Exercise performance increases coincident to body weight over the first two years following cardiac transplantation.

BACKGROUND: To determine whether exercise performance changed over time once patients stabilized after heart transplantation, metabolic stress testing was performed in patients one and two yr post-heart transplantation. METHODS: The patient cohort includes those transplanted in our program who survived at least two yr and were able to perform metabolic stress tests during their one- and two-yr annual evaluations. Standard stress test parameters were assessed, including weight, body surface area, rest and exercise heart rate (HR) and blood pressure (BP), exercise time, anaerobic threshold (AT), and maximum VO2 (MVO2). Ejection fraction by echo was also collected. Each patient served as their own control and data were compared using paired t-testing. RESULTS: Fifty patients were included in the cohort, 48 of whom were able to exercise to at least AT. Patient weight increased from year 1 to year 2 (82.4 ± 15.1 vs. 85.0 ± 17.0 kg, p = 0.035). Systolic BP increased approximately 40 mmHg with exercise with no change in diastolic BP, and there was no difference between years 1 and 2. HR increased approximately 25 bpm with exercise. There was no difference in resting HR but exercise HR increased significantly between yrs (148 ± 15 bpm vs. 154 ± 18 bpm, p = 0.017). Both VO2 at AT and MVO2 increased significantly from year 1 to year 2 (1116 ± 347 mL/min vs. 1192 ± 313 mL/min, p = 0.049 and 1523 ± 337 mL/min vs. 1599 ± 356 mL/min, p = 0.012, respectively) but when corrected for body weight, there were no differences (VO2-AT 13.6 ± 4.0 mL/kg/min vs. 14.0 ± 4.0 mL/kg/min; MVO2 18.7 ± 4.2 mL/kg/min vs. 18.8 ± 4.1 mL/kg/min). All other measured parameters were not different. There was a weak but statistically significant correlation between change in peak HR and change in VO2 at AT between one and two yr post-transplantation (r = 0.30, p = 0.04). CONCLUSIONS: We conclude that exercise performance as measured by VO2 can increase over time post-heart transplantation and in our cohort appears to be related to both an increase in body weight and an increase in HR from years 1 and 2.

Pre-orthotopic heart transplant estimated glomerular filtration rate predicts post-transplant mortality and renal outcomes: An analysis of the UNOS database.

BACKGROUND: Pre-orthotopic heart (OHT) serum creatinine correlates with post-OHT outcomes, but there is limited information on the relationship between pre-OHT estimated glomerular filtration rate (eGFR) and adjusted short- and long-term survival and renal outcomes post-OHT. METHODS: Using the United Network of Organ Sharing (UNOS) database we estimated pre-OHT eGFR using the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in patients aged ≥18 years who underwent OHT between 1988 and 2013. Patients were stratified into 5 eGFR categories (≥90, 60 to 89, 45 to 59, 30 to 44 and <30 ml/min/1.73 m2) using each equation. The primary outcome was to determine whether pre-OHT eGFR independently predicted post-OHT mortality. RESULTS: A total of 30,090 patients were included in the study; of these, 46.1% and 39.9% had an eGFR <60 ml/min/1.73 m2 by MDRD and CKD-EPI, respectively. Compared with eGFR ≥90 ml/min/1.73 m2, the adjusted hazard ratio of mortality was 1.09 (95% confidence interval [CI] 1.02 to 1.26) for eGFR 45 to 59 ml/min/1.73 m2, 1.22 (95% CI -1.23 to 1.31) for eGFR 30 to 44 ml/min/1.73 m2 and 1.55 (95% CI 1.41 to 1.70) for eGFR <30 ml/min/1.73 m2 by MDRD. There was no advantage for CKD-EPI over MDRD in determining post-OHT mortality. Pre-OHT eGFR by either equation was predictive of post-OHT end-stage renal disease (ESRD) and the need for kidney transplantation, with the highest risk in those with pre-OHT eGFR <30 ml/min/1.73 m2 by either equation. CONCLUSIONS: Pre-OHT eGFR was independently associated with mortality, ESRD and kidney transplantation after OHT. There was no advantage of CKD-EPI over MDRD in determining post-OHT mortality or renal outcomes.

Neurological events during long-term mechanical circulatory support for heart failure: the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) experience.

