Prognostic Value of Cardiac MRI and FDG PET in Cardiac Sarcoidosis: A Systematic Review and Meta-Analysis.

Background There is no consensus regarding the relative prognostic value of cardiac MRI and fluorodeoxyglucose (FDG) PET in cardiac sarcoidosis. Purpose To perform a systematic review and meta-analysis of the prognostic value of cardiac MRI and FDG PET for major adverse cardiac events (MACE) in cardiac sarcoidosis. Materials and Methods In this systematic review, MEDLINE, Ovid Epub, CENTRAL, Embase, Emcare, and Scopus were searched from inception until January 2022. Studies that evaluated the prognostic value of cardiac MRI or FDG PET in adults with cardiac sarcoidosis were included. The primary outcome of MACE was assessed as a composite including death, ventricular arrhythmia, and heart failure hospitalization. Summary metrics were obtained using random-effects meta-analysis. Meta-regression was used to assess covariates. Risk of bias was assessed using the Quality in Prognostic Studies, or QUIPS, tool. Results Thirty-seven studies were included (3489 patients with mean follow-up of 3.1 years ± 1.5 [SD]); 29 studies evaluated MRI (2931 patients) and 17 evaluated FDG PET (1243 patients). Five studies directly compared MRI and PET in the same patients (276 patients). Left ventricular late gadolinium enhancement (LGE) at MRI and FDG uptake at PET were both predictive of MACE (odds ratio [OR], 8.0 [95% CI: 4.3, 15.0] [P < .001] and 2.1 [95% CI: 1.4, 3.2] [P < .001], respectively). At meta-regression, results varied by modality (P = .006). LGE (OR, 10.4 [95% CI: 3.5, 30.5]; P < .001) was also predictive of MACE when restricted to studies with direct comparison, whereas FDG uptake (OR, 1.9 [95% CI: 0.82, 4.4]; P = .13) was not. Right ventricular LGE and FDG uptake were also associated with MACE (OR, 13.1 [95% CI: 5.2, 33] [P < .001] and 4.1 [95% CI: 1.9, 8.9] [P < .001], respectively). Thirty-two studies were at risk for bias. Conclusion Left and right ventricular late gadolinium enhancement at cardiac MRI and fluorodeoxyglucose uptake at PET were predictive of major adverse cardiac events in cardiac sarcoidosis. Limitations include few studies with direct comparison and risk of bias. Systematic review registration no. CRD42021214776 (PROSPERO) © RSNA, 2023 Supplemental material is available for this article.

Extracorporeal Membrane Oxygenation for Graft Dysfunction Early After Heart Transplantation: A Systematic Review and Meta-analysis.

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a prevailing option for the management of severe early graft dysfunction. This systematic review and individual patient data (IPD) meta-analysis aims to evaluate (1) mortality, (2) rates of major complications, (3) prognostic factors, and (4) the effect of different VA-ECMO strategies on outcomes in adult heart transplant (HT) recipients supported with VA-ECMO. METHODS AND RESULTS: We conducted a systematic search and included studies of adults (≥18 years) who received VA-ECMO during their index hospitalization after HT and reported on mortality at any timepoint. We pooled data using random effects models. To identify prognostic factors, we analysed IPD using mixed effects logistic regression. We assessed the certainty in the evidence using the GRADE framework. We included 49 observational studies of 1477 patients who received VA-ECMO after HT, of which 15 studies provided IPD for 448 patients. There were no differences in mortality estimates between IPD and non-IPD studies. The short-term (30-day/in-hospital) mortality estimate was 33% (moderate certainty, 95% confidence interval [CI] 28%-39%) and 1-year mortality estimate 50% (moderate certainty, 95% CI 43%-57%). Recipient age (odds ratio 1.02, 95% CI 1.01-1.04) and prior sternotomy (OR 1.57, 95% CI 0.99-2.49) are associated with increased short-term mortality. There is low certainty evidence that early intraoperative cannulation and peripheral cannulation reduce the risk of short-term death. CONCLUSIONS: One-third of patients who receive VA-ECMO for early graft dysfunction do not survive 30 days or to hospital discharge, and one-half do not survive to 1 year after HT. Improving outcomes will require ongoing research focused on optimizing VA-ECMO strategies and care in the first year after HT.

