Endomyocardial Biopsy In Patients Research Articles

Routine application of cardiac magnetic resonance imaging in patients with suspected myocarditis from immune checkpoint inhibitor therapy

Abstract Background Cardiovascular adverse events including myocarditis associated with immune checkpoint inhibitor (ICI) therapy remain a challenge in clinical practice. Diagnostic assessment of ICI-related myocarditis (ICI-M) is challenging due to a variable phenotype, confounding effects and limited sensitivity of diagnostic tools. Cardiac magnetic resonance imaging (CMR) is used to diagnose non-ICI myocarditis, but evidence on diagnostic sensitivity is low, particularly in patients with a discrete phenotype. Here, we aim to assess the impact of CMR in patients with suspected ICI-related myocarditis and relate to final diagnosis including endomyocardial biopsy findings. Methods All consecutive patients receiving CMR for suspected ICI-M between September 2019 and January 2024 were included and retrospectively analysed. CMR parameters were correlated with clinical, laboratory and echocardiographic parameters and stratified for presence or absence of myocarditis as per final diagnosis. Results A total of 55 patients who received CMR for suspected ICI-related myocarditis were analysed, including 25 patients with confirmed ICI-M as per final diagnosis and 30 patients with cardiotoxicity other than myocarditis or no cardiotoxicity (ICI-O). The mean age (ICI-M versus ICI-O) was 65.7±13.6 versus (vs.) 67.3±9.9 (p=0.61) years, 32.0% vs. 26.7% (p=0.67) were female, and 40.0% vs. 26.7% (p=0.29) had pre-existing coronary heart disease. Cardiac biomarkers and echocardiographic data did not differ between the groups. In CMR analysis, presence of late gadolinium enhancement (LGE) was associated with ICI-M (56.0% vs. 26.7%, p=0.027). Myocardial oedema was generally rare and not associated with ICI-M. Endomyocardial biopsy (EMB) was used in 6 out of 55 patients (10.9%) with suspected ICI-M. In 4 of these 6 patients (66.7%) EMB confirmed ICI-M diagnosis. Of note, only 2/4 patients with EMB-confirmed myocarditis showed abnormal CMR findings. Conclusion The diagnostic assessment of ICI-M is challenged by low sensitivity of common diagnostic measures, often requiring a multimodal approach. Presence of LGE in CMR was associated with ICI-M, but sensitivity and specificity are low. Our data emphasize the high value of EMB in patients with clinically suspected ICI-M despite inconspicuous CMR. Prospective data to improve diagnostic criteria are needed.

Endomyocardial biopsy in patients with myocarditis - still justified in the CMR era? A single-centre experience

Abstract Background Endomyocardial biopsy (EMB) is still considered the diagnostic gold standard for myocarditis. However, in the past decades, cardiac magnetic resonance (CMR) was established as a non-invasive tool supporting the diagnosis of myocarditis. Furthermore, there is often reluctance in performing EMB due to rare but potentially severe complications. We therefore sought to identify patient subgroups that could potentially derive benefits from EMB. This involved a comprehensive analysis of the diagnostic and therapeutic outcomes resulting from the procedure at our centre. Methods In this retrospective single-centre study, data of all patients presenting with (peri-) myocarditis between 01/2016 and 06/2023 at our tertiary care centre were included. Frequency of histological confirmation of acute myocarditis and histology leading to immunosuppressive therapy were analysed according to patient risks. Prespecified risk factors were (i) LV-EF ≤30%, (ii) presence of severe arrhythmias (VF, VT, high grade AV-block) or (iii) pre-existing autoimmune disease. Furthermore, the subgroup of recurrent myocarditis cases was analysed separately. Results A total of 150 consecutive patients (36.7 ± 15.5 years, 77.3% male) were included in this study. 26/150 patients had a documented EF ≤30%, 13/150 an EF >30% with another risk factor and 111/150 an EF>30% without another risk factor. EMB was performed in 21/26 patients with EF ≤30% (80.7%), in 7/13 patients with EF >30% and another risk factors (53.8%) and in 16/111 (14%) patients without risk factors. EMB led to the initiation of immunosuppressive therapy in 11/28 patients with risk factors (39.3%) and in none of the patients without risk factors (0/16, 0%, p=0.003)(figure 1). With respect to the subgroup of patients presenting with recurrent myocarditis (n=10), no specific therapy was performed. Conclusion Due to a high therapeutic yield for initiation of immunosuppressive therapy in non-infectious myocarditis, performing EMB should be considered in all high-risk patients. In patients without clinical risk factors including cases of recurrent or relapsing myocarditis no specific therapy was initiated.

