Need For Endomyocardial Biopsy Research Articles

Use of Bone Scintigraphy in The Diagnosis of Cardiac Amyloidosis

Cardiac amyloidosis is a rare and progressive condition caused by the buildup of amyloid in the heart. There are two common forms of cardiac amyloidosis: light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). The deposition of amyloid in the extracellular matrix of the myocardium leads to heart failure over time, and if left untreated, it can even be fatal. For this reason, early diagnosis is essential for both prognosis and improving patients' quality of life. Since cardiac amyloidosis is a potentially treatable condition, early diagnosis is key to improving patient survival and quality of life. There is now compelling evidence showing that nuclear imaging plays a fundamental role in the non-invasive diagnosis of transthyretin cardiac amyloidosis. Due to its high sensitivity and specificity, radiotracer compounds that target the bones are considered sufficient for establishing the diagnosis, avoiding the need for endomyocardial biopsy. In this study, we analyzed data obtained from examinations conducted on patients referred to the Cardiology Department of the "San Giovanni di Dio e Ruggi d'Aragona" University Hospital, who presented with suspected cardiac amyloidosis. These patients underwent scintigraphy with 99mTc-HMDP (hydroxymethylenediphosphonate), using a large-field computerized gamma camera with a parallel-hole collimator and SPECT. After performing early whole-body planar acquisitions at 5 minutes and late acquisitions at 3 hours after intravenous administration of approximately 700 MBq of Tc-99m HMDP, myocardial uptake was observed. Subsequently, targeted acquisitions and SPECT tomographic studies were performed on the myocardial uptake areas. All acquired images were subsequently subjected to quantitative and qualitative analysis, allowing us to extract a large number of parameters reflecting morphological and predictive characteristics using radiomics and more or less automated analysis algorithms. This analysis enabled us to obtain quantitative information that is not apparent in a qualitative image analysis. The ability to extract hidden information from digital medical images is of particular interest as it can enhance the predictive capabilities of existing automatic segmentation algorithms. Extracting new information that was previously hidden can be utilized for automatic image segmentation.

Abstract 17626: Apolipoprotein A-IV-Associated Cardiac Amyloidosis: A Classic Presentation of a Rare Condition

Introduction: A 65-year-old male with type one diabetes mellitus underwent a pancreas and kidney transplant approximately seven years ago and has received chronic tacrolimus. He presented with subacute dyspnea on exertion, orthopnea, and edema. His background also includes ongoing chronic kidney disease stage 3A, orthostatic hypotension, and spinal stenosis. On exam, he had abdominal and lower extremity swelling. An echocardiogram showed preserved LVEF, concentric hypertrophy, hyperrefractile myocardium, reduced longitudinal strain with apical sparing, and a tiny pericardial effusion. Hypothesis: His echocardiogram indicated an infiltrative process such as amyloidosis or tacrolimus cardiotoxicity or possibly hypertrophic cardiomyopathy. Methods: Free light chains and protein studies with mass-fixation demonstrated no monoclonal gammopathy. PYP scan was negative for transthyretin amyloidosis. A cardiac MRI showed patchy subendocardial and midmyocardial delayed gadolinium enhancement, supporting the clinical suspicion for cardiac amyloidosis. With the need to exclude tacrolimus toxicity as well, subsequent endomyocardial biopsy revealed apolipoprotein A-IV-associated cardiac amyloidosis (Figure 1). Results: Apolipoprotein A-IV-associated cardiac amyloidosis occurs in about 0.6% of patients with cardiac amyloid and has classic manifestations of LV outflow obstruction, microvascular disease, and especially renal insufficiency. When these features occur in patients with clinical and imaging findings suggesting cardiac amyloidosis despite negative testing for more common types of amyloidosis, clinicians should proceed with endomyocardial biopsy to evaluate for less common forms. Conclusions: We report a rare case of apolipoprotein A-IV-associated cardiac amyloidosis. This case highlights the need for endomyocardial biopsy when clinical suspicion for cardiac amyloidosis persists despite negative testing.

