Prognostic value of myocardial flow reserve obtained by 82-rubidium positron emission tomography in long-term follow-up after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of death following heart transplantation (HTx) and non-invasive prognostic methods in long-term CAV surveillance are needed. We evaluated the prognostic value of myocardial flow reserve (MFR) obtained by 82-rubidium (82Rb) positron emission tomography (PET). METHODS: Recipients undergoing dynamic rest-stress 82Rb PET between April 2013 and June 2017 were retrospectively evaluated in a single-center study. Evaluation by PET included quantitative myocardial blood flow and semiquantitative myocardial perfusion imaging. Patients were grouped by MFR (MFR ≤ 2.0 vs MFR > 2.0) and the primary outcome was all-cause mortality. RESULTS: A total of 50 patients (68% men, median age 57 [IQR: 43 to 68]) were included. Median time from HTx to PET was 10.0 (6.7 to 16.0) years. In 58% of patients CAV was documented prior to PET. During a median follow-up of 3.6 (2.3 to 4.3) years 12 events occurred. Survival probability by Kaplan-Meier method was significantly higher in the high-MFR group (log-rank P = .02). Revascularization (n = 1), new CAV diagnosis (n = 1), and graft failure (n = 4) were more frequent in low-MFR patients. No retransplantation occurred. CONCLUSIONS: Myocardial flow reserve appears to offer prognostic value in selected long-term HTx recipients and holds promise as a non-invasive method for CAV surveillance possibly guiding management strategy.

Three decades of heart transplantation: experience and long-term outcome.

Objectives. Heart transplantation (HTx) has become an established treatment option in patients with end-stage heart failure. The aim of this study was to report on long-term outcome over the past three decades. Design. Consecutive adult patients receiving first-time and isolated HTx from October 3, 1990, to November 2, 2020, at Rigshospitalet, Copenhagen, Denmark, were retrospectively evaluated. Data were obtained from the Scandinavian Transplant Registry and patient medical records. Recipients were grouped by time of transplantation (early era: 1990-1999; mid era: 2000-2009; recent era: 2010-2020). Results. A total of 384 recipients (77% men, median age 50 [IQR: 40-57]) were included. Median number of HTx procedures per year was 12 (10-14). Overall, 22% of patients were bridged to HTx with a mechanical circulatory support device. Median survival for the whole cohort was 13.8 years and improved numerically from the early era (12.6 years) to the mid era (14.9 years). Median survival conditional on survival to 1-year follow-up after HTx was 16.1 years. Survival probability by Kaplan-Meier method improved significantly from the mid to the recent era (log-rank p = .02). Conclusions. Heart transplantation remains an excellent treatment for selected patients with end-stage heart failure and long-term outcome has improved significantly over the past decades.

Steroid withdrawal after heart transplantation in adults.

Corticosteroids (CSs) are a key component of immunosuppressive treatment after heart transplantation (HTx). While effectively preventing acute rejection, several adverse effects including diabetes, hypertension, osteoporosis, and hyperlipidemia are associated with long-term use. As these complications may impair long-term outcome in HTx recipients, withdrawal of CSs is highly desirable, however, no uniform approach exists. Previous experience suggests that CS withdrawal can be accomplished without an increase in the incidence of acute rejection and even carrying a survival benefit. Also, common complications related to long-term CS use appear to be less frequent following CS discontinuation. Recipients who successfully discontinue CSs, however, likely belong to an immune-privileged subset of patients with low risk of post-transplant complications. Available studies evaluating CS withdrawal are highly heterogeneous and consensus on optimal timing and eligibility for withdrawal is lacking. Efforts to improve the understanding of optimal CS withdrawal strategy are of great importance in order to safely promote CS weaning in eligible patients and thereby alleviate the adverse effects of long-term CS use on post-transplant outcomes. The purpose of this review was to evaluate different protocols of CS withdrawal after HTx in terms of clinical outcomes and to explore criteria for successful CS withdrawal.

Comparing neuropathy in multiple myeloma and AL amyloidosis.

