Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients.

INTRODUCTION: Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR). METHODS: In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen. RESULTS: The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir. CONCLUSION: This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

Reliability of QuantiFERON®-CMV in predicting CMV recurrence in heart transplant recipients: A single-center retrospective study.

BACKGROUND: Recurrence after Cytomegalovirus (CMV) infection in heart transplant recipients is difficult to predict, in spite of its high incidence. Secondary prophylaxis could reduce this burden; however, its duration remains unestablished. We evaluated the QuantiFERON®-CMV test to see if it could predict CMV recurrence and help optimize the duration of secondary prophylaxis. METHODS: This observational retrospective single center study included all heart transplant recipients who developed CMV infection between 2019 and 2021, with the CD8+ T-cell-mediated CMV immunity QuantiFERON®-CMV test assessed at the time of (val)ganciclovir curative treatment completion. The main outcomes were CMV recurrence and duration of secondary prophylaxis. Secondary outcomes included immunosuppressive regimen, rejection, lymphocyte count, CMV viral load, infection type, and duration as possible confounding factors for recurrence. RESULTS: Among the 15 patients included, five (33%) experienced recurrence, of whom three (60%) had a positive QuantiFERON®-CMV test. The duration of secondary prophylaxis was similar regardless of QF-CMV positivity. No confounding factor was significantly associated with CMV recurrence; however, it occurred in only 1/7 (14%) of the patients receiving an everolimus-containing immunosuppressive regimen. CONCLUSION: In the population of heart transplant recipients, most of whom received ATG-based induction, the QuantiFERON®-CMV assay may not accurately predict CMV recurrence and would have not helped refining the duration of secondary prophylaxis in our patients. Other cell-mediated immunity tests and strategies in this specific population, including everolimus-containing regimens, may help predict and manage CMV recurrence.

Diuretic dose is a strong prognostic factor in ambulatory patients awaiting heart transplantation.

AIMS: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT). METHODS AND RESULTS: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05). CONCLUSIONS: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients.

Prognosis value of Forrester's classification in advanced heart failure patients awaiting heart transplantation.

AIMS: The value of Forrester's perfusion/congestion profiles assessed by invasive catheter evaluation in non-inotrope advanced heart failure patients listed for heart transplant (HT) is unclear. We aimed to assess the value of haemodynamic evaluation according to Forrester's profiles to predict events on the HT waitlist. METHODS AND RESULTS: All non-inotrope patients (n = 837, 79% ambulatory at listing) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 with right heart catheterization (RHC) were included. The primary outcome was a combined criteria of waitlist death, delisting for aggravation, urgent HT or left ventricular assist device implantation. Secondary outcome was waitlist death. The 'warm-dry', 'cold-dry', 'warm-wet', and 'cold-wet' profiles represented 27%, 18%, 27%, and 28% of patients, respectively. At 12 months, the respective rates of primary outcome were 15%, 17%, 25%, and 29% (P = 0.008). Taking the 'warm-dry' category as reference, a significant increase in the risk of primary outcome was observed only in the 'wet' categories, irrespectively of 'warm/cold' status: hazard ratios, 1.50; 1.06-2.13; P = 0.024 in 'warm-wet' and 1.77; 1. 25-2.49; P = 0.001 in 'cold-wet'. CONCLUSIONS: Haemodynamic assessment of advanced HF patients using perfusion/congestion profiles predicts the risk of the combine endpoint of waitlist death, delisting for aggravation, urgent heart transplantation, or left ventricular assist device implantation. 'Wet' patients had the worst prognosis, independently of perfusion status, thus placing special emphasis on the cardinal prominence of persistent congestion in advanced HF.

Right heart catheterization in advanced systolic heart failure. What are the most useful haemodynamic parameters for risk stratification?

BACKGROUND: Previous studies have shown that pulmonary hypertension is a predictor of mortality in patients with systolic heart failure (SHF). Persistent pulmonary hypertension after a reactivity test is associated with a worse outcome after transplantation. Recent studies have shown the utility of different haemodynamic parameters. AIMS: To define best haemodynamic parameters for risk stratification in patients with advanced systolic heart failure. METHODS: We included 425 consecutive patients who underwent a right heart catheterization with an inotropic challenge if indicated. RESULTS: During a median (interquartile range) follow-up of 1.67 (0.49-4.49) years, there were 151 major cardiac events (126 cardiovascular deaths and 25 postoperative deaths after ventricular assist device implantation or heart transplantation). The most powerful independent predictors of major cardiac events were baseline right atrial pressure (RAP) (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.06-1.12; P<0.0001) and baseline pulmonary vascular resistance (PVR) (HR: 1.10; 95% CI: 1.03-1.17; P=0.002). After inotropic challenge, the only independent predictor was mean pulmonary arterial pressure (mPAP) (HR: 1.06; 95% CI: 1.03-1.09; P<0.0001). The combination of PVR (≤or>3 Wood units), RAP (30mmHg) was the best predictor of major events. CONCLUSION: We suggest using a simple algorithm based on baseline PVR, baseline RAP and mPAP after the inotropic challenge for the risk stratification of stable patients with advanced systolic heart failure.

