Quantitative myocardial tissue characterization by cardiac magnetic resonance in heart transplant patients with suspected cardiac rejection.

Distinct histopathologic changes occur in acute cellular rejection (ACR), antibody-mediated rejection (AMR), and biopsy-negative rejection (BNR). Cardiovascular magnetic resonance (CMR)-based myocardial tissue characterization can be used to quantify these changes. We assessed T1, T2, and extracellular volume fraction (ECV) by CMR in patients with subtypes of rejection. T1, T2, and ECV were quantified at the mid-ventricular level and compared between patients with and without rejection. The association between quantitative tissue characteristics and the combined outcome of death, retransplantation, heart failure hospitalization, or myocardial infarction was evaluated with a Cox-proportional hazards model. In 46 patients, mean age 53.3 ± 13.7 years, 71.7% male, at a median of 7.4 years from transplant, average myocardial T1 was increased in BNR compared with no rejection (1057 vs 1012 msec, P = .006). Average myocardial T2 was elevated in all types of rejection, P < .05. In a cox-proportional hazards model, higher T2 values were associated with an increase in the combined clinical outcome (adjusted HR 1.21, 95% CI 1.06-1.37, P = .004) after adjusting for left ventricular mass index. Myocardial tissue characteristics are abnormal in all subtypes of rejection, and abnormal T2 quantified by CMR provides additional prognostic value.

Does ex vivo perfusion lead to more or less intimal thickening in the first-year post-heart transplantation?

BACKGROUND: The Organ Care System (OCS), an ex vivo heart perfusion platform, represents an alternative to the current standard of cold organ storage that sustains the donor heart in a near-physiologic state. Previous reports showed that this system had significantly shortened the cold ischemic time from standard cold storage (CS). However, the effect of reduced ischemic injury against the coronary vascular bed has not been examined by intravascular ultrasound (IVUS). METHODS: Between August 2011 and February 2013, heart transplant (HTx) candidates enrolled in the PROCEED 2 trial were randomized to either CS or OCS. IVUS was performed at 4-6 weeks (baseline) and repeated 1 year after transplantation. The change in maximal intimal thickness (MIT) and other clinical outcomes were examined. RESULTS: Thirty-nine patients were randomized and underwent HTx by OCS (n=16) or CS (n=18). Of these, 18 patients (OCS: n=5, CS: n=13) with paired IVUS were examined. There were no significant differences in the change of MIT and other clinical outcomes between the groups. CONCLUSION: The incidence of cardiac allograft vasculopathy in donor hearts preserved with the OCS versus CS was similar. These results suggest that this ex vivo allograft perfusion system is a promising and valid platform for donor heart transportation.

Revealing a new mode of sensitization induced by mechanical circulatory support devices: Impact of anti-AT1 R antibodies.

BACKGROUND: Increased levels of angiotensin II type 1 receptor (AT1 R) antibody have been shown to be associated with allograft rejection. This study aims to determine the rate of development of antibody to AT1 R after mechanical circulatory support device (MCS) implantation, and if the development of strong binding AT1 R antibodies is associated with survival. METHODS: Eighty-eight patients who had one MCS implantation were accessed based on serum availability. Mechanical circulatory support devices in this cohort included pneumatic bilateral paracorporeal ventricular assist device, continuous flow left ventricular assist device, and total artificial heart. RESULTS: Of 88 patients, seven patients had AT1 R antibodies ≥40 U/mL preimplantation. For 81 patients who had AT1 R antibodies <40 U/mL, the median value was 8 U/mL. Of these 81 patients, AT1 R antibody levels in 55 (68%) patients reached the saturated concentration (≥40 U/mL) postimplantation (P < .0001), with the highest percentage of patients with the saturated level of AT1 R antibody observed in the pneumatic bilateral paracorporeal ventricular assist device group. Compared to patients without the saturated level of AT1 R antibodies, patients with the saturated AT1 R antibody level had lower 18-month survival (P = .040). CONCLUSION: Mechanical circulatory support devices implantation significantly increases AT1 R antibody levels. The saturated level of AT1 R antibodies is associated with lower patient survival postimplantation.