Prognostic value of electroanatomic-guided endomyocardial biopsy in patients with myocarditis, arrhythmogenic cardiomyopathy and non dilated left ventricular cardiomyopathy

A wide variety of non-invasive and invasive techniques for SCD risk stratification in non ischemic cardiomyopathy (NICM) have been proposed, including left ventricular (LV) ejection fraction, QRS duration, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and invasive electrophysiologic study with or without three-dimensional electroanatomic mapping (3D-EAM), to identify and characterize the arrhythmogenic substrate. There is still no clear consensus on the risk stratification in this clinical setting.The aim of our study is to characterize the 3D-EAM substrate in patients with the same clinical presentation of unexplained complex VAs and NICM using CMR, three-dimensional electranatomic mapping (3D-EAM) in association with endomyocardial biopsy (EMB) and genetic screening, as a more precise and early diagnostic assessment may provide important subsequent prognostic impact. The study was designed as a prospective multi-center observational evaluation and the patient follow-up was scheduled at 6 months interval. We enrolled 125 patients distinct into four different group by complete diagnostic work-up: myocarditis, non-dilated left ventricular cardiomyopathy, arrhythmogenic cardiomyopathy and control group. The four groups were compared in terms of clinical, imaging and 3D-EAM data. At multivariate analysis sustained VT/VF on admission [HR: 3.64 (1.79–7.4), p < 0.001], total bipolar scar area of left and right ventricle detected by 3D-EAM [HR: 2.24 (1.13–4.49), p = 0.02], histological diagnosis of myocarditis by 3D-EAM guided endomyocardial biopsy (EBM) [HR: 2.79 (1.04–7.44), p = 0.01] were independent predictors of complex VAs or death at follow-up. 3D-EAM guided EMB represent not only a valid diagnostic tool to identify the arrhythmogenic substrate in patients with NICM and ventricular arrhythmic phenotype but also an important predictor of complex Vas at long term follow-up.

Current barriers and recommendations on the diagnosis of transthyretin amyloid cardiomyopathy: a Delphi study

ObjectivesThis study has been conducted to investigate the non-invasive diagnostic journey of patients with a transthyretin amyloid cardiomyopathy (aTTR-CM) in Turkey, identify the challenges and uncertainties encountered on the path to diagnosis from the perspectives of expert physicians, and develop recommendations that can be applied in such cases.MethodsThis study employed a three-round modified Delphi method and included 10 cardiologists and five nuclear medicine specialists. Two hematologists also shared their expert opinions on the survey results related to hematological tests during a final face-to-face discussion. A consensus was reached when 80% or more of the panel members marked the “agree/strongly agree” or “disagree/strongly disagree” option.ResultsThe panelists unanimously agreed that the aTTR-CM diagnosis could be established through scintigraphy (using either 99mTc-PYP, 99mTc-DPD, or 99mTc-HMPD) in a patient with suspected cardiac amyloidosis (CA) without a further investigation if AL amyloidosis is ruled out (by sFLC, SPIE and UPIE). In addition, scintigraphy imaging performed by SPECT or SPECT-CT should reveal a myocardial uptake of Grade ≥2 with a heart-to-contralateral (H/CL) ratio of ≥1.5. The cardiology panelists recommended using cardiovascular magnetic resonance (CMR) and a detailed echocardiographic scoring as a last resort before considering an endomyocardial biopsy in patients with suspected CA whose scintigraphy results were discordant/inconclusive or negative but still carried a high clinical suspicion of aTTR-CM.ConclusionThe diagnostic approach for aTTR-CM should be customized based on the availability of diagnostic tools/methods in each expert clinic to achieve a timely and definitive diagnosis.