Combining donor derived cell free DNA and gene expression profiling for non-invasive surveillance after heart transplantation.

BACKGROUND: Donor-derived cell free DNA (dd-cfDNA) and gene expression profiling (GEP) offer noninvasive alternatives to rejection surveillance after heart transplantation; however, there is little evidence on the paired use of GEP and dd-cfDNA for rejection surveillance. METHODS: A single center, retrospective analysis of adult heart transplant recipients. A GEP cohort, transplanted from January 1, 2015 through December 31, 2017 and eligible for rejection surveillance with GEP was compared to a paired testing cohort, transplanted July 1, 2018 through June 30, 2020, with surveillance from both dd-cfDNA and GEP. The primary outcomes were survival and rejection-free survival at 1 year post-transplant. RESULTS: In total 159 patients were included, 95 in the GEP and 64 in the paired testing group. There were no differences in baseline characteristics, except for less use of induction in the paired testing group (65.6%) compared to the GEP group (98.9%), P < .01. At 1-year, there were no differences between the paired testing and GEP groups in survival (98.4% vs. 94.7%, P = .23) or rejection-free survival (81.3% vs. 73.7% P = .28). CONCLUSIONS: Compared to post-transplant rejection surveillance with GEP alone, pairing dd-cfDNA and GEP testing was associated with similar survival and rejection-free survival at 1 year while requiring significantly fewer biopsies.

Diagnostic Accuracy of Cardiac MRI versus FDG PET for Cardiac Sarcoidosis: A Systematic Review and Meta-Analysis.

Background There is limited consensus regarding the relative diagnostic performance of cardiac MRI and fluorodeoxyglucose (FDG) PET for cardiac sarcoidosis. Purpose To perform a systematic review and meta-analysis to compare the diagnostic accuracy of cardiac MRI and FDG PET for cardiac sarcoidosis. Materials and Methods Medline, Ovid Epub, Cochrane Central Register of Controlled Trials, Embase, Emcare, and Scopus were searched from inception until January 2022. Inclusion criteria included studies that evaluated the diagnostic accuracy of cardiac MRI or FDG PET for cardiac sarcoidosis in adults. Data were independently extracted by two investigators. Summary accuracy metrics were obtained by using bivariate random-effects meta-analysis. Meta-regression was used to assess the effect of different covariates. Risk of bias was assessed using the Quality Assessment Tool for Diagnostic Accuracy Studies-2 tool. The study protocol was registered a priori in the International Prospective Register of Systematic Reviews (Prospero protocol CRD42021214776). Results Thirty-three studies were included (1997 patients, 687 with cardiac sarcoidosis); 17 studies evaluated cardiac MRI (1031 patients) and 26 evaluated FDG PET (1363 patients). Six studies directly compared cardiac MRI and PET in the same patients (303 patients). Cardiac MRI had higher sensitivity than FDG PET (95% vs 84%; P = .002), with no difference in specificity (85% vs 82%; P = .85). In a sensitivity analysis restricted to studies with direct comparison, point estimates were similar to those from the overall analysis: cardiac MRI and FDG PET had sensitivities of 92% and 81% and specificities of 72% and 82%, respectively. Covariate analysis demonstrated that sensitivity for FDG PET was highest with quantitative versus qualitative evaluation (93% vs 76%; P = .01), whereas sensitivity for MRI was highest with inclusion of T2 imaging (99% vs 88%; P = .001). Thirty studies were at risk of bias. Conclusion Cardiac MRI had higher sensitivity than fluorodeoxyglucose PET for diagnosis of cardiac sarcoidosis but similar specificity. Limitations, including risk of bias and few studies with direct comparison, necessitate additional study. © RSNA, 2022 Online supplemental material is available for this article.

