A heart transplant center experience with basiliximab induction strategies: A double edged sword?

BACKGROUND: The use of induction immunosuppression for heart transplantation (HT) is debated given the uncertain benefit and potential risks of infection and malignancy. METHODS: This is a retrospective single-center analysis of 475 consecutive HT recipients from 2003 to 2020 grouped by use of induction with basiliximab group (BG) and the no basiliximab group (NBG). Subgroup analysis by era compared pre-2016 standard-basiliximab (BX) induction and 2016-2020 with selective-BX use as part of a calcineurin-inhibitor-sparing regimen. RESULTS: When adjusted for confounders (sex, age, PRA, eGFR), the BG was less likely to have acute cellular rejection (ACR) (OR.42, p < .001), but had more antibody mediated rejection (AMR) (OR 11.7, p < .001) and more cardiac allograft vasculopathy (CAV) (OR 3.8, p = .04). There was no difference between BG and NBG in the incidence of malignancies or infections. When stratified by era (pre-2016 vs. 2016-2020), ACR remained less common in the BG than the NBG (36% vs. 50%, p = .045) groups, while AMR remained more common (9.7 vs. 0% p = .005). There was no significant difference in conditional survival comparing pre-and post-2016 NBG (HR 2.20 (95% CI.75-6.43); however, both pre-2016 BG and post-2016 BG have significantly higher mortality (HR 2.37 [95% CI 1.02-5.50) and HR 2.69 (95% CI 1.08-6.71), p = .045 and.03, respectively]. CONCLUSION: Basiliximab reduces the incidence of ACR but increases the risk of AMR, CAV, and may be associated with increased mortality. Mechanistic studies are needed to describe a potential T-cell-escape mechanism with enhanced humoral immunity.

Incidence of acute rejection and patient survival in combined heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p < 0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p = 0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p = 0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5 years (CHLT 82.1% vs. HA 80.9% [p = 0.73]; CHLT 82.1% vs. HA 80.9% [p = 0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.

Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection.

BACKGROUND: Endomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury-acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes. METHODS: Plasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR. RESULTS: Three patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients' donor exosomes. CONCLUSIONS: Anti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.

Clinical utility of surveillance and clinically prompted right heart catheterization in patients listed for heart transplantation.

BACKGROUND AND OBJECTIVES: The 2016 ISHLT guidelines recommend that patients listed for orthotopic heart transplantation (OHT) undergo periodic surveillance right heart catheterization (RHC) to re-assess hemodynamics (Class I, level of evidence C). However, the impact of RHC on management remains unclear. The aim of this study was to determine the utility of both surveillance and clinically prompted RHCs in patients listed for OHT. METHODS: A retrospective study was conducted in adult patients listed for OHT at our hospital from 2006 through 2014. Each patient included had at least one RHC after being listed for OHT. The primary outcome was management change: hospitalization, surgery (OHT or mechanical circulatory support [MCS]), change in United Network for Organ Sharing (UNOS) status, or initiation/modification of vasoactive drugs, diuretics or neurohormonal blockade. RESULTS: Of the 194 patients included, 85 (43%) patients had more than one RHC. The median time between listing and transplantation was 115 days. Of the 376 RHCs performed, 187 (50%) were prompted by a clinical change; 189 (50%) were performed for surveillance. In 90.4% of clinically prompted RHCs and 42.9% of surveillance RHCs, a clinically important management change was implemented. Initiation/modification of vasoactive drugs, placement of MCS and/or change in UNOS transplant status occurred in 61 (33%) of the clinically prompted RHCs and 26 (14%) of the surveillance RHCs. Patients who underwent management change were more likely to receive a heart transplant (HR 1.58; CI 1.15-2.18) without an increased rate of death over the study period compared to those who did not have a management change. Multivariable analysis revealed that a hemoglobin level <12.2 g/dL (OR 2.96; CI 1.36-6.42) and a total bilirubin level >0.9 mg/dL (OR 5.07; CI 2.09-12.3) were predictors of management change. CONCLUSIONS: In patients awaiting OHT, RHCs prompted by clinical instability or routine surveillance resulted in frequent management changes, including earlier heart transplant and MCS implant. Our study supports the Class I recommendation to perform surveillance RHC in patients listed for OHT and suggests that centers should consider maintaining a low threshold for repeat RHC during the formal waiting time.

Timing of Gastrointestinal Bleeding After Implantation of Left Ventricular Assist Devices Associates With Anatomic Location, Presentation, and Management.