Eligibility and Potential Benefit of Transcatheter Edge-to-Edge Repair in a Contemporary Cohort With Heart Failure: Evidence From a Large Integrated Health Care Delivery System.

Background: The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. Methods: Eligibility for TEER based on Food and Drug Administration (FDA) labeling: (1) HF symptoms, (2) moderate-severe or severe MR, (3) left ventricular ejection fraction (LVEF) 20% to 50%, (4) left ventricular end-systolic dimension 7.0 cm, and (5) receiving GDMT (blocker + angiotensin-converting enzyme inhibitor/angiotensin receptor blocker). The proportion (%) of patients eligible for TEER. The hypothetical number needed to treat to prevent or postpone adverse outcomes was estimated using relative risk reductions from published hazard ratios in the registration trial and the observed event rates. Results: We identified 50,841 adults with HF and known LVEF. After applying FDA criteria, 2461 patients (4.8%) were considered eligible for transcatheter mitral valve replacement (FDA+), with the vast majority of patients excluded (FDA-) based on a lack of clinically significant MR (N = 47,279). FDA+ patients had higher natriuretic peptide levels and were more likely to have a prior HF hospitalization compared to FDA- patients. Although FDA+ patients had a more dilated left ventricle and lower LVEF, median (25th-75th) left ventricular end-systolic dimension (cm) was low at 4.4 (3.7-5.1) and only 30.8% had severely reduced LVEF. FDA+ patients were at higher risk of HF-related morbidity and mortality. The estimated number needed to treat to potentially prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months in FDA+ patients. Conclusions: There is a low prevalence of TEER eligibility based on FDA criteria primarily due to absence of moderate-severe or severe MR. FDA+ patients are a high acuity population and may potentially derive a robust clinical benefit from TEER based on pivotal studies. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER in real-world populations.

Acceptable Post-Heart Transplant Outcomes Support Temporary MCS Prioritization in the New OPTN|UNOS Heart Allocation Policy.

BACKGROUND: Temporary mechanical circulatory support (MCS) devices are generally used short term to maintain adequate organ perfusion in patients with advanced heart failure and cardiogenic shock. Unacceptably high waitlist mortality in this cohort motivated changes to heart allocation policy, which recognized the severity of illness by prioritization for temporary MCS and broader sharing in the new U.S. donor heart allocation policy. We evaluated the post-heart transplant outcomes for patients bridged with temporary MCS, a control population not bridged with MCS, and a cohort bridged with durable MCS. METHODS: The heart transplant research database was queried to identify patients bridged with temporary MCS and bridged with durable MCS who went directly to heart transplant in our center. Temporary MCS included Impella, intra-aortic balloon pump, and extracorporeal membrane oxygenation. Post-transplant endpoints were assessed at 30 days, 6 months, and 1 year. RESULTS: From 2010 to 2017, a total of 23 patients were bridged to heart transplant with temporary MCS and 548 were transplanted without MCS bridge. Patients bridged with temporary MCS had younger age, lower body mass index, and higher frequencies of prior blood transfusion and Status 1 (1A/1B) listing at transplant compared to patients not bridged with MCS (all P < .001). Despite the severity of illness in patients bridged with temporary MCS, post-transplant outcomes were indistinguishable from those in patients transplanted without MCS bridge, with no difference in 30-day, 6-month, or 1-year survival or 1-year freedom from cardiac allograft vasculopathy, nonfatal major adverse cardiac events, any-treated rejection, acute cellular rejection, or antibody-mediated rejection (P = .23-.97). Similarly, compared to 157 patients bridged with durable MCS, no differences in post-transplant outcomes were identified for the temporary MCS cohort (P = .15-.94). CONCLUSION: Temporary MCS as a bridge to transplant achieves similar post-transplant outcomes at 1 year compared to no MCS and durable MCS. These encouraging findings support recent changes in the Organ Procurement and Transplantation Network | United Network Organ Sharing (OPTN|UNOS) adult heart allocation policy.

Outcomes of Heart Transplantation in Cardiac Amyloidosis Patients: A Single Center Experience.

