Hasin, Tal

BACKGROUND: The immunologic risk associated with preformed donor-specific allo-antibodies (DSA) against human leukocyte antigens (HLA) in heart transplant (HTX) recipients is unclear. The goal of this study was to evaluate potential role of DSA on the progression of cardiac allograft vasculopathy (CAV) in HTX recipients. METHODS: The presence of DSA against HLA was evaluated using solid phase Single Antigen Bead assay (One Lambda, Inc., Canoga Park, CA; Luminex platform) before transplant in 35 HTX recipients. Using alloantibody specification analysis, 11% (4/35) and 20% (7/35) had DSA against donor Class I and II HLA respectively including the one patient who had both (DSA I & II+) . 71% (25/35) of patients had no demonstrable DSA (DSA-). All patients had negative cytotoxicity cross match. Baseline three-dimensional intravascular ultrasound studies (3D IVUS) were performed at 1.0 [0.18, 1.4] year after transplant. Follow up 3D IVUS exams were performed 0.92 [0.85, 1.04] years after the baseline exam. RESULTS: The increase in mean plaque (media and intima) volume (PV) was accelerated in the DSA II+ group as compared to the DSA- group (0.87±1.9 mm (3)/mm vs. 0.16±1.8 mm (3)/mm) but the vessel volume index (follow up vessel volume/ baseline vessel volume) was similar between groups (1.08±0.5 vs. 1.09± 0.4; p=0.9). Plaque index (PI) (PV/vessel volume x 100 [%]) increased significantly in the DSA II+ group (17.9±6.3%) but not in the DSA- group (-13.6±13.2%, P=0.02). None of these values were significant in the DSA I+ only group. Treatment with Sirolimus did not affect PI progression between the DSA II+ and DSA- groups (PI progression: 15.9±8.7% vs. -11.7±7.1%, P=0.03). Age, gender, lipid and uric acid levels, prevalence of diabetes, ischemic time, time between IVUS examinations, the use of steroids, mycophenolate vs. azathioprine or calcineurin inhibitors vs. sirolimus were not different between the groups (P>0.4 for all). CONCLUSIONS: Heart transplant recipients with clearly defined anti-Class II DSA are at risk for accelerated cardiac allograft vasculopathy. Whether interventions to minimize the risk of DSA such as virtual crossmatch, desensitization and complement inhibition will retard CAV remains to be proven.

Renal function improves early after left ventricular assist device (LVAD) implantation but later decline has been observed. We sought to determine the occurrence and evaluate possible causes for this decline. In 62 consecutive patients with HeartMateII LVAD with available calculated glomerular filtration rate (GFR, ml/min/1.73 m2) 1 year after implant, GFR was assessed repeatedly and possible predictors for decline from 3 to 12 months were investigated. Post-mortem renal specimens for patients supported with an LVAD were evaluated. GFR 54.5 ± 19.5 at admission increased to 66.4 ± 22.3 preoperatively and to 79.2 ± 30.1 ~1 month after implantation. Subsequently at ~3 months GFR declined to 74.7 ± 25.4, at ~6 months to 68.8 ± 23.1, and ~1 year after implant to 63.9 ± 17.7. Glomerular filtration rate at 1 year was significantly lower (p < 0.0001, p < 0.0001, p = 0.005) than GFR 1, 3, and 6 months after implant. Early rise in GFR after surgery was not associated with late decline. Shorter bypass time (β = −0.09, p = 0.048) and higher albumin 3 months after LVAD (β = 14.4, p = 0.025) were significantly associated with less later decline in GFR. Arteriosclerosis was identified in autopsy renal specimens. In conclusion, early gains in renal function after LVAD implant are not sustained in many patients. Patient, device, and operative factors may influence long-term renal function in these patients.

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.

Background— Operative mortality after left ventricular assist device (LVAD) implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we treat our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables 1 month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes after the initial successful LVAD implantation. Methods and Results— We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device for their association with a compound end point (90-day mortality, readmission for heart failure, or New York Heart Association class III or higher at the end of the 90-day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, interventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E-wave deceleration time, and the ratio of deceleration time to E-wave velocity (mitral deceleration index [MDI]). Four patients died during the 30- to 90-day period, 6 patients were readmitted for heart failure, and 25 patients were considered to have New York Heart Association class III or higher at the end of the 90-day period. Variables associated with adverse outcome included increased ELAP (odds ratio, 1.30 [1.16–1.48]; P <0.0001), MDI <2 ms/[cm/s] (odds ratio, 4.4 implantation [1.22–18]; P =0.02) and decreased tricuspid lateral annulus velocity (odds ratio, 0.70 implantation [0.48–0.95]; P =0.02). A leftward deviation of interventricular septum was associated with a worse outcome (odds ratio, 3.03 implantation [1.21–13.3]; P =0.01). Conclusions— Mortality and heart failure after LVAD surgery appear to be predominantly determined by echocardiographic evidence of inefficient unloading of the left ventricle and persistence of right ventricular dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.