Getting ahead of the game: in-hospital initiation of HFrEF therapies.

Hospitalizations for heart failure (HF) have become a global problem worldwide. Each episode of HF decompensation may lead to deleterious short- and long- term consequences, but on the other hand is an unique opportunity to adjust the heart failure pharmacotherapy. Thus, in-hospital and an early post-discharge period comprise an optimal timing for initiation and optimization of the comprehensive management of HF. This timeframe affords clinicians an opportunity to up titrate and adjust guideline-directed medical therapies (GDMT) to potentially mitigate poor outcomes associated post-discharge and longer-term. This review will cover this timely concept, present the data of utilization of GDMT in HF populations, discuss recent evidence for in-hospital initiation and up-titration of GDMT with a need for post-discharge follow-up and implementation this into clinical practice in patients with heart failure and reduced ejection fraction.

Impact of diabetes mellitus on clinical outcomes after heart transplantation.

PURPOSE: Diabetes mellitus (DM) is common among recipients of heart transplantation (HTx) but its impact on clinical outcomes is unclear. We evaluated the associations between pretransplant DM and posttransplant DM (PTDM) and outcomes among adults receiving HTx at a single center. METHODS: We performed a retrospective study (range 01/2008 - 07/2018), n = 244. The primary outcome was survival; secondary outcomes included acute rejection, cardiac allograft vasculopathy, infection requiring hospitalization, macrovascular events, and dialysis initiation post-transplant. Comparisons were performed using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: Pretransplant DM was present in 75 (30.7%) patients and was associated with a higher risk for infection requiring hospitalization (p < 0.05), but not with survival or other outcomes. Among the 144 patients without pretransplant DM surviving to 1 year, 29 (20.1%) were diagnosed with PTDM at the 1-year follow-up. After multivariable adjustment, PTDM diagnosis at 1-year remained associated with worse subsequent survival (hazard ratio 2.72, 95% confidence interval 1.03-7.16). Predictors of PTDM at 1-year included cytomegalovirus seropositivity and higher prednisone dose (> 5 mg/day) at 1-year follow-up. CONCLUSIONS: Compared to HTx recipients without baseline DM, those with baseline DM have a higher risk for infections requiring hospitalization, and those who develop DM after HTx have worse survival.

Risk factors for early development of cardiac allograft vasculopathy by intravascular ultrasound.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss. While there are numerous post-transplant factors which may increase the risk of the development of CAV, there is a paucity of data on the impact of donor-derived atherosclerosis (DA), early discontinuation of prednisone, and early initiation of proliferation signal inhibitors (PSI) as assessed by intravascular ultrasound (IVUS). METHODS: Retrospective single-center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually for 5 years. DA was defined as a baseline maximal intimal thickness (MIT) ≥0.5 mm, and CAV development was defined as MIT ≥1 mm or an increase in MIT ≥0.5 mm at year 1 compared with baseline or an increase in 0.3 mm annually thereafter. Clinical risk factors for CAV were identified using multivariable hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation and PSI initiation and CAV. RESULTS: Of 282 patients screened, 186 patients had a 1-year angiogram. The mean age of those included in the cohort was 51 ± 11 years, 70% were male, 58% were Caucasian, and 27% were supported by a left ventricular assist device. Donor atherosclerosis was present in 40%. The cumulative incidence of CAV at 5 years is 41% in DA- vs. 59% in DA + (p = .012). Donor age was a strong predictor of DA (p = .016). Significant risk factors for CAV included male sex (HR = 4.141, p = .001), non-Caucasian race (HR = 1.98, p = .011), BMI < 18 kg/m2 (HR = 4.596, p = .042), longer ischemic time (HR = 1.374, p = .028), older donor age (HR = 1.158, p = .009), and rejection with hemodynamic compromise within the first year (HR = 2.858, p = .043). Prednisone discontinuation within 1 year was associated with a lower risk of CAV (HR 0.58 p = .047). Initiation of proliferation signal inhibitors (PSI) within 2 years resulted in fewer cases of CAV (HR 0.397 p < .001). CONCLUSION: In patients with an angiogram at 1 year, those with DA were significantly more likely to develop CAV. Lower incidence of CAV by IVUS was seen in patients who discontinued prednisone in the first year or had initiation of a PSI within two years of transplantation. Knowledge of early IVUS may allow a more tailored approach to patient management.