Peripheral neuropathy (PN) is frequent in patients with monoclonal gammopathy due to plasma cell dyscrasia, but little is known about the comparative impact of nerve dysfunction in different disorders. We compared clinical and laboratory results between two diagnostic groups. We recruited 76 untreated multiple myeloma (MM) and 27 AL amyloidosis (ALA) patients for evaluation of symptoms, clinical findings and nerve conduction studies (NCS). We diagnosed significant PN using total neuropathy scores (TNS > 7) in 17.6% of MM and 48.1% of ALA patients and in 27.7% of MM and 35.7% of ALA patients using NCS findings. TNS score grades were significantly higher in the AL amyloidosis patients (Fisher's exact test: P = .02) but a NCS based PN diagnosis was not significantly different (Fisher's exact test: P = .13). A significantly higher TNS vibration (P = .04) and pin (P = .02) sensory sign and TNS reflex (P = .04) sign score was found in amyloidosis patients. Likewise, quantitative sensory thresholds for vibration was higher in amyloidosis patients (Welsh ANOVA: P = .01). NCS revealed signs of more frequent axonal tibial neuropathy with significantly lower motor response amplitudes (P = .02) and resulting higher TNS scores (P = .002), while sural nerve sensory response amplitudes were without significant difference (P = .86). We found more severe TNS grades of PN in AL amyloidosis patients compared with MM patients. We also found higher sensory symptoms scores and higher thresholds for vibration but similar sensory involvement using NCS. The NCS exclusively showed signs of an axonal neuropathy.

Intravascular ultrasound-guided selection for early noninvasive cardiac allograft vasculopathy screening in heart transplant recipients.

BACKGROUND: Noninvasive screening for cardiac allograft vasculopathy (CAV) instead of invasive coronary angiography (ICA) within the first 3 to 5 years after heart transplantation (HTx) is controversial. We evaluated a strategy of intravascular ultrasound (IVUS)-guided conversion to early noninvasive screening post-HTx. METHODS: A single-center study of 103 consecutive HTx recipients from 2008 to 2018 undergoing ICA at 1 year post-HTx. Of 88 patients with normal 1-year ICA, sixty-six patients underwent IVUS examination for risk stratification by maximal intimal thickness (MIT) into (i) low-risk group (MIT < 0.5 mm) (n = 41, 62%) followed noninvasively versus (ii) high-risk group (MIT ≥ 0.5 mm) (n = 25, 38%) followed with yearly ICA. Both groups underwent ICA at year 5 post-HTx. We evaluated a combined endpoint of angiographic CAV and death at 5-year follow-up post-HTx. RESULTS: Median (IQR) age was 51 (33-60) years, and 62% were male. Follow-up was 1443 (1125-1456) days. Survival free from angiographic CAV (Kaplan-Meier) differed significantly between groups (log-rank p < .0001). A subgroup of 27 patients completed ICA at year 5, and the proportion of angiographic CAV was significantly lower in low-risk patients (p < .0001). CONCLUSION: IVUS-guided selection for early noninvasive CAV screening appears to be safe and holds promise as a novel strategy for early risk stratification and CAV surveillance post-HTx.

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n = 115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53 years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness)BL-3Y was not significantly different between groups (P = 0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r = -0.025, P = 0.83). The number of 1R was not a significant predictor of ∆MITBL-3Y (P = 0.58), and no significant interaction with treatment was found (P = 0.98). The burden of mild ACR was not associated with CAV development.

Characteristics and long-term outcome of patients with systemic immunoglobulin light-chain amyloidosis.

BACKGROUND/AIMS: Immunoglobulin light-chain (AL) amyloidosis is a systemic disorder that causes progressive organ dysfunction. The optimal treatment strategy requires accurate patient stratification with an emphasis on the extent of cardiac involvement. Reports on its prognosis are sparse and predominantly originate from highly selected centers. We aimed to evaluate patient characteristics and outcomes in a cohort treated at a single center. METHODS: This is a single-center retrospective study of 63 consecutive patients diagnosed with AL amyloidosis between January 2000 and December 2012. Patients were evaluated by treatment strategy and cardiac involvement. RESULTS: The mean age at diagnosis was 61.4 years (±8.9), and 39 patients (62%) were male. Thirty-two (51%) patients presented with cardiac amyloid involvement (CA) and the remaining 31 (49%) had noncardiac amyloidosis (NCA). The median follow-up time was 12.7 months (0.3-90.8), and 38 (60%) patients died during follow-up. The median overall survival (OS) was 29 months (95% CI 12.1-57.2) and the OS was not significantly lower for patients with CA compared to NCA (log-rank = 0.21). CONCLUSION: The prognosis in AL amyloidosis is grave, but the outcome with treatment in the current series was comparable to those in series from larger centers. CA did not significantly predict the OS.

The Impact of Age and Body Composition on the Agreement between Estimated and Measured GFR in Heart Transplant Recipients.

