Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.

Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are approved for multiple cancers but can result in ICI-associated myocarditis, an infrequent but life-threatening condition. Elevations in cardiac biomarkers, specifically troponin-I (cTnI), troponin-T (cTnT), and creatine kinase (CK), are used for diagnosis. However, the association between temporal elevations of these biomarkers with disease trajectory and outcomes has not been established. METHODS: We analyzed the diagnostic accuracy and prognostic performances of cTnI, cTnT, and CK in patients with ICI myocarditis (n=60) through 1-year follow-up in 2 cardio-oncology units (APHP Sorbonne, Paris, France and Heidelberg, Germany). A total of 1751 (1 cTnT assay type), 920 (4 cTnI assay types), and 1191 CK sampling time points were available. Major adverse cardiomyotoxic events (MACE) were defined as heart failure, ventricular arrhythmia, atrioventricular or sinus block requiring pacemaker, respiratory muscle failure requiring mechanical ventilation, and sudden cardiac death. Diagnostic performance of cTnI and cTnT was also assessed in an international ICI myocarditis registry. RESULTS: Within 72 hours of admission, cTnT, cTnI, and CK were increased compared with upper reference limits (URLs) in 56 of 57 (98%), 37 of 42 ([88%] P=0.03 versus cTnT), and 43 of 57 ([75%] P<0.001 versus cTnT), respectively. This increased rate of positivity for cTnT (93%) versus cTnI ([64%] P<0.001) on admission was confirmed in 87 independent cases from an international registry. In the Franco-German cohort, 24 of 60 (40%) patients developed ≥1 MACE (total, 52; median time to first MACE, 5 [interquartile range, 2-16] days). The highest value of cTnT:URL within the first 72 hours of admission performed best in terms of association with MACE within 90 days (area under the curve, 0.84) than CK:URL (area under the curve, 0.70). A cTnT:URL ≥32 within 72 hours of admission was the best cut-off associated with MACE within 90 days (hazard ratio, 11.1 [95% CI, 3.2-38.0]; P<0.001), after adjustment for age and sex. cTnT was increased in all patients within 72 hours of the first MACE (23 of 23 [100%]), whereas cTnI and CK values were less than the URL in 2 of 19 (11%) and 6 of 22 (27%) of patients (P<0.001), respectively. CONCLUSIONS: cTnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis. A cTnT:URL ratio <32 within 72 hours of diagnosis is associated with a subgroup at low risk for MACE. Potential differences in diagnostic and prognostic performances between cTnT and cTnI as a function of the assays used deserve further evaluation in ICI myocarditis.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

State-of-the-Art of Endomyocardial Biopsy on Acute Myocarditis and Chronic Inflammatory Cardiomyopathy.

PURPOSE OF REVIEW: Histologic evidence of myocardial inflammatory infiltrate not secondary to an ischemic injury is required by current diagnostic criteria to reach a definite diagnosis of myocarditis. Endomyocardial biopsy (EMB) is therefore often indicated for the diagnosis of myocarditis, although it may lack sufficient sensitivity considering the limited possibility of myocardial sampling. Improving the diagnostic yield and utility of EMB is of high priority in the fields of heart failure cardiology and myocarditis in particular. The aim of the present review is to highlight indications, strengths, and shortcomings of current EMB techniques, and discuss innovations currently being tested in ongoing clinical studies, especially in the setting of acute myocarditis and chronic inflammatory cardiomyopathy. RECENT FINDINGS: EMB provides unique diagnostic elements and prognostic information which can effectively guide the treatment of myocarditis. Issues affecting the diagnostic performance in the setting of acute myocarditis and chronic inflammatory cardiomyopathies will be discussed in this review in the light of recent expert consensus documents on the management of these conditions and on indication to EMB. Recent innovations using electroanatomic mapping (EAM)-guided EMB and fluoroscopic-guided EMB during temporary mechanical circulatory support have improved the utility of the procedure. EMB remains an important diagnostic test whose results need to be interpreted in the context of (1) clinical pre-test probability, (2) timing of sampling, (3) quality of sampling (4) site of sampling, (5) histologic type of myocarditis, and (6) analytic methods that are applied. Herein we will review these caveats as well as perspectives and innovations related to the use of this diagnostic tool.

Femoral Access for Iliac Branched Endoprosthesis Deployment in Patients with a Prior Bifurcated Aortic Stent Graft.