Heart Transplantation After Acute Aortic Dissection in an Adolescent With Marfan Syndrome.

This report presents the case of a 14-year-old patient with clinical features of Marfan syndrome who underwent an emergency Bentall procedure for acute type A aortic dissection. The patient required postoperative extracorporeal membrane oxygenation and was listed for heart transplantation because of persistent left ventricular failure caused by an intimal tear and thrombosis of the left main coronary artery. Heart transplantation was performed 5 days after the first procedure, and the patient was discharged 60 days after admission.

Characteristics and outcome of ambulatory heart failure patients receiving a left ventricular assist device.

AIMS: Despite regularly updated guidelines, there is still a delay in referral of advanced heart failure patients to mechanical circulatory support and transplant centres. We aimed to analyse characteristics and outcome of non-inotrope-dependent patients implanted with a left ventricular assist device (LVAD). METHODS AND RESULTS: The ASSIST-ICD registry collected LVAD data in 19 centres in France between February 2006 and December 2016. We used data of patients in Interagency Registry for Mechanically Assisted Circulatory Support Classes 4-7. The primary endpoint was survival analysis. Predictors of mortality were searched with multivariable analyses. A total of 303 patients (mean age 61.0 ± 9.9 years, male sex 86.8%) were included in the present analysis. Ischaemic cardiomyopathy was the leading heart failure aetiology (64%), and bridge to transplantation was the main implantation strategy (56.1%). The overall likelihood of being alive while on LVAD support or having a transplant at 1, 2, 3, and 5 years was 66%, 61.7%, 58.7%, and 55.1%, respectively. Age [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.00-1.05; P = 0.02], a concomitant procedure (HR 2.32, 95% CI 1.52-3.53; P < 0.0001), and temporary mechanical right ventricular support during LVAD implantation (HR 2.94, 95% CI 1.49-5.77; P = 0.002) were the only independent variables associated with mortality. Heart failure medications before or after LVAD implantation were not associated with survival. CONCLUSION: Ambulatory heart failure patients displayed unsatisfactory survival rates after LVAD implantation. A better selection of patients who can benefit from LVAD may help improving outcomes.

Fatal Enterovirus-related Myocarditis in a Patient with Devic's Syndrome Treated with Rituximab.

Enteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses - in particular, the Coxsackie B viruses - are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies.

Comparison of Outcomes and Mortality in Patients Having Left Ventricular Assist Device Implanted Early -vs- Late After Diagnosis of Cardiomyopathy.

LVAD implantation in patients with a recently diagnosed cardiomyopathy has been poorly investigated. This work aims at describing the characteristics and outcomes of patients receiving a LVAD within 30 days following the diagnosis of cardiomyopathy. Patients from the ASSIST-ICD study was divided into recently and remotely diagnosed cardiomyopathy based on the time from initial diagnosis of cardiomyopathy to LVAD implantation using the cut point of 30 days. The primary end point of the study was all-cause mortality at 30-day and during follow-up. A total of 652 patients were included and followed during a median time of 9.1 (2.5 to 22.1) months. In this population, 117 (17.9%) had a recently diagnosed cardiomyopathy and had LVAD implantation after a median time of 15.0 (9.0 to 24.0) days following the diagnosis. This group of patients was significantly younger, with more ischemic cardiomyopathy, more sudden cardiac arrest (SCA) events at the time of the diagnosis and were more likely to receive temporary mechanical support before LVAD compared with the remotely diagnosed group. Postoperative in-hospital survival was similar in groups, but recently diagnosed patients had a better long-term survival after hospital discharge. SCA before LVAD and any cardiac surgery combined with LVAD implantation were identified as 2 independent predictors of postoperative mortality in recently diagnosed patients. In conclusion, rescue LVAD implantation for recently diagnosed severe cardiomyopathy is common in clinical practice. Such patients experience a relatively low postoperative mortality and have a better long-term survival compared with remotely diagnosed patients.

Septuagenarian population has similar survival and outcomes to younger patients after left ventricular assist device implantation.