Outcomes and clinical impact of early endomyocardial biopsy in patients with fulminant myocarditis

Outcomes and clinical impact of early endomyocardial biopsy in patients with fulminant myocarditis

Endomyocardial biopsy and its significance in the diagnosis of non-coronary heart disease. Clinical observation

Objective: to analyze the results of 27 endomyocardial biopsies in patients with various non­coronary myocardial diseases. Materials and methods. 27 diagnostic myocardial biopsies were performed in patients with the clinical picture of non­coronary myocardial diseases treated in the “A.A. Vishnevsky NMIC VMT” of the Russian Ministry of Defense in 2021–2022. There were 22 men and 5 women. The age ranged from 19 to 68 years (mean age 44 years). Results. Among 27 patients studied, inflammatory myocardial disease was detected in16 (59.2%); Inflammatory pericardial disease in 4 (14.8%); No inflammatory changes were detected in 7 (25.9%). Among 16 patients (59.2%) with inflammatory myocardial diseases, immunohistochemical signs of inflammatory myocardial disease were detected in 8 (50%) patients with cardiomyopathies (hypertrophic, arrhythmogenic). Myocarditis with wall amyloidosis was detected in 3 (18.7%). Myocardial cardiosclerosis was diagnosed in 5 (31.2%) cases. According to the results of myocardial virologic study, viral genome was detected in myocardium in 14 (51.8%) patients out of 27: in 9 (64.2%) cases this was a monoinfection with parvovirus B19, in 4 (28.5%) cases it was associated with herpes virus type 6 and in 1 case (7.14%) – a monoinfection with SARS­CoV­2 was revealed. Conclusions. The nosologic principle of selection was a prerequisite of high informativity of EMB in all 27 patients. The obtained data emphasize the necessity of EMB in those cases when clinical manifestations of the disease cannot be explained by the underlying pathology. Keywords: myocarditis, viral infection, endomyocardial biopsy, non­coronary heart disease

Additional diagnostic value of electron microscopic examination in endomyocardial biopsy in patients with suspected non-ischemic cardiomyopathy

BackgroundElectron microscopy enables a finely detailed analysis of ultra-structural features, and hence, it generally has an added diagnostic value to light microscopy alone. However, no studies have verified the additional diagnostic value of electron microscopic examination in patients with suspected non-ischemic cardiomyopathy. MethodsA total of 294 consecutive patients with non-ischemic cardiomyopathy who underwent endomyocardial biopsy were prospectively enrolled. Patients were divided into three groups according to left ventricular morphology assessed using echocardiography. Myocardial specimens were collected from the right ventricular septum and examined by light microscopy. Electron microscopy was performed subsequently to evaluate the additional diagnostic value. ResultsAltogether, 294 patients were analyzed, including 160 (55 %), 96 (33 %), and 35 (12 %) patients who were diagnosed with primary, secondary, and unclassified cardiomyopathy, respectively. In patients with dilated cardiomyopathy-like morphology, the detection rate of disease-specific histological findings was relatively low compared to that in patients with other cardiac morphologies. The additional diagnostic value of electron microscopy was observed in eight patients, including five with Fabry disease, one with cardiac amyloidosis, one with mitochondrial cardiomyopathy, and one with triglyceride deposit cardiomyovasculopathy. Among the 18 cardiac amyloidosis cases, electron microscopy detected amyloid fibrils in all patients, whereas light microscopy could not detect amyloid deposition in 1 patient. Among one of five patients with Fabry disease, light microscopy did not show obvious vacuolated cardiomyocytes, but zebra bodies were detected by electron microscopy, leading to the diagnosis of cardiac Fabry disease. The diagnostic value of electron microscopic examination in patients with cardiac sarcoidosis was not observed. ConclusionsThe additional diagnostic value of electron microscopy was observed in patients with secondary cardiomyopathy, in whom light microscopy did not show disease-specific histological findings. Electron microscopy should be performed in cases where secondary cardiomyopathy is strongly suspected with no disease-specific findings by light microscopy.

Safety and usefulness of left ventricular endomyocardial biopsy in new- onset acute heart failure requiring mechanical support by an Impella® device

BackgroundIn patients with de novo acute heart failure (AHF) requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO), endomyocardial biopsy (EMB) has been recently shown to be feasible and a helpful method to clarify differential diagnoses, including acute myocarditis. This study aimed to evaluate the feasibility and safety of EMB in patients with a left ventricular (LV) implanted Impella® device. Methods and resultsThis retrospective, single-center study involves 22 cardiogenic shock patients [SCAI shock stage: C (91%)] requiring mechanical circulatory support (MCS) either by Impella® axial pumps [20 patients (91%)] alone or in combination with VA-ECMO [2 patients (9%)] between December 2017 and January 2022. Coronary artery disease (CAD) or severe valvular heart disease were excluded. The study's primary endpoint was to verify the safety of EMB during MCS. Furthermore, histopathological analysis of the EMB samples was described. 30 LV-EMB procedures were performed. No major complications were reported (death, sustained ventricular tachycardia, need for cardiopulmonary resuscitation, cardiac tamponade, stroke, major bleeding). In 14 patients (64%), EMB-derived histology/immunohistology led to the definitive diagnosis of acute myocarditis. ConclusionsEMB can be safely performed in patients suffering from cardiogenic shock requiring an Impella®-based MCS without the risk of major complications. In about 50% of the patients, relevant inflammatory heart disease could be detected, which required a change in treatment decisions.