This series describes an innovative technique to deploy iliac branched endoprostheses (IBEs) in patients with preexisting endovascular aneurysm repair (EVAR). It demonstrates an alternative approach that may be preferred when brachial access is anatomically challenging or when access site complications are of concern. We detail a technique that uses transfemoral access to bring IBE device components up and over an infrarenal endograft bifurcation and into proper position. This series suggests that endovascular specialists should consider the advantages and disadvantages of a transfemoral approach when selecting the best method of repairing a patient's iliac artery aneurysm after prior EVAR.

Trends in vena cava filter insertions and "prophylactic" use.

BACKGROUND: Prophylactic vena cava filter (VCF) use in patients without venous thromboembolism is common practice despite ongoing controversy. Thorough analysis of the evolution of this practice is lacking. We describe trends in VCF use and identify events associated with changes in practice. METHODS: Using the National Inpatient Sample, we conducted a retrospective observational study of U.S. adult hospitalizations from 2000 to 2014. Trends in prophylactic VCF insertion were analyzed both across the entire study population and within subgroups according to trauma status and type of concurrent surgery. Annual percentage change (APC) was calculated, and trends were analyzed using Poisson regression. RESULTS: Among 461,904,314 adult inpatients (median [interquartile range] age, 58.1 [38.5-74.3] years; 39.6% male), the incidence of VCF insertion increased rapidly at first (from 0.19% to 0.35%; APC, 11.2%; 95% confidence interval [CI], 10.3%-12.2%; P < .001), then at a slower rate after the publication of the Prévention du Risque d'Embolie Pulmonaire par Interruption Cave 2 (PREPIC2) trial in 2005 (from 0.35% to 0.42%; APC, 4.4%; 95% CI, 2.8%-6.0%; P < .001), and it began decreasing after the 2010 Food and Drug Administration (FDA) safety alert (from 0.42% to 0.32%; APC, -5.5%; 95% CI, -6.5% to -4.6%; P < .001). The percentage of total VCFs that had a prophylactic indication increased quickly before publication of the PREPIC2 trial (APC, 19.5%; 95% CI, 17.9%-21.0%; P < .001), increased at a slower rate after publication in 2005 (APC, 4.4%; 95% CI, 2.6%-6.2%; P < .001), and dropped after the FDA safety alert, stabilizing at 18.5% for the last 3 years (APC, -0.3%; 95% CI, -2.2% to 1.7%; P = .8). Subgroups most associated with prophylactic VCF insertion were operative trauma (odds ratio [OR], 10.9; 95% CI, 10.2-11.7), orthopedic surgery (OR, 4.7; 95% CI, 4.3-5.2), and neurosurgical procedures (OR, 3.9; 95% CI, 3.6-4.2). All groups except orthopedic surgery experienced a deceleration in prophylactic VCF growth after the publication of PREPIC2. Meanwhile, the FDA safety alert was associated with a decrease in prophylactic VCF insertions for all groups except other major surgery. CONCLUSIONS: Whereas publication of the PREPIC2 trial led to a deceleration in prophylactic VCF insertion growth, the FDA alert had a bigger impact, leading to declining rates of prophylactic VCF use. Further investigations of prophylactic insertion of VCF in trauma, orthopedic, and neurosurgical patients are needed to determine whether current levels of use are justified.

Preoperative inflammatory status as a predictor of primary patency after femoropopliteal stent implantation.