BACKGROUND: Left ventricular assist device (LVAD) implantation may be an attractive alternative therapeutic option for elderly patients with heart failure who are ineligible for heart transplantation. AIM: We aimed to describe the characteristics and outcomes of elderly patients (i.e. aged≥70 years) receiving an LVAD. METHODS: This observational study was conducted in 19 centres between 2006 and 2016. Patients were divided into two groups-younger (aged<70 years) and elderly (aged≥70 years), based on age at time of LVAD implantation. RESULTS: A total of 652 patients were included in the final analysis, and 74 patients (11.3%) were aged≥70 years at the time of LVAD implantation (maximal age 77.6 years). The proportion of elderly patients receiving an LVAD each year was constant, with a median of 10.6% (interquartile range 8.0-15.4%) per year, and all were implanted as destination therapy. Elderly and younger patients had similar durations of hospitalization in intensive care units and total lengths of hospital stays. Both age groups experienced similar rates of LVAD-related complications (i.e. stroke, bleeding, driveline infection and LVAD exchange), and the occurrence of LVAD complications did not impact survival in the elderly group compared with the younger group. Lastly, when compared with younger patients implanted as destination therapy, the elderly group also exhibited similar mid-term survival. CONCLUSION: This work strongly suggests that selected elderly adults can be scheduled for LVAD implantation.

Relation of Body Mass Index to Outcomes in Patients With Heart Failure Implanted With Left Ventricular Assist Devices.

We aimed at characterizing the impact of low and high body mass index (BMI) on outcomes after left-ventricular assist device (LVAD) surgery and define the predictors of mortality in patients with abnormal BMI (low/high). This study was conducted in 19 centers from 2006 to 2016. Patients were divided based on their baseline BMI into 3 groups of BMI: low (BMI ≤18.5 kg/m²); normal (BMI = 18.5 to 24.99 kg/m²) and high (BMI ≥25 kg/m²) (including overweight (BMI = 25 to 29.99 kg/m²), and obesity (BMI ≥30 Kg/m²)). Among 652 patients, 29 (4.4%), 279 (42.8%) and 344 (52.8%) had a low-, normal-, and high BMI, respectively. Patients with high BMI were significantly more likely men, with more co-morbidities and more history of ventricular/supra-ventricular arrhythmias before LVAD implantation. Patients with abnormal BMI had significantly lower survival than those with normal BMI. Notably, those with low BMI experienced the worst survival whereas overweight or obese patients had similar survival. Four predictors of mortality for LVAD candidates with abnormal BMI were defined: total bilirubin ≥16 µmol/L before LVAD, hypertension, destination therapy, and cardiac surgery with LVAD. Depending on the number of predictor per patients, those with abnormal BMI may be divided in 3 groups of 1-year mortality risk, i.e., low (0 to 1 predictor: 29% and 31%), intermediate (2 to 3 predictors, 51% and 52%, respectively), and high (4 predictors: 83%). In conclusion, LVAD recipients with abnormal BMI experience lower survival, especially underweight patients. Four predictors of mortality have been identified for LVAD population with abnormal BMI, differentiating those a low-, intermediate-, and high risks of death.

Successful treatment of Aspergillus fumigatus sternal osteomyelitis with isavuconazole in a heart transplant recipient.

A 65-year-old man was diagnosed with an invasive Aspergillus fumigatus infection with sternal osteomyelitis 4 months after heart transplantation. Unfortunately, after 8 weeks patient developed severe cutaneous and neurological toxicities induced by voriconazole leading to drug discontinuation. Therefore, isavuconazole was chosen as second-line therapy. The patient presented a favorable outcome and tolerance was excellent after ten months monotherapy. Here, we report for a first time, an successful isavuconazole-based treatment of sternal osteomyelitis aspergillosis in a cardiac recipient.

Outcomes of Left Ventricular Assist Device Implantation in Patients With Uncommon Etiology Cardiomyopathy.

The impact of uncommon etiology cardiomyopathies on Left-ventricular assist device (LVAD)-recipient outcomes is not very well known. This study aimed to characterize patients with uncommon cardiomyopathy etiologies and examine the outcomes between uncommon and ischemic/idiopathic dilated cardiomyopathy. This observational study was conducted in 19 centers between 2006 and 2016. Baseline characteristics and outcomes of patients with uncommon etiology were compared to patients with idiopathic dilated/ischemic cardiomyopathies. Among 652 LVAD-recipients included, a total of 590 (90.5%) patients were classified as ischemic/idiopathic and 62 (9.5%) patients were classified in the "uncommon etiologies" group. Main uncommon etiologies were: hypertrophic (n = 12(19%)); cancer therapeutics-related cardiac dysfunction (CTRCD) (n = 12(19%)); myocarditis (n = 11(18%)); valvulopathy (n = 9(15%)) and others (n = 18(29%)). Patients with uncommon etiologies were significantly younger with more female and presented less co-morbidities. Additionally, patients with uncommon cardiomyopathies were less implanted as destination therapy compared with ischemic/idiopathic group (29% vs 38.8%). During a follow-up period of 9.1 months, both groups experienced similar survival. However, subgroup of hypertrophic/valvular cardiomyopathies and CTRCD had significantly higher mortality compared to the ischemic/idiopathic or myocarditis/others cardiomyopathies. Conversely, patients with myocarditis/others etiologies experienced a better survival. Indeed, the 12-months survival in the myocarditis/others; ischemic/idiopathic and hypertrophic/CTRCD/valvulopathy group were 77%; 65%, and 46% respectively. In conclusion, LVAD-recipients with hypertrophic cardiomyopathy, valvular heart disease and CTRCD experienced the higher mortality rate.