BACKGROUND: Progression of heart failure can lead to cardiac transplantation, but when patients are ineligible, long-term mechanical circulatory support may improve survival. The REMATCH trial showed that left ventricular assist devices (LVADs) prolonged survival in patients with end-stage disease, but with a significant number of adverse events. We report on the neurological outcomes in the REMATCH trial. METHODS AND RESULTS: We examined new neurological events in the 129 patients randomized to either LVAD placement (n=68) or medical management (n=61), classified as stroke, transient ischemic attack, toxic-metabolic encephalopathy, and other. There were 46 neurological events: 42 in 30 LVAD patients and 4 in 4 patients in the medical arm (chi2, 30/68 versus 4/61, P<0.001). Sixteen percent of the LVAD patients had a stroke, with a rate of 0.19 per year (95% CI, 0.10 to 0.33), many occurring in the postoperative period. The stroke rate in the medical arm was 0.052. A Kaplan-Meier survival analysis showed a 44% reduction in the risk of stroke or death in the LVAD group versus the optimal medical group (P=0.002). The mean interval from implantation to stroke was 221.8 days (+/-70.4 days). History of stroke, age, and sepsis were not stroke risk factors in the LVAD group. CONCLUSIONS: Fewer than half of the patients in the LVAD group had a neurological event, and there were few neurological deaths. Survival analysis combining stroke or death demonstrated a significant benefit for long-term circulatory support with an LVAD over medical therapy. Future trials will need to address prospectively all neurological outcomes, including neurocognitive function, and the role of long-term neuroprotection.

Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine.

BACKGROUND: Long-term treatment of heart transplantation recipients with cyclosporine (CsA) results in chronic nephrotoxic effects, which frequently lead to progressive renal failure. Transforming growth factor (TGF)-beta and other fibrogenic molecules are leading candidates for these effects, because CsA is known to induce TGF-beta. In this study we compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases, and tissue inhibitors of metalloproteinases in kidneys from recipients of heterotopic heart transplants treated with CsA for 30 and 180 days. METHODS: Using a clinically relevant experimental rodent model (strain combination Wistar Furth [RT1u] into Lewis [RT1l]), heterotopic heart transplantation was performed, creating disparate cardiac allografts. The transplant study population was divided into three groups: controls and those receiving CsA immunosuppression therapy to maintain graft survival for 30-day and 180-day periods. Comparisons were made of intrarenal expression of TGF-beta, collagen, fibronectin, metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of MMP-2, using reverse transcriptase-polymerase chain reaction. Intrarenal expression of TGF-beta protein was also compared using immunochemical staining technique, and circulating levels of TGF-beta protein were quantified by ELISA. RESULTS: Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9, and tissue inhibitor of MMP-2 was significantly increased in rats treated with CsA for 180 days compared with untreated rats and those treated for 30 days. Circulating levels and intrarenal expression of TGF-beta were also significantly increased in rats treated for 180 days. CONCLUSION: Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.

Alloimmune induction of endothelial cell-derived interferon-gamma-inducible chemokines.

BACKGROUND: The interaction between host lymphocytes and endothelial cells on the transplanted organ is believed to play an important role in acute and chronic graft rejection. Trafficking and recruitment of lymphocytes to the site of inflammation is known to be controlled by several cytokines and chemokines. It is unclear whether endothelial cells themselves can be a source of inflammatory chemoattractant molecules on alloimmune induction. METHODS: Using a semiquantitative polymerase chain reaction method, the authors analyzed the expression of chemokine mRNA coding for interferon (IFN)-gamma-induced protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) in a pool of human aortic endothelial cells. Both of these chemokines are known to be induced by IFN-gamma. Endothelial cell-derived chemokine mRNA was assayed at rest, after IFN-gamma activation, and after co-culture with allogeneic peripheral blood mononuclear cells (PBMC) from normal blood donors with and without a monoclonal antibody to IFN-gamma. Finally, protein release into the media was assayed using an enzyme-linked immunosorbent assay to IP-10. RESULTS: Mig and IP-10 were expressed in human endothelial cells both after IFN-gamma treatment and after PBMC co-culture. Furthermore, the expression of both of these endothelial cell-derived chemokines was dependent on IFN-gamma because PBMC-induced expression was blocked with anti-IFN-gamma. IP-10 levels in the endothelial cell supernatant increased from a baseline of 13.4+/-10.8 pg/mL to 299.5+/-13.4 pg/mL (P<0.0001) with exposure to PBMC and was likewise inhibited by anti-IFN-gamma A-b (33.8+/-17.8 pg/mL). CONCLUSIONS: Vascular endothelial cells are capable of producing inflammatory chemokines when activated and potentially serve to amplify the allogeneic response.