OBJECTIVE: The purpose of this study was to evaluate the impact of preoperative inflammatory status, as determined by complete blood count test parameters, on 12- and 24-month patency of femoropopliteal stenting for peripheral arterial disease. METHODS: We retrospectively analyzed baseline clinical and angiographic data among 138 patients (median age, 73 years; 46% female) from 2005 to 2014 at our institution with preoperative complete blood count test values and information of patency for at least 12 months after first-time femoropopliteal stenting. Patients were stratified into tertiles on the basis of preoperative blood counts to evaluate associations with in-stent restenosis (ISR) leading to loss of primary patency, defined by a Doppler velocity ratio ≥2.5:1, computed tomography angiography demonstrating ≥50% luminal narrowing within the stent, or reintervention. RESULTS: Univariate analysis determined that the 81 patients (59%) who experienced ISR within 12 months had significantly higher preoperative white blood cell (WBC), platelet, neutrophil, and lymphocyte counts than the 57 patients (41%) whose stents remained patent for longer than 12 months (8.7 vs 6.7 [P < .001], 246 vs 184 [P < .001], 5.7 vs 4.7 [P = .001], and 1.8 vs 1.2 [P = .004], respectively). Compared with patients in the lower WBC tertile (n = 45) who had a median patency of 19.4 months, those in the upper WBC tertile (n = 44) had a median patency of only 7.0 months and a 3.3-fold increased risk for ISR after adjusting for age, sex, lesion type, TransAtlantic Inter-Society Consensus II score, tibial vessel runoff, antiplatelet therapy, presence of diabetes, critical limb ischemia, adjunct procedures, hyperlipidemia, and end-stage renal disease in multivariate analysis (P < .001). Compared with patients in the lower platelet tertile (n = 45) who had a median patency of 16.9 months, those in the upper platelet tertile (n = 47) had a median patency of 7.1 months and a 2.7-fold increased adjusted risk (P = .001). Compared with patients in the lower neutrophil tertile (n = 33) who had a median patency of 14.3 months, those in the upper neutrophil tertile (n = 33) had a median patency of 6.2 months and a 3.2-fold increased adjusted risk (P = .001). After adjusting for covariates, patients divided into tertiles by lymphocyte counts exhibited no significant differences for ISR. CONCLUSIONS: Routine preoperative tests that determine baseline inflammatory status may provide strong clinical utility in assessing potential risk stratification of patients for ISR after femoropopliteal stenting. Circulating WBCs, platelets, and neutrophils may be important inflammatory mediators of ISR.

The Impact of Surgical Care Improvement Project Measures on In-Hospital Outcomes following Elective Vascular Procedures.

BACKGROUND: As part of the Surgical Care Improvement Project (SCIP), a national quality partnership of organizations including the Centers for Medicare and Medicaid Services and the Centers for Disease Control and Prevention implemented several perioperative guidelines regarding antibiotic, venous thromboembolism (VTE), and beta-blocker prophylaxis for surgical patients. We evaluated the effect of SCIP on in-hospital surgical site infections (SSI), graft infections, VTE, myocardial infarctions (MIs), cardiac complications, mortality, and length of stay following elective major vascular surgery. METHODS: Using International Classification of Diseases, Ninth Revision (ICD-9) diagnostic and procedure codes, we identified elective open abdominal aneurysm repair (OAR), endovascular aneurysm repair (EVAR), carotid endarterectomy (CEA), major lower extremity amputation, and lower extremity bypass (LEB) procedures in the National Inpatient Sample from 2000 to 2012. Logistic regression and generalized linear models controlling for covariates were used to compare postoperative in-hospital outcomes before and after SCIP implementation (pre-SCIP era 2000-2005 versus post-SCIP era 2009-2012). RESULTS: In the post-SCIP era, the rate of in-hospital SSI following OAR increased from 1.0% to 1.6% (P < 0.05). Nonetheless, there were improvements in in-hospital SSI (in EVAR and CEA), graft infections (in OAR, EVAR, and LEB for tissue loss), VTE (in CEA), MI (in EVAR and LEB for tissue loss), cardiac complication (in all procedures except OAR), mortality (in EVAR, CEA, major lower extremity amputation, and LEB for tissue loss), and length of stay (in all procedures except OAR) (all P < 0.05). However after adjusting for covariates, SCIP was only associated with reducing SSI in CEA and major lower extremity amputation, graft infections in OAR and LEB for tissue loss, VTE in LEB for claudication or rest pain, mortality in OAR, and length of stay in all procedures except EVAR and CEA. CONCLUSIONS: Implementation of SCIP measures was associated with slight improvements in a few in-hospital outcomes following vascular procedures. Additional measures that are more specific to the clinical and technical challenges of treating vascular disease may be more effective for improving the management of vascular patents.

Reconstruction of "unreconstructable" critical limb ischemia with hybrid techniques.

This case describes the surgical repair of critical limb ischemia in a patient with diffuse multilevel peripheral arterial disease. It demonstrates the value of patient-specific approaches that employ hybrid endovascular and open surgical techniques to reconstruct blood flow in patients who are not ideal candidates for traditional revascularization. We detail a technique that combines endarterectomy, femoropopliteal bypass, angioplasty, and stenting. This case suggests that innovative hybrid approaches can be used to achieve limb salvage in some patients with multilevel peripheral vascular disease who would otherwise undergo primary amputation.