A novel therapy for an unusual problem: IL-1 receptor antagonist for recurrent post-transplant pericarditis.

Heart transplant (HTx) recipients are at increased risk of pericardial disease. Idiopathic recurrent pericarditis has not been previously described following HTx. We describe a 35-year-old male who was admitted with pericarditis and moderate pericardial effusion 10 months after HTx. Two weeks before his admission, his prednisone had been tapered off. A thorough infectious workup and endomyocardial biopsy was unrevealing. He was started on colchicine with the addition of tapering prednisone regimen of 40 mg daily due to unresolved pain. Over the next several years, he had three recurrent episodes of pericarditis requiring re-initiation of prednisone with extensive investigations negative for rejection, autoimmune, and infectious causes. Cardiac MRI confirmed pericardial inflammation. Due to his recurrent course and inability to wean off prednisone, anakinra, an IL-1 receptor antagonist, was started at 100 mg sc daily. This allowed successful discontinuation of prednisone. He is now 34 months post-transplant without recurrence on anakinra and colchicine maintenance. Due to the overlap between idiopathic recurrent pericarditis and auto-inflammatory diseases, there is growing evidence for utilizing IL-1 receptor antagonists in this condition. While pericarditis is common in the HTx population, this is the first report of successful use of an IL-1 receptor blocker for pericarditis in this population.

Parvovirus B19-induced severe anemia in heart transplant recipients: Case report and review of the literature.

We report a case of a 64-year-old woman who developed transfusion-dependent anemia after cardiac transplantation, the etiology of which was unknown after initial comprehensive evaluation. At the suggestion of the Transplant Infectious Diseases consultant, microbial agents with red blood cell tropism pertinent to this patient such as Parvovirus B 19 (B19V) were investigated. The B19V viral load by PCR in peripheral blood was >100 000 000 copies/ml and after treatment with intravenous immunoglobulin (IVIG), her anemia resolved. Here, we summarize the clinical and virologic characteristics, treatment, and outcome of fifteen cases of B19V-induced anemia in heart transplant recipients. Spontaneous recovery from anemia secondary to B19V has also been reported in some heart transplant recipients, possibly due to an absence of their B19V P-antigen receptor and/or reduction in their immunosuppression. Therefore, in heart transplant patients, B19V should be suspected early as a cause of severe anemia of unknown etiology. The extent that B19V-induced anemia is underdiagnosed in heart transplant recipients is unknown.

Outcomes of patients with infection related to a ventricular assist device after heart transplantation.