P.045 Biopsies of the transverse carpal ligament and tenosynovium for tissue confirmation of transthyretin amyloidosis

Background: Transthyretin Amyloidosis (ATTR) is a common cause of both cardiomyopathy and carpal tunnel syndrome, with many patients needing carpal tunnel release (CTR). Although tafamidis is now an approved treatment of ATTR cardiomyopathy, insurers in most provinces require biopsy confirmation of amyloidosis. Endomyocardial biopsy is often the chosen approach due to optimal sensitivity, albeit with risk of serious adverse events such as stroke, cardiac tamponade, and arrhythmias. CTR may present an ideal opportunity for obtaining amyloidosis biopsy confirmation. Methods: ATTR patients undergoing CTR had biopsy of their transverse carpal ligament (TCL) and/or flexor tenosynovium to assess the sensitivity of both sites for biopsy confirmation of amyloidosis. Results: Twelve patients consecutively underwent biopsies during CTR, with 4 (33%) having bilateral CTR and biopsy. Among 16 TCL biopsies and 14 tenosynovium biopsies, 100% demonstrated amyloid deposition. Another patient had isolated tenosynovium biopsy without CTR and also demonstrated amyloidosis. There were no serious adverse events, and 1/13 (8%) had wound dehiscence requiring repeat suturing. Conclusions: Biopsy of the TCL and/or tenosynovium during CTR is safe, cost-effective, and sensitive, and may represent an alternative to endomyocardial biopsy in patients requiring tissue confirmation for tafamidis approval. ATTR patients eligible for tafamidis may benefit from early neurology assessment.

Clinical impact of the pathological quantification of myocardial fibrosis and infiltrating T lymphocytes using an endomyocardial biopsy in patients with hypertrophic cardiomyopathy

BackgroundThe impact of quantitative pathological findings derived from endomyocardial biopsies (EMB) on clinical prognosis in patients with hypertrophic cardiomyopathy (HCM) remains unclear. MethodsWe retrospectively studied 55 consecutive HCM patients who underwent EMB. We quantified the collagen area fraction (CAF), the cardiomyocyte diameter, the nuclear area and circularity, and the number of myocardial infiltrating CD3+ cells using EMB samples by image analyzing software. The primary clinical endpoint was defined as a composite including cardiovascular death, admission due to heart failure and ventricular arrhythmia. ResultsDuring the median follow-up of 37.2 months, the primary endpoint was found in 12 patients. No significant difference in the risk score of 5-year sudden cardiac death was observed between the event-occurrence group and the event-free group. In the multivariable Cox proportional-hazard analysis, CAF [hazard ratio (HR) per 10% increase: 1.555, 95% CI: 1.014–2.367, p = 0.044] and the number of infiltrating CD3+ cells (HR per 10% increase: 1.231, 95% CI: 1.011–1.453, p = 0.041) were the independent predictors of the primary endpoint, while the myocardial diameter and the nuclear irregularity had no significant prognostic impact. Kaplan-Meier survival curves demonstrated that patients with both higher CAF and higher number of CD3+ cells had the worst prognosis (log-rank, P < 0.001). ConclusionsThe higher CAF and the higher number of infiltrating CD3+ cells quantified using EMB samples were the independent predictors of poor clinical outcomes in patients with HCM. Cardiomyocyte diameter and nuclear irregularity did not significantly impact the clinical prognosis.

Initiation of noninvasive surveillance for allograft rejection in heart transplant patients>1 year after transplant.