BACKGROUND: Estimated GFR (eGFR) has shown poor agreement with measured GFR (mGFR) in several populations. We investigated the impact of age and body composition on the accuracy and precision of eGFR in heart transplant (HTx) recipients. METHODS: In a longitudinal, observational, retrospective study design, patients receiving first-time HTx with at least one registered mGFR value within 15 months after HTx and a corresponding plasma creatinine were included. GFR was measured by 51Cr-EDTA and eGFR calculated by creatinine-based CKD-EPI formula. RESULTS: A total of 150 patients with a total of 723 mGFR measurements were included. During the first year after HTx, mean weight increased by 4.2 kg (CI: 3.2 to 5.1) followed by an annual decrease of 0.35 kg/year (Cl: -0.05 to 0.74). mGFR increased by 7.5 mL/min (Cl: 3.2 to 11.8) the first year but was stable hereafter (0.0 mL/min/year; CI: -1.0 to 1.0). The initial weigh gain and increase in mGFR were most pronounced in patients <45 years. Neither eGFR adjusted nor unadjusted for BSA detected the initial increase in mGFR. At 1 year after HTx, limits of agreement on the Bland-Altman plot were -37.2 to 33.1 mL/min with a bias of -2.1 mL/min (Cl: -5.0 to 0.9). In patients <45 years, eGFR significantly overestimated mGFR by 7.1 mL/min (Cl: 1.0 to 13.2) and showed a significant lower precision than patients >45 years. There was no effect of BMI class, weight, BSA, or change in BMI class on the difference between eGFR and mGFR. CONCLUSION: eGFR is, on average, accurate but imprecise in HTx patients. The agreement is affected by age but not body composition.

Association between routine measures of graft function and mortality in heart transplant recipients.

OBJECTIVE: To date, long-term graft dysfunction, an important cause of death after heart transplantation, has been defined as a left ventricular ejection fraction (LVEF) of ≤40% or right atrial pressure (RAP) of ≥15 mm Hg. Empirical associations between measures of cardiac function and mortality post-transplant remain, however, unestablished. METHODS: We conducted a retrospective two-centre cohort study of consecutive adults who underwent heart transplant between 2002 and 2017. We evaluated the association between LVEF and RAP and mortality, including rejection and cardiac allograft vasculopathy as additional time-dependent covariates using Cox proportional hazard models. We applied restricted cubic splines to both LVEF and RAP. RESULTS: Of 590 eligible heart transplant recipients, of whom 72% were male with a mean age of 49 years, 410 received their transplant at Toronto General Hospital and 180 at Rigshospitalet. We observed a 5% absolute risk increase for 1-year mortality, from 11% to 16%, when the LVEF dropped to 53% (HR 1.71 for LVEF of 53% compared with 60%, 95% CI 1.36 to 2.14) or when the RAP increased to 12 mm Hg (HR 1.49 for RAP of 12 mm Hg compared with 5 mm Hg, 95% CI 1.04 to 2.13). CONCLUSION: In this study, we observed that small changes in graft function at any time post-transplant are associated with an increased mortality. Our results suggest that the current definition of graft dysfunction may underestimate patient risk of adverse outcomes.

Effect of Calcineurin Inhibitor-Free, Everolimus-Based Immunosuppressive Regimen on Albuminuria and Glomerular Filtration Rate After Heart Transplantation.

BACKGROUND: Albuminuria in maintenance heart transplantation (HTx) is associated with poor renal response when switching to a calcineurin inhibitor (CNI)-lowered or CNI-free immunosuppressive regimen using everolimus (EVR), but the significance of albuminuria associated with EVR treatment after early CNI withdrawal in de novo HTx is unknown. METHODS: We tested if measured glomerular filtration rate (mGFR, by chrome-ethylenediaminetetraacetic acid clearance) was associated with urine albumin/creatinine ratio (UACR) post-HTx in a subgroup of patients included in the Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitor Avoidance trial, where de novo HTx patients (n = 115) were randomized to EVR with complete CNI elimination 7 to 11 weeks post-HTx or standard CNI immunosuppression. RESULTS: In 66 patients, UACR measures were available at 1 year. In 7 patients in the EVR group, a CNI was reintroduced within 12 months. Median mGFR was significantly higher in the EVR group both 1 and 3 years post-HTx (P = 0.0004 and P = 0.03, respectively). Median UACR at 1 year was significantly higher in the EVR group (P = 0.002). There was no correlation between log(UACR) at 1 year and mGFR at 1 or 3 years (r = -0.01, P = 0.9 and r = 0.15, P = 0.26, respectively) and in the EVR group between log(UACR) at 1 year and change in mGFR (Δ1-3 years) (r = 0.27, P = 0.14). Excluding patients in the EVR group in whom a CNI was reintroduced did not significantly change the results. CONCLUSIONS: The effects of EVR with early CNI withdrawal after HTx on albuminuria and renal function seem dissociated; hence, the clinical significance of albuminuria in this setting is uncertain and should not necessarily rule out EVR-based immunosuppression.