BACKGROUND & AIMS: Continuous-flow left ventricular assist devices (LVADs) for advanced heart failure have been associated with gastrointestinal bleeding (GIB). We examined the association between time of GIB after LVAD implantation and bleeding location (determined by endoscopy), etiology, and patient outcomes. METHODS: We performed a retrospective study of consecutive patients who underwent implantation of continuous-flow LVADs from 2008 through 2015. We analyzed data on anatomic location of GIB, etiology, length of hospital stay, transfusion requirement, time to endoscopy, and readmission to the hospital within 30 days (30-day readmission). RESULTS: GIB developed in 59 of the 271 patients (22%). Higher proportions of patients with GIB during their index hospitalization for LVAD implantation had upper or lower GIB (86.7%) than patients with GIB during a subsequent hospitalization (50.0%; P = .013). Patients with GIB during their index hospitalization also had lower rates of middle GIB (0 vs 20.5%; P = .052), higher rates of overt GIB (100% vs 63.6%; P = .006), longer hospital stays (24 days vs 11 days; P < .001), and more transfusions before endoscopy (7 units vs 4 units; P = .021) than patients with GIB during a subsequent hospitalization. There were no significant differences between groups in time to endoscopy (2 days vs 2.5 days) or 30-day readmission (6.7% vs 9.3%). Angiodysplasias were identified in 100% of patients with middle GIB compared to 48.5% of patients with upper or lower GIB (P < .001) in whom a bleeding lesion was identified. CONCLUSION: In a retrospective study of patients who underwent implantation of continuous-flow LVADs, we found that timing of GIB associates with the location and severity of bleeding. Although patients with LVADs have an overall increase in risk of middle GIB, patients with GIB during their index LVAD hospitalization should undergo initial evaluation by upper endoscopy and colonoscopy, due to insufficient time for development of small bowel angiodysplasias. Patients who later develop GIB should be evaluated early for middle GI bleeding.

Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction.

PURPOSE: Prior studies demonstrate an association between specific beta-adrenergic receptor (ß-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to differences in left ventricular remodeling. This study was undertaken to explore the relationship between LV remodeling after myocardial infarction and polymorphisms in the cardiac ß1-AR and ß2-AR genes. METHODS: After first ST-segment elevation myocardial infarction (STEMI), 122 patients on chronic ß1 receptor antagonist therapy underwent baseline and 6-month LV volume evaluation. We assessed the relationships between changes in LV volumes and the polymorphisms in ß1-AR, ß1-Arg389Gly and ß1-Ser49Gly, and in ß2-AR, ß2-Gly16Arg and ß2-Gln27Glu. RESULTS: We found that patients homozygous for the ß2-Glu27 variant were 5.2 times more likely to be in the group with the highest end systolic volume (ESV) progression (OR 5.2, 95%CI 1.4-19.0). They were also more likely to have the largest progression of end diastolic volume (EDV) and decrease in LV ejection fraction (LVEF). For those with baseline LV dysfunction, being homozygous for Arg at amino acid position 389 in ß1-AR was associated with decreases in ESV (-46 mL, CI -3.1, -88) and EDV (-40 mL, CI -1.1, -79) and an increase in LVEF (11%, CI 0.3, 22). CONCLUSION: We found that polymorphisms of the ß1-AR and ß2-AR genes are associated with differential LV remodeling in patients treated with a ß1 receptor antagonist following STEMI.

Effects of aspirin responsiveness and platelet reactivity on early vein graft thrombosis after coronary artery bypass graft surgery.

OBJECTIVES: The purpose of this study was to determine if an incomplete response to or inadequate antiplatelet effect of aspirin, or both, contribute to saphenous vein graft (SVG) occlusion after coronary artery bypass graft (CABG) surgery. BACKGROUND: Thrombosis is the predominant cause of early SVG occlusion. Aspirin, which inhibits cyclooxygenase-1 activity and thromboxane generation in platelets, reduces early SVG occlusion by one-half. METHODS: Aspirin responsiveness and platelet reactivity were characterized 3 days and 6 months after coronary artery bypass graft surgery in 229 subjects receiving aspirin monotherapy by platelet aggregation to arachidonic acid, adenosine diphosphate, collagen and epinephrine, Platelet Function Analyzer-100 (Siemens Healthcare Diagnostics, Newark, Delaware) closure time (CT) using collagen/epinephrine agonist cartridge and collagen/adenosine diphosphate (CADP) agonist cartridge, VerifyNow Aspirin assay (Accumetrics, Inc., San Diego, California), and urine levels of 11-dehydro-thromboxane B(2) (UTXB(2)). SVG patency was determined 6 months after surgery by computed tomography coronary angiography. RESULTS: Inhibited arachidonic acid-induced platelet aggregation, indicative of aspirin-mediated cyclooxygenase-1 suppression, occurred in 95% and >99% of subjects 3 days and 6 months after surgery, respectively. Despite this, 73% and 31% of subjects at these times had elevated UTXB(2). Among tested parameters, only UTXB(2) and CADP CT measured 6 months after surgery correlated with outcome. By multivariate analysis, CADP CT of ≤88 s (odds ratio: 2.85, p = 0.006), target vessel diameter of ≤1.5 mm (odds ratio: 2.38, p = 0.01), and UTXB(2) of ≥450 pg/mg creatinine (odds ratio: 2.59, p = 0.015) correlated with SVG occlusion. CADP CT and UTXB(2) in combination further identified subjects at particularly high and low risk for SVG occlusion. CONCLUSIONS: Aspirin-insensitive thromboxane generation measured by UTXB(2) and shear-dependent platelet hyper-reactivity measured by Platelet Function Analyzer-100 CADP CT are novel independent risk factors for early SVG thrombosis after coronary artery bypass graft surgery.