Gene expression profiling (GEP) and donor-derived, cell-free DNA (dd-cfDNA) measurement are alternative methods to endomyocardial biopsy (EMB) to monitor for rejection following heart transplantation. We aim to describe our use of GEP and dd-cfDNA in heart transplant recipients>1-year post-transplantation. This is a single-center, retrospective study in post-transplant recipients. For patients who were>1-year post-transplantation and deemed to be at elevated clinical risk for rejection, we collected both GEP and dd-cfDNA every 3 months. Baseline characteristics including GEP, dd-cfDNA levels, rejection episodes, and number of biopsies were obtained. Since July 2019, there were 18 patients being followed with GEP and dd-cfDNA who were>1-year post-transplantation. Nine EMBs had been performed in seven patients due to as follows; three due to elevated GEP ({greater than or equal to} 34), one due to elevated dd-cfDNA ({greater than or equal to} .20%), two due to elevations of both GEP and dd-cfDNA, two due to clinical rejection and one to follow up a post rejection episode. One of the two biopsies due to elevations of both GEP and dd-cfDNA showed acute cellular rejection grade 2R. None of the biopsies due to either an elevation in the GEP or dd-cfDNA revealed any significant rejection. In this study, the use of both GEP and dd-cfDNA led to an increased number of EMB in patients>1-year post-transplantation. Further studies are needed to validate these findings and evaluate long-term consequences of these diagnostic tests in this population.

Safety of endomyocardial biopsy in new-onset acute heart failure requiring veno-arterial extracorporeal membrane oxygenation

Abstract Background Refractory cardiogenic shock (CS) complicating new onset acute heart failure (new-AHF) is a medical emergency, requiring immediate mechanical circulatory support (MCS) to prevent hemodynamic deterioration. When non-invasive testing is impossible, endomyocardial biopsy (EMB) has an important role in determining the etiology of new-AHF. Purpose The aim of this study was to determine the procedural safety of EMB in patients with new-AHF requiring VA-ECMO. Additionally, we describe the detection rate of an underlying etiology of new-AHF on histopathological examination. Methods A retrospective, multicenter cohort of patients undergoing EMB while requiring VA-ECMO for new-AHF between 1990 and 2020 was compared with a cohort of non-transplant related biopsies not requiring VA-ECMO. Primary endpoint of the study was the safety of EMB with a secondary endpoint being the detection rate of an underlying etiology causing new-AHF on histopathologic examination. Results A total of 23 patients underwent EMB while requiring VA-ECMO (10.0%), 125 (54.3%) during an unplanned admission and 82 (35.7%) in elective setting. Major complications occurred in 8.3% of all procedures with a significantly higher rate in patients requiring VA-ECMO (26.1% vs. 8.0% vs. 3.7%,p=0.003), predominately due to occurrence of sustained ventricular tachycardia or need of resuscitation (13.0% vs. 3.2% vs. 1.2%,p=0.02). EMB led to a histopathological diagnosis in 78.3% of the patients requiring VA-ECMO which consisted primarily of patients with myocarditis (73.9%). Conclusions EMB in patients requiring VA-ECMO can be performed albeit with a substantial risk of major complications. This risk of the procedure was offset by a high detection rate of an underlying etiology on histopathological examination. The important therapeutic and prognostic implications of EMB in this population warrant further refinement to improve procedural safety. Funding Acknowledgement Type of funding sources: None. Major safety endpoints according to EMB

Features of the expression of fibroblast growth factor in patients with idiopathic atrial fibrillation and verified myocarditis