BACKGROUND: Indications for heart transplantation are expanding to include amyloid light chain (AL) and transthyretin-related (TTR) amyloidosis. Previously, AL amyloid had been a contraindication to heart transplantation given inferior outcomes. These patients typically have biventricular failure requiring mechanical circulatory support (MCS). We report the outcomes of patients with end-stage cardiac amyloidosis who underwent cardiac transplantation, including some who were bridged to transplantation with a durable biventricular MCS METHODS: The records for patients with cardiac amyloidosis who underwent cardiac transplant between 2010 and 2018 were reviewed. Primary endpoint was post-transplant 1-year survival. Secondary endpoints included 1-year freedom from cardiac allograft vasculopathy (as defined by stenosis ≥ 30% by angiography), nonfatal major adverse cardiac events (myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and any rejection. RESULTS: A total of 46 patients received heart transplantation with a diagnosis of either AL or TTR amyloidosis. Of these, 7 patients were bridged to transplantation with a durable biventricular MCS device (6 AL, 1 TTR) and 39 patients were transplanted without MCS bridging. The MCS group consisted of 5 total artificial hearts and 2 biventricular assist devices. The 1-year survival was 91% for the entire cohort, 83% for those with AL amyloidosis, 94% for those with TTR amyloidosis, and 86% for those who received MCS bridging. CONCLUSIONS: Cardiac transplantation can be safely performed in selected amyloidosis patients with reasonable short-term outcomes. Those bridged to transplantation with biventricular MCS appear to have short-term outcomes similar to those transplanted without MCS. Larger numbers and longer observation are required to confirm these findings.

Dual-organ transplantation in older recipients: outcomes after heart-kidney transplant versus isolated heart transplant in patients aged ≥65 years.

OBJECTIVES: Combined heart-kidney transplantation has successful outcomes. With an increasing number of patients with end-stage heart disease, there is a high incidence of significant renal insufficiency that may necessitate combined heart-kidney transplant. Outcomes for heart-kidney transplant recipients aged ≥65 years are not well described. METHODS: Between 2010 and 2015, 163 recipients ≥65 years of age were transplanted in a single centre: 12 heart-kidney and 151 isolated heart transplants. Outcomes assessed were estimated glomerular filtration rate at 1, 6 and 12 months after transplant, the need for dialysis, 1-year survival, 1-year freedom from rejection, 1-year freedom from cardiac allograft vasculopathy and 1-year freedom from non-fatal major adverse cardiac events. RESULTS: Recipient ages were 67.8 ± 1.6 and 69.0 ± 2.8 years for heart-kidney transplant and isolated heart transplant, and pretransplant estimated glomerular filtration rates were 26.6 ± 9.4 vs 55.2 ± 18.9, respectively. At 1 month (66.3 ± 31.4 vs 67.2 ± 28.0, P = 0.92), 6 months (68.1 ± 21.3 vs 60.5 ± 19.6, P = 0.20) and 12 months (58.6 ± 21.5 vs 52.4 ± 18.5, P = 0.27) post-transplant, estimated glomerular filtration rate was similar for heart-kidney transplant versus isolated heart transplant. There was a trend towards reduced 1-year freedom from temporary dialysis after heart-kidney transplant relative to isolated heart transplant (75.0% vs 90.4%, P = 0.06) without a difference in 1-year freedom from chronic dialysis (100% vs 95.2%, P = 0.46). There were no differences in 1-year survival, 1-year freedom from any treated rejection, acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy and non-fatal major adverse cardiac events. CONCLUSIONS: For patients ≥65 years old, heart-kidney transplant can achieve outcomes on par with heart transplant alone.

Combined heart and kidney transplantation-Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound?

