age of subjects was 54 +/- 2 years; mean ejection fraction, 21 +/- 5%; end-diastolic diameter and end-systolic diameter, 73 +/- 10 and 61 +/- 11 mm, respectively. TSP-1 mRNA expression in ventricular tissue from HF patients was lower (159.04 +/- 14.55 ng-equivalents [ng-equiv]) than in controls (234 +/- 30.66 ng-equiv; P < .05). Tissue from HF subjects also showed lower levels of TGF-beta1 (68.42 +/- 4.36 vs 80.58 +/- 5.26 ng-equiv; P < .05). TSP-1 mRNA levels correlated positively with TGF-beta1 (P = .001; R(2) = .2), and lower TSP-1 mRNA levels were observed with increasing left ventricular diameters. CONCLUSIONS Patients with end-stage HF show decreased TSP-1 mRNA levels, which agrees with published results showing lower circulating TSP-1. Ventricular dilatation observed in these patients may be related to lower expression of TSP-1. Surprisingly, TGF-beta1 mRNA levels were lower in failing hearts, which suggested that fibrogenesis takes place in earlier phases of HF.

Assessment of Peripheral Endothelial-Dependent Vasodilatation Within the First Year After Heart Transplantation

BACKGROUND Peripheral endothelial dysfunction (ED) has been found in patients with severe heart failure. Whether ED improves after heart transplantation (HTx) is still a matter of controversy. METHODS Forearm endothelium-dependent vasoreactivity was assessed in 40 patients after HTx. Flow-mediated vasodilatation (FMD) was measured by high-resolution brachial artery ultrasound to assess endothelial function at 1, 6, and 12 months after HTx. Cardiac allograft vasculopathy (CAV) was assessed by coronary angiography at 1 and 12 months and by intravascular ultrasound (IVUS) at 1 year. RESULTS Mean FMD at 1 month was 1.9% +/- 2.6%, improving to 3.3% +/- 3.2% at 6 months (p < 0.005) and to 5.1% +/- 3.4% at 1 year (p < 0.0001). FMD was significantly impaired in 33 patients (82%) at 1 month, in 27 (67%) at 6 months, and in 19 (47%) at 1 year after HTx. CAV was diagnosed by IVUS in 19 patients (63%) at 1 year. Patients without peripheral ED at 1 month had lower incidence of increased intimal thickness of 0.5 mm or more at 1 year after HTx (20% vs 75%, p < 0.01). CONCLUSIONS Impairment of peripheral FMD was highly prevalent soon after HTx and was present in nearly 50% of patients at 1 year. Patients without peripheral ED at 1 month were associated with lower probability of CAV. Although more studies are needed, the evaluation of peripheral endothelial function at 1 month after HTx could be potentially useful to identify patients at lower risk of CAV.

Bosentan in heart transplantation candidates with severe pulmonary hypertension: efficacy, safety and outcome after transplantation

Increased pulmonary vascular resistance (PVR) is associated with increased right ventricular failure and mortality after heart transplantation.

Outcome After Steroid Withdrawal in Heart Transplantation

BACKGROUND There is a lack of consensus and insufficient data to assess the impact of late steroid withdrawal after heart transplantation (HTx). The aim of the study was to investigate the security and feasibility of corticosteroid withdrawal at 1 year after transplantation. METHODS AND RESULTS Steroid withdrawal was attempted after at least 12 months of treatment in 86 HTx patients who fulfilled the criteria. At 1 and 3 months after drug discontinuation, patients underwent 2 endomyocardial biopsies (EMB). After a mean follow-up of 25 +/- 13 months, 63% of the patients remained steroid free. In 30 patients (35%) corticosteroids were reinitiated, in 15 cases because of acute rejection (7%), 5 (6%) because of worsening renal function, 5 (6%) because of malignancy, 3 (4%) because of adverse effects of immunosuppressive drugs, and 2 because of severe allograft coronary artery disease. Four patients (5%) died after drug discontinuation. There was a significant decrease in total cholesterol (198 +/- 35 to 181 +/- 38 mg/dL; P < .001) and low-density lipoprotain (LDL) cholesterol levels (113 +/- 30 to 105 +/- 30 mg/dL; P < .001). There were no differences in mortality between patients with and without corticosteroids. CONCLUSION Steroid withdrawal is feasible and safe in HTx patients. In our study, it was successfully maintained in 63% of the patients. EMB is helpful to identify patients with acute rejection at 1 and 3 months after withdrawal. Short- to mid-term metabolic benefits are significant reductions in serum total and LDL cholesterol.

Primary immunosuppression and outcome differences after heart transplantation: tacrolimus versus cyclosporine.

BACKGROUND The superiority of tacrolimus (Tac) as primary immunosuppression for heart transplantation (HT) compared with cyclosporine (CsA) is still under debate. Outcomes of comparison studies are not consistent; the duration of these studies has been limited. The aim of this study was to evaluate long-term outcomes of patients undergoing HT based on primary immunosuppression regime. METHODS AND RESULTS We analyzed a single-center registry of all HT patients between 1998 and 2009, comparing outcomes based on primary immunosuppressions (Tac or CsA). Patients who died before starting immunosuppression were excluded. A total of 197 patients entered the study; 103 received Tac and 94 CsA. There were no differences between groups in baseline characteristics, United Network for Organ Sharing status 1A or ventricular assist device use, except for ischemia time (195 ± 50 min in Tac group vs 182 ± 55 min in CsA; P = .08) and days on waiting list (164 ± 155 vs 100 ± 73; P < .001). After mean follow-ups of 4.5 ± 2.3 years in the Tac group and 6.3 ± 4.3 years in the CsA group, there were 19 and 36 deaths, respectively. Kaplan-Meier analysis showed increased survival for the Tac group (log rank P = .04). Tac also was significantly superior to CsA regarding mortality (relative risk 0.55; 95% confidence interval, 0.31-0.98; P = .04). CONCLUSIONS In our series the use of tacrolimus resulted in improved long-term survival compared with cyclosporine. At 1-year follow-up, there were no differences in acute rejection episodes or the appearance of vasculopathy.