Abstract Introduction Myocarditis and inflammatory changes in the myocardium can be one of the causes of the development and progression of atrial fibrillation (AF). The biomarker FGFβ is involved in the processes of angiogenesis, repair of heart tissues and stimulates fibroblasts. Purpose To assess the dynamics and to identify the relationship of fibroblast growth factor (FGFβ) expression and myocardial inflammatory diseases revealed by the results of histological examination of endomyocardial biopsy in patients with various forms of idiopathic AF. Methods Subjects were 40 patients (41.0±9.2 y.o.) with idiopathic AF, the arrhythmic history constituted 4.9±3.9 years. The patients were divided into 3 groups: 1–with paroxysmal AF (n=15), 2–persistent (n=12), 3–long-term persistent (n=13) depending on the form of AF. All patients underwent radiofrequency ablation (RFA) of the pulmonary veins and endomyocardial byopsy with histologic and immunohistochemical studies. In 1st group active lymphocytic myocarditis (ALM) were found in 40% patients (n=6); in 2d and 3d groups – 66.7% (n=8 in each gr.). All other patients showed signs of lymphocytic infiltration (LI). The serum levels of FGFβ determined all patients in prior to intervention (T1) and in 6 months after RFA (T2). Results Comparative analysis showed, in patients with morphologically verified ALM, the FGFb levels in 6 months after RFA in 1st gr. was significantly higher than in 3d gr. (p=0.036). In patients gr.1 with ALM the levels of FGFb was higher (at stages T1 and T2) than in patients with LI (p=0.055 and p=0.06, respectively). In 1st gr., a positive association between the levels of FGFb (T1) and the degree of activity of inflammatory processes caused in 6 months after RFA (R=0.95 p=0.005) were identified. In 1st gr., the relationship between the degree of activity of inflammatory processes and fibrotic changes (R=−0.77 p=0.009) and an association of FGFb with the value of cardiac ejection fraction was obtained (R=0.90 p=0.037). In 2d gr., strong correlations of FGFb with the degree of activity of inflammatory processes (R=0.79 p=0.019) and ejection fraction (RT1=0.73 p=0.039, RT2=0.96 p=0.0002) were revealed. In 3d gr., the FGFb levels was significantly higher in patients with LI than with ALM (14.74 [13.28; 14.80] and 6.92 [5.65; 9.90] pg/ml, respectively; p=0.048). In 3d gr., the severity of fibrotic changes was associated with FGFb expression (RT1=−0.73 p=0.041, RT2=−0.85 p=0.008). Conclusion The relationships of FGFb with the degree of activity of inflammatory processes in groups with paroxysmal and persistent AF were revealed. In patients with active lymphocytic myocarditis, the FGFb level was significantly higher in paroxysmal AF than in long-term persistent AF. Our study showed, increased expression of FGFb is associated with inflammatory processes of active lymphocytic myocarditis, and may be due to intense proliferation and differentiation of fibroblasts in paroxysmal AF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Cardiology Research Institute, Tomsk NRMC

Safety of Endomyocardial Biopsy in New-Onset Acute Heart Failure Requiring Veno-Arterial Extracorporeal Membrane Oxygenation.

Endomyocardial biopsy (EMB) has an important role in determining the pathogenesis of new-onset acute heart failure (new-AHF) when noninvasive testing is impossible. However, data on safety and histopathologic outcomes in patients requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is lacking. A retrospective, multicenter cohort of patients undergoing EMB while requiring VA-ECMO for new-AHF between 1990 and 2020 was compared with a cohort of nontransplant related biopsies not requiring VA-ECMO. Primary end point of the study was to determine the safety of EMB. Additionally, we describe the underlying pathogenesis causing new-AHF based on histopathologic examination of the samples obtained. A total of 23 patients underwent EMB while requiring VA-ECMO (10.0%), 125 (54.3%) during an unplanned admission, and 82 (35.7%) in elective setting. Major complications occurred in 8.3% of all procedures with a significantly higher rate in patients requiring VA-ECMO (26.1% versus 8.0% versus 3.7%, P=0.003) predominately due to the occurrence of sustained ventricular tachycardia or need of resuscitation (13.0% versus 3.2% versus 1.2%, P=0.02). EMB led to a histopathologic diagnosis in 78.3% of the patients requiring VA-ECMO which consisted primarily of patients with myocarditis (73.9%). EMB in patients requiring VA-ECMO can be performed albeit with a substantial risk of major complications. The risk of the procedure was offset by a histopathologic diagnosis in 78.3% of the patients, which for the majority consisted of patients with myocarditis. The important therapeutic and prognostic implications of establishing an underlying pathogenesis causing new-AHF in this population warrant further refinement to improve procedural safety.

Initiation of Noninvasive Surveillance for Allograft Rejection in a Cohort of Heart Transplant Patients >1 Year after Transplant: An Exploratory Analysis