Sarcoidosis diagnosed on granulomas in the explanted heart after transplantation: Results of a French nationwide study.

BACKGROUND: Cardiac sarcoidosis (CS) is a challenging diagnosis. Patients may progress to end-stage congestive heart failure and require cardiac transplantation without ever having been diagnosed. Characteristics and outcomes of patients with granulomas in the explanted hearts are unknown. METHODS: All French heart transplantation centers were contacted to participate in the study. Each center searched through local databases for the cases of non-caseating granuloma in the explanted hearts between 2000 and 2017. Data before and after transplantation were recorded from medical charts. Survival of CS and all- cause heart transplantation patients were compared. RESULTS: Fifteen patients (10 men, 5 women) received a diagnosis of CS based on pathologic data of the explanted heart and were recruited for the study. All patients were diagnosed as non-ischemic dilated or hypertrophic cardiomyopathy and presented congestive heart failure. Eight patients (53%) had ventricular rhythm disturbances, and 3 (20%) a complete heart block. Ten out of 13 patients (77%) had extracardiac radiological signs compatible with sarcoidosis on chest computed tomography (CT) scans. One patient died 3 months after transplantation from infectious complications. The 14 remaining patients were still alive at the end of the study (median follow-up of 28.8 months). One patient had a second heart transplantation 5 years later because of chronic allograft vasculopathy. One patient presented a relapse of CS confirmed by myocardial biopsies 9 years after transplantation, requiring an escalation of immunosuppressive therapy. CONCLUSION: CS may be undiagnosed before heart transplantation. In 77% of cases, sarcoidosis could have been detected before transplantation with non-invasive imaging techniques.

Assessment of potential heart donors: A statement from the French heart transplant community.

Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors.

Case report: Brincidofovir-induced reversible severe acute kidney injury in 2 solid-organ transplant for treatment of cytomegalovirus infection.

RATIONALE: Resistant cytomegalovirus-mediated infections are increasing in solid organ recipient with few available alternative treatments. Brincidofovir is an oral broad-spectrum antiviral in development for prevention and treatment of viral infection, particularly cytomegalovirus. PATIENTS CONCERNS: Although brincidofovir is an analogue of cidofovir, previous studies reported no renal toxicity. DIAGNOSES: Here, we report 2 cases of severe tubular necrosis in solid organ recipients, 1 heart and 1 kidney transplant. INTERVENTIONS: Both patients received brincidofovir for the treatment of cytomegalovirus infection with mutation of UL-97. They presented an acute kidney injury without any occurrence of other clinical event such as introduction of nephrotoxic drug, graft rejection, urinary tract obstruction or infection, and calcineurin inhibitor overdosage. In each case, renal biopsy showed extended tubular necrosis. OUTCOMES: The discontinuation of brincidofovir led to improve renal function without other any intervention. Reintroduction of brincidofovir in case 1, due to the absence of other medical alternative, led to a new episode of acute kidney injury. One more time, renal biopsy showed tubular necrosis and patient recovered renal function after discontinuation. LESSONS: To our knowledge, this is the first report of brincidofovir-mediated renal adverse event. Clinicians may be aware of this severe complication in this specific population.

Drug interaction between dabrafenib and immunosuppressive drugs: about one case.

Melanoma is a major public health problem. In recent years, it has been shown that melanoma can be characterized by specific oncogenes mutations such as the BRAF mutation, leading to the development of new therapeutic drugs. Dabrafenib is an inhibitor of BRAF, approved as a first-line treatment of metastatic or unresectable stage 3 or 4 melanoma with the BRAF mutation. Few studies have evaluated the drug interaction potential of dabrafenib. This molecule is an enzyme inducer that increases the synthesis of drug-metabolizing enzymes, including CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT enzymes. Accordingly, the plasma concentrations of drugs metabolized by these enzymes are decreased. The decrease in plasma concentrations may cause a reduction or even loss of the clinical effect of these drugs. Many drugs metabolized by these enzymes may be affected, especially midazolam, warfarin, or rifampicin. However, interactions with immunosuppressants have not been described. Everolimus and tacrolimus are two immunosuppressive drugs metabolized by CYP3A4. We report a case of drug interaction between dabrafenib and immunosuppressive drugs (everolimus, tacrolimus), observed in a transplanted heart patient, requiring dosage adjustment of its immunosuppressive treatment to avoid graft rejection.