BACKGROUND: Despite significant advances in durable mechanical support survival, infectious complications remain the most common adverse event after ventricular assist device (VAD) implantation and the leading cause of early death after transplantation. In this study, we aim to describe our local infectious epidemiology and review short-term survival and infectious incidence rates in the post-transplantation period and assess risk factors for infectious episodes after transplantation. METHODS: Retrospective single-center study of all consecutive adult heart transplant patients from 2008 to 2017. Survival data were estimated and summarized using the Kaplan-Meier method. We quantified and evaluated the difference in the incidence rate between patients with and without infection using a Fine-Gray model. The outcome of interest is the time to first infection diagnosis with post-transplant death as the competing event. RESULTS: Among 278 heart transplant patients, 74 (26.5%) underwent LVAD implantation. Twenty-one patients (28.3%) developed an infection while supported by an LVAD. When compared to patients supported by an LVAD without a preceding infection, BMI was significantly greater (31.2 vs 27.8 kg/m2 , P = .03). Median follow-up post-transplantation was 3.01 years. Significant risk factors for the competing risk regression for infection after heart transplantation include LVAD infection (HR 1.94, [95% CI] 1.11-3.39, P = .020) and recipient COPD (HR 2.14, [95% CI] 1.39-3.32, P = .001) when adjusted for recipient age, gender, hypertension, diabetes mellitus, and body mass index. CONCLUSIONS: Patients with LVAD-related infection had a significantly increased risk of infectious complications after heart transplantation. Further research on the avoidance of induction agents and reduced maintenance immunosuppression in this patient population is warranted.

De novo donor-specific HLA antibodies in heart transplantation: Do transient de novo DSA confer the same risk as persistent de novo DSA?

BACKGROUND: It is estimated that 25%-35% of heart transplant recipients develop de novo donor-specific antibodies (dnDSA). One factor that appears to play a role in clinical outcomes is DSA persistence. The objective of this study was to determine the incidence of transient and persistent dnDSA in a Canadian heart transplant population and to evaluate their impact on coronary allograft vasculopathy (CAV), graft function, and mortality. METHODS: A retrospective study of consecutive adult and transitioned pediatric heart transplant recipients (2008-2015) in Toronto was performed. Clinical demographics were collected prospectively. HLA antibody testing was performed using Luminex single antigen assays. In statistical analysis, dnDSA was modeled as a time dependent covariate. RESULTS: During a median follow-up of 4.1 years, dnDSA were detected in 42 (23%) with a median time to detection of 329 days (156-740); 27 (64%) developed persistent dnDSA. Persistent dnDSA conferred an increased risk of death with a HR 4.0 (95%CI 1.4-12.1) when adjusted recipient age, CAV, and cytomegalovirus status. CONCLUSIONS: Transient dnDSA were not associated with adverse outcomes after heart transplantation. This suggests that transient dnDSA may not require enhanced immunosuppression, increased HLA antibody monitoring, or additional physiological assessment. By knowing the transient dnDSA status, clinicians may minimize both recipient morbidity and cost without increasing harm.

Accepting hepatitis C virus-infected donor hearts for transplantation: Multistep consent, unrealized opportunity, and the Stanford experience.

The current mismatch between supply and demand of organs has prompted transplant clinicians to consider innovative solutions to broaden the donor pool. Advancements of direct-acting antiviral agent (DAA) therapy for hepatitis C virus (HCV) have allowed entertaining the use of viremic donor organs in nonviremic recipients. In this report, we describe the evolution of HCV treatment, ethics and informed consent, cost-effectiveness of HCV medications in treating acute HCV post-transplantation, and the Stanford experience with two HCV-viremic donor heart transplantations. We describe excellent short-term outcomes post-heart transplantation with HCV NAT-positive organs. The availability of this therapy may expand the donor pool. While we await larger-scale clinical data on the effectiveness and safety of DAA therapy in patients after heart transplantation, many transplant centers have already started accepting organs from HCV-infected donors, balancing the unknown long-term risks versus the benefits of shorter wait times and expansion of the donor pool. Protocols and multidisciplinary teams are needed to effectively communicate risk to potential recipients, to ensure timely DAA access, and to implement appropriate clinical follow-up in order to achieve excellent clinical outcomes and to maximize the donor pool by utilizing HCV-infected organs for heart transplantation.

The prognostic significance of frailty compared to peak oxygen consumption and B-type natriuretic peptide in patients with advanced heart failure.