BACKGROUND: Because cardiac and renal disease are physiologically related and often coexist, the prevalence of combined heart and kidney transplantation (HKTx) has significantly increased over the last few years. It has been suggested that combined organ allografts modulate the immune system favorably for one or both allografts resulting in successful clinical outcomes. However, whether the addition of kidney transplantation has a protective immune effect against developing cardiac allograft vasculopathy (CAV) has not been fully investigated. METHODS: From March 2010 to September 2018, 30 HKTx recipients who had baseline (4-6 weeks) and 1-year intravascular ultrasound (IVUS) were matched with 60 isolated heart transplant (HTx-alone) recipients using propensity scores. First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), maximal percent stenosis (MPS), percent atheroma volume (PAV), and incidence of rapid plaque progression were compared between the groups. RESULTS: First-year coronary plaque progression was significantly decreased in HKTx recipients compared with HTx-alone recipients by change in the MIT (0.11 ± 0.14 mm vs 0.40 ± 0.32 mm, p < 0.001), MIA (0.52 ± 1.52 mm2 vs 1.86 ± 2.68 mm2, p = 0.002), MPS (2.10% ± 5.64 percentage points vs 7.22% ± 8.59 percentage points, p = 0.001), and PAV (1.62% ± 3.07 percentage points vs 5.90% ± 5.92 percentage points, p < 0.001). Rapid plaque progression occurred in 2 of 30 in HKTx (6.7%) and in 22 of 60 HTx alone (36.7%), p = 0.002. CONCLUSIONS: Combined heart and kidney transplantation is associated with a decrease in CAV by coronary plaque progression on IVUS. These results suggest that HKTx may have an immune modulating benefit over HTx alone.

Change in lymphocyte to neutrophil ratio predicts acute rejection after heart transplantation.

AIMS: Most immunosuppressive drugs provide targeted immunosuppression by selective inhibition of lymphocyte activation and proliferation. This study evaluated whether a change in the lymphocyte to neutrophil ratio (LNR) is related to acute rejection. METHODS: In 74 cardiac transplant recipients peripheral blood lymphocyte and neutrophil counts were measured soon after (baseline) and three, six, and 12months after heart transplantation. The primary endpoint was the incidence of acute rejection. RESULTS: Significant acute rejection after heart transplantation occurred in 20 patients (27%) during a median follow-up of 49.4 [IQR 37.4-61.1] months. LNR significantly increased over time (0.1149±0.1354 at baseline, 0.2330±0.2266 at 3months, 0.2961±0.2849 at 6months, and 0.3521±0.2383 at 12months; P<0.001), especially during the first 3months in the group without acute rejection. The area under the curve of the change in LNR during the first three months (ΔLNR) for acute rejection was 0.565 (95% CI 0.420 to 0.710, P=0.380) on ROC curve analysis. The best cutoff value of Δ LNR to differentiate those with and without acute rejection was ≤0.046 by ROC curve analysis. Kaplan-Meier analysis revealed that the low ΔLNR group (≤0.046) had a significantly higher rate of acute rejection than the high ΔLNR group (>0.046) (37.5% vs. 19.0%, log-rank: P=0.0358). The low ΔLNR for the first 3months was an independent predictor of clinically significant acute rejection after adjusting for cytomegalovirus donor seropositive and recipient seronegative. CONCLUSIONS: The results of this study suggest that ΔLNR over the first 3months after heart transplantation is a strong and independent predictor of acute rejection after heart transplantation. ΔLNR can be used as an early biomarker for predicting of acute rejection after heart transplantation.

The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation.

BACKGROUND: The aim of this study was to determine the value of the ratio of the percentage of circulating regulatory cluster of differentiation 4 T cells (%Tregs) to the percentage of endothelial progenitor cells (%EPCs; Treg/EPC ratio) for predicting clinically significant acute rejection. METHODS: Peripheral blood %Tregs and %EPCs were quantified in 91 cardiac transplant recipients using flow cytometry at a mean of 42 ± 13 days after transplant. The primary end point was clinically significant acute rejection, defined as an event that led to an acute augmentation of immunosuppression in conjunction with an International Society for Heart and Lung Transplantation grade ≥ 2R in a right ventricular endomyocardial biopsy specimen or non-cellular rejection (specimen-negative rejection) with hemodynamic compromise (decrease in left ventricular ejection fraction by > 25%). RESULTS: Significant rejection occurred in 27 recipients (29.7%) during a median of 49.4 months (interquartile range, 37.0-62.0 months). The mean %Tregs and %EPCs were not significantly different between those with and without an episode of significant rejection, but the mean Treg/EPC ratio was significantly lower in recipients with significant rejection (44.9 vs 106.7, p = 0.001). Receiver operating characteristic curve analysis showed an area under the curve value for significant rejection for a Treg/EPC ratio of 0.712. The best cutoff value of the Treg/EPC ratio that distinguished between those with or without significant rejection was ≤ 18 by receiver operating characteristic curve analysis. Kaplan-Meier analysis revealed that patients with a Treg/EPC ratio of ≤ 18 had a significantly higher rate of rejection than those with a Treg/EPC ratio > 18 (61.5% vs 16.9%, log-rank p < 0.0001). A low Treg/EPC ratio was an independent predictor of significant rejection. CONCLUSIONS: A low Treg/EPC ratio measured soon after heart transplantation is an independent predictor of acute rejection. The Treg/EPC ratio has potential as an early biomarker after heart transplantation for predicting acute rejection.