Purpose Gene expression profiling (GEP) and donor-derived, cell-free DNA (dd-cfDNA) measurement are alternative methods to endomyocardial biopsy (EMB) to monitor for rejection following heart transplantation. Both tests were individually validated but the utility of the combined use is unclear, especially in patients >1-year post-transplantation. We aim to describe our use of GEP and dd-cfDNA in heart transplant recipients >1-year post-transplantation. Methods This is a retrospective study conducted at The Queen's Medical Center, a non-heart transplant center located in Hawai'i, which cares for heart transplant recipients in a shared-care model with transplant centers located on the mainland. A protocol for GEP and dd-cfDNA for our patients was started in July 2019. For patients who were >1-year post-transplantation and were clinically deemed to be at an elevated risk for rejection, we collected both GEP and dd-cfDNA every 3 months. Baseline characteristics including GEP, dd-cfDNA, rejection episodes, and number of EMB were obtained. Results Since July 2019, there were 18 patients being followed with GEP and dd-cfDNA who were >1-year post-transplantation. The majority were male (72%), the mean age was 57.3±12.8 years, the average time from transplantation was 7.2.±1.6 years. Since then, 9 EMBs had been performed due to reasons as follows; 3 for elevated GEP (≥ 34), 1 for elevated dd-cfDNA ( ≥ 0.20%), 2 for elevations of both GEP and dd-cfDNA, 2 for clinical rejection and 1 to follow up a post-rejection episode. Of the 2 biopsies due to elevations of both GEP and dd-cfDNA, 50% showed evidence of acute rejection (acute cellular rejection grade 2R). None of the other 4 biopsies due to either an elevation in the GEP or dd-cfDNA alone revealed any significant rejection. We also followed 18 patients >1-year post-transplantation without the routine use of GEP or dd-cfDNA. None experienced clinical episodes of rejection or had any EMB performed. Conclusion In this study, the use of both GEP and dd-cfDNA led to an increased number of EMB in patients >1-year post-transplantation. Patients were at higher risk of rejection if they have elevation of both GEP and dd-cfDNA. Further studies are needed to validate these findings and evaluate long-term consequences of these diagnostic tests in patients who are > 1-year post-transplantation.

Trends in post–heart transplant biopsies for graft rejection versus nonrejection

With alternatives such as gene profiling available for surveillance after orthotopic heart transplantation, we sought to evaluate the utilization of endomyocardial biopsies (EMBs) for hospitalized patients after heart transplantation. Surveillance EMBs in patients with and without complications were evaluated from the 2004 to 2014 National Inpatient Sample. Over the study period, there was no significant change in the number of EMB procedures performed (P = 0.44). Of 37,955 EMBs, 2283 (6%) were in the setting of graft complications, while 35,672 EMBs were not related to graft complications. EMBs in graft complications did not show a significant increase in length of stay over time (P = 0.06), but had a significant increase in cost over time (P = 0.001). However, those with graft complications had an average of a 5-day longer length of stay (P < 0.001) and costs that were $88,816 (P < 0.001) more expensive compared with those without graft complications. In conclusion, the vast majority of in-hospital EMBs were not related to heart transplantation complications. Nevertheless, EMB hospitalizations with graft complications showed significantly greater length of stay and cost. With the COVID-19 pandemic, it seems more effective to use minimal-contact health surveillance methods rather than invasive EMBs.

Clinical Impact of the Pathological Quantification of Myocardial Fibrosis and Infiltrating T Lymphocytes Using an Endomyocardial Biopsy in Patients with Hypertrophic Cardiomyopathy

Clinical Impact of the Pathological Quantification of Myocardial Fibrosis and Infiltrating T Lymphocytes Using an Endomyocardial Biopsy in Patients with Hypertrophic Cardiomyopathy

18F-FDG uptake of the right ventricle is an important predictor of histopathologic diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis

BackgroundThe aim of this study was to determine whether right ventricle (RV) 18F-fluorodeoxyglucose (FDG) uptake can predict positive findings of endomyocardial biopsy (EMB) in patients with cardiac sarcoidosis (CS). Methods70 consecutive patients with clinically diagnosed CS who had undergone FDG PET were registered in the present study. Patients without EMB (n = 42) were excluded. Ultimately, 28 patients were studied. EMB samples were obtained from the RV septum. We evaluated the FDG uptake on six segments (RV, left ventricle anterior, septal, lateral, inferior, and apex). ResultsPositive EMB was found in six patients (21%). Patients were divided into two groups according to positive (n = 12 [43%]) or negative (n = 16 [57%]) RV FDG uptake. Patients with positive RV FDG uptake had a significantly higher frequency of positive EMB than those without (42% vs. 6%, P = 0.024). On the other hand, there was no EMB-predictive value for the FDG uptakes in the other five segments, the cardiac metabolic volume, total lesion glycolysis, left ventricular ejection fraction, or any electrocardiogram findings. ConclusionsFDG uptake of the RV but no other heart segment was associated with positive EMB in CS patients. The presence of RV FDG uptake could improve the rate of positive EMB up to 42% in patients with CS.

Lone Atrial Flutter in Children and Adolescents: Is It Really \u201cLone\u201d?