Frailty assessment has become an integral part of the evaluation of potential candidates for heart transplantation and ventricular assist device (HTx/VAD). The impact of frailty, as a heart failure risk factor or to identify those who will derive the greatest benefit with HTx/VAD remains unclear. The aim of this study was to evaluate the independent prognostic relevance of frailty assessment from peak oxygen consumption (peak VO2 ) or B-type natriuretic peptide (BNP) on mortality in patients referred for advanced heart failure therapies. Frailty was measured using modified Fried frailty criteria. In 201 consecutive patients, during a median follow-up of 17.5 months (IQR 11-29.2), there were 25 (12.4%) deaths. One-year survival was 100%, 94%, and 78% in nonfrail, prefrail, and frail patients, respectively (log rank P = .0001). Frailty was associated with a twofold increase risk of death (HR 2.01, P < .0001, 95% CI 1.42-2.84). When adjusted for BNP or peak VO2 , frailty was not associated with a significant risk of all-cause death. However, when peak VO2 is stratified into two categories (≥12 mL/kg/min vs <12 mL/kg/min), frailty was associated with increased mortality in patients with a lower peak VO2 (HR 1.72, P = .006).

Early pneumopericardium after heart transplantation.

A 60-year-old woman with a history of dilated cardiomyopathy underwent heart transplantation. One month post discharge, she presented to clinic with low-grade fever and productive cough. Her chest radiograph showed air-fluid levels in the pericardial silhouette. Transthoracic echocardiogram showed a large complex pericardial collection with no evidence of cardiac tamponade. The patient was urgently taken to the operating room for exploration. A large "egg-shaped" mass in the pericardium measuring 10 × 12 cm with gaseous material was aspirated. As the posterior wall of the mass was firmly adhered to the right atrium, the capsule was incompletely excised. We present the case of a potentially life-threatening complication post transplantation that required surgical debridement and life-long antibiotic suppressive therapy. To our knowledge, this is the first report of purulent pericardial collection caused by Enterobacter cancerogenous. Further research is required to better understand the biology of this microorganism and the role it may play as a pathogen in immunocompromised patients following solid organ transplantation.

Advances in heart failure: a review of biomarkers, emerging pharmacological therapies, durable mechanical support and telemonitoring.

The purpose of this review is to provide an overview of diagnosis, prognosis and management of heart failure (HF) with reduced ejection fraction (HFrEF). Specifically, this review is divided into three sections. The first section will address biomarkers. The discovery of biomarkers has allowed further understanding of the pathophysiology of HF and provides insight into potential therapeutic targets. This review will focus on novel applications of natriuretic peptides (NPs) in clinical trials. Next, emerging biomarkers of HF, such as ST2, galectin-3 and copeptin, will be discussed. The second section aims to highlight HF therapies, including novel drugs and durable devices. The last section will review home haemodynamic monitoring and mobile health. We aim to provide context for the understanding of novel diagnostic and therapeutic advances in HF that are still in phase II or III trials, and have yet to become widely available.

Rejection Surveillance After Heart Transplantation: Is Paired Noninvasive Testing the New Gold Standard?

Rejection surveillance after heart transplantation has traditionally relied on numerous endomyocardial biopsies, most of which occur during the first posttransplant year. With the introduction of gene expression profiling and, more recently, donor-derived cell-free DNA, a great proportion of surveillance is being performed noninvasively with both tests. Although patients have welcomed the use of paired testing because of the decreased risk and inconvenience, interpretation of both tests can sometimes be challenging, particularly when the test results are discordant. Growing evidence from both single-center experiences and large national databases has given insights that have allowed the field to operationalize dual testing and provide physicians with algorithms to approach paired testing. The increased use of noninvasive testing has also begun to challenge the role of biopsy as the gold standard for graft monitoring, not only for rejection but over the life of the heart transplant. In a growing number of circumstances, cell-free DNA not only may be a better means of assessing rejection but could also redefine how clinicians approach the diagnosis and even treatment of graft injury. As the heart transplant community garners more experience and generates more data, the current paradigms of heart transplant surveillance will continue to be challenged.