Use of durable mechanical circulatory support on outcomes of heart-kidney transplantation.

OBJECTIVES: Previous studies have demonstrated that preheart transplant mechanical circulatory support (MCS) can lead to a small but significant increase in mortality. However, data on outcomes of patients with MCS who require simultaneous heart-kidney transplant are limited. METHODS: A retrospective review of simultaneous heart-kidney transplantations (HKTxs) performed at a single institution over a 5-year period was performed. Patients were divided based on the preoperative use of durable MCS. Renal graft-related end points were evaluated, including glomerular filtration rate following transplantation, prevalence of delayed renal graft function and freedom from antibody and cellular-mediated graft rejection. Patient-specific outcomes, including survival and frequency of non-fatal major adverse cardiac events at 1 year, were additionally assessed. RESULTS: During the study period, 50 HKTxs were performed, 14 of which had preoperative MCS. HKTx patients with and without MCS implantations had a similar prevalence of delayed graft function (57.1% vs 50.0%; P = 0.757). A numerical trend was observed towards a reduced glomerular filtration rate 1-month post-transplant in patients without an MCS device (81.2 ± 32.8 vs 64.4 ± 27.5; P = 0.072), but no significant difference was observed at 6 and 12 months. No significant difference was observed on the need for post-transplant renal replacement therapy, non-fatal major adverse cardiac events, freedom from graft rejection and overall survival at 1 year. CONCLUSIONS: The use of preoperative MCS in patients undergoing combined HKTx was not found to affect renal graft function post-transplantation and does not seem to be associated with increase in morbidity or mortality.

Characterizing Predictors and Severity of Vasoplegia Syndrome After Heart Transplantation.

BACKGROUND: Vasoplegia is characterized as a severe vasodilatory shock after cardiac surgery, and can be associated with substantial morbidity. Increased systemic inflammation and endothelial dysfunction, often related to prolonged cardiopulmonary bypass times, anesthesia, or mechanical circulatory support have been shown to be associated with the development of vasoplegia. We sought to identify risk factors and the impact of various degrees of vasoplegia after heart transplantation. METHODS: A retrospective review was conducted of 244 consecutive patients who underwent heart transplantation over a 3-year period. Patients were divided into three groups: no vasoplegia, mild vasoplegia (requiring one vasopressor), and moderate/severe vasoplegia (more than two vasopressors). One-year survival, freedom from rejection, and postoperative complication rates were assessed. Risk factors for vasoplegia subgroups were retrospectively identified. RESULTS: Vasoplegia syndrome was observed in 34.3% of patients after heart transplantation (mild, 74.1%; moderate/severe, 25.9%). Cardiopulmonary bypass time was significantly longer and pretransplant creatinine was significantly higher in the moderate/severe vasoplegia group. There was a strong trend toward greater use of mechanical circulatory support among moderate/severe vasoplegia patients compared with mild and no vasoplegia patients. After heart transplantation, 1-year survival, freedom from rejection, and need for hemodialysis were not significantly different between groups. CONCLUSIONS: Vasoplegia syndrome is common after heart transplantation. Risk factors for increased severity include longer cardiopulmonary bypass times and elevated preoperative creatinine. Although higher rates of mortality or graft rejection were not detected, vasoplegia was associated with prolonged intubation, greater blood product usage, and lengthened hospital stay. Further studies involving larger cohorts are warranted.