Atrial flutter (AFL) in children and adolescents beyond the neonatal period in the absence of any underlying myocardial disease (“lone AFL”) is rare and data is limited. Our study aims to present clinical and electrophysiological data of presumed “lone AFL” in pediatric patients and discuss the role of endomyocardial biopsy (EMB) and further follow-up. Since July 2005, eight consecutive patients at a median age of 12.7 (range 10.4–16.7) years presenting with presumed “lone AFL” after negative non-invasive diagnostic work-up had electrophysiological study (EPS) and induction of cavotricuspid isthmus (CTI) conduction block by radiofrequency (RF) current application. In 6/8 patients EMB could be taken. Induction of CTI conduction block was achieved in all patients. Histopathological examination of EMB from the right ventricular septum exhibited myocarditis or cardiomyopathy in 4/6 patients, respectively. During follow-up, 4/8 patients had recurrent arrhythmia (AFL n = 2, wide QRS complex tachycardia n = 1, monomorphic premature ventricular contractions n = 1) after the ablation procedure. 3/4 patients with recurrent arrhythmia had pathological EMB results. The remaining patient with recurrent arrhythmia had a negative EMB but was diagnosed with Brugada syndrome during further follow-up. Taking together results of EMB and further clinical course, only 3/8 patients finally turned out to have true “lone AFL”. Our study demonstrates that true “lone AFL” in children and adolescents is rare. EMB and clinical course revealed an underlying cardiac pathology in the majority of the individuals studied. EMB was very helpful in order to timely establish the diagnosis of myocarditis or cardiomyopathy.

Parvovirus B19 NS1 and VP1/2 mRNAs expression indicates viral activity in endomyocardial biopsy-based diagnosis of patients with unexplained heart failure

Abstract Background Human erythroparvovirus-1 (B19V) is the most frequently found virus in endomyocardial biopsies (EMBs). Recent studies have detected B19V genomes in various organs of symptomatic and asymptomatic individuals including endothelial cells of the heart muscle. Accordingly, B19V as a causative pathogen of myocardial damage has been questioned. To date, the majority of studies focused on the presence of viral DNA in the myocardium, but lack the analysis of viral RNAs as markers for viral activity. In contrast to latent infection, the expression of viral mRNAs is of clinical importance as we could demonstrate in previous studies. Only recently, novel antiviral treatment strategies have become available. A sensitive and specific method to identify and monitor patients that will profit from antiviral treatment is a prerequisite for successful therapy. During this study, we established a new PCR-based diagnostic method to characterize the expression of B19V RNAs coding for the non-structural (NS1) and capsid protein (VP1/2) in endomyocardial biopsies of patients with unexplained heart failure and demonstrated its feasibility in a clinical setting of molecular diagnostics. Methods To quantify B19V RNA expression, we developed real-time (reverse transcription) polymerase chain reactions (qPCRs) targeting the NS1 and VP1/2 regions of B19V genome. 576 randomly selected EMBs of patients with unexplained heart failure were tested for B19V genomes and transcription intermediates using qPCR and nested PCR. Results 403 of 576 (69.9%) EMBs were positive for B19V genomes (B19V DNA). Viral loads ranged from 15 to 51,118 genome equivalents/μg isolated DNA. Of the 403 B19V DNA-positive samples, B19V mRNAs NS1 and/or VP1/2, indicating viral activity, could be detected in 155/403 (38.4%) EMBs using the newly established B19V qPCRs. 89/403 samples were characterized by only NS1 mRNA detection while 24/403 revealed only VP1/2 mRNA expression. Detection of both intermediates was successful in 42/403 samples. Patients characterized by active B19V infection presented with a significantly reduced left ventricular ejection fraction (30.7±13.1%) in contrast to virus free patients (35.5±15.9%; p=0.025) or latently infected patients (34.7±15.7; p=0.043). Conclusion Our newly established molecular testing will improve detection and quantification of B19V. As we could demonstrate here, it is essential to screen for both viral transcription intermediates, the NS1 and VP1/2 viral mRNAs, in order to precisely differentiate between latent infection or a clinically relevant B19V-infection with transcriptional activity of the heart muscle. The results of our study revealed that a remarkable high proportion of 26.9% (155/576) of patients with unexplained heart failure is affected by transcriptional active B19V infection of the myocardium. Prospective studies must be conducted to evaluate our findings and furthermore, effective antiviral treatment strategies need to be adapted. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): IKDT GmbHn