Abstract 15922: Integrative Analysis of Extracellular Vesicles in Heart Transplant Rejection: From Biomarker Discovery to Novel Immune Mechanisms

Introduction: At the forefront of post-heart transplant care is early detection of transplant rejection. However, the current gold standard for detecting acute cellular transplant rejection is recurrent invasive endomyocardial biopsies (EMB). We aimed at developing a non-invasive biomarker for acute cellular heart transplant rejection (ACR) using a plasma extracellular vesicle (EV) platform. Methods: Peripheral and coronary sinus plasma samples were prospectively collected from 183 (31.7% female) patients from 2020 to 2023 during routine surveillance EMB. A discovery cohort comprised five patients who displayed ISHLT 0-1R biopsy followed by an ISHLT 2R grade rejection event. Plasma EVs were isolated from the baseline (0-1R) and rejection (2R) time points. Subsequently, integrative analysis of plasma EV proteomic, miRNomic, and metabolomics was performed pairwise with the samples. Results: The study collected 943 sample time points from 183 patients. Of these sample collections, 43 (4.5%) cases were 2R rejections. Our proteomic analysis of the plasma EVs identified 28 proteins found explicitly during a grade 2R rejection and 87 differentially expressed proteins during a 2R rejection event. An Ingenuity Pathway Analysis (IPA) analysis of the upregulated proteins highlighted EVs mediated mTOR signaling and antigen presentation as central to rejection events. Although all patients in the discovery cohort were negative for antibody-mediated rejection (AMR), the proteomic findings also revealed increased B-cell receptor signaling, implying a mechanistic intersection of ACR and AMR. Conclusions: A distinct set of proteins were found in plasma EVs during ACR events, providing potentially specific and sensitive biomarkers to reduce the need for EMB that could be exploited for ACR diagnosis. The proteins identified formed an immune signaling network that suggests a novel role for EVs in ACR pathogenesis.

State-of-the-Art Imaging of Infiltrative Cardiomyopathies: A Scientific Statement From the American Heart Association.

Infiltrative cardiomyopathies comprise a broad spectrum of inherited or acquired conditions caused by deposition of abnormal substances within the myocardium. Increased wall thickness, inflammation, microvascular dysfunction, and fibrosis are the common pathological processes that lead to abnormal myocardial filling, chamber dilation, and disruption of conduction system. Advanced disease presents as heart failure and cardiac arrhythmias conferring poor prognosis. Infiltrative cardiomyopathies are often diagnosed late or misclassified as other more common conditions, such as hypertrophic cardiomyopathy, hypertensive heart disease, ischemic or other forms of nonischemic cardiomyopathies. Accurate diagnosis is also critical because clinical features, testing methodologies, and approach to treatment vary significantly even within the different types of infiltrative cardiomyopathies on the basis of the type of substance deposited. Substantial advances in noninvasive cardiac imaging have enabled accurate and early diagnosis. thereby eliminating the need for endomyocardial biopsy in most cases. This scientific statement discusses the role of contemporary multimodality imaging of infiltrative cardiomyopathies, including echocardiography, nuclear and cardiac magnetic resonance imaging in the diagnosis, prognostication, and assessment of response to treatment.

Non-invasive diagnosis of cardiac rejection using small non-coding RNAs

Abstract Background Endomyocardial biopsy is the standard technique for rejection surveillance in heart transplantation recipients and is an invasive method with important limitations and clearly associated with both a risk of procedural complications and serious long-term sequelae when performed repeatedly. All of these considerations highlight the need to identify non-invasive alternative methods capable of discriminating between the different grades of rejection and reducing the need for endomyocardial biopsy. Purpose We conducted a non-targeted transcriptomic study focused on identifying serum small non-coding RNAs, mainly aimed on the less studied types, to evaluate their diagnostic accuracy for detecting rejection episodes. Methods We included consecutive serum samples from transplant recipients undergoing routine endomyocardial biopsies. Non-coding RNA sequencing analysis (Illumina HiSeq 2500) was performed on 40 samples, 28 diagnosed with RCA (RCA Grade 1R, n=16; and RCA Grade ≥2R, n=12) and 12 samples without cardiac rejection. Results 636 non-coding RNAs were detected among the scaRNAs, snoRNAs, snRNAs and miscRNAs biotypes. But, neither piRNA nor siRNA biotypes were detected. Of all of them, 41 were altered in patients with rejection Grade ≥2R, finding no alteration in the scaRNAs biotype. Three molecules of miscRNA biotype showed the best results with excellent diagnostic capacity in moderate/severe rejection: RN7SL840P (AUC=0.938, p<0.01), Y_RNA [ENSG00000223302] (AUC=0.931, p<0.0001) and Y_RNA [ENSG00000202273] (AUC=0.903, p<0.001). In addition, RN7SKP5 showed a good capacity for the diagnosis of Grade ≥2R (AUC=0.806, p<0.05) and preserving the accuracy at Grade 1R (AUC=0.781, p<0.05). Conclusions The 6.5% of the small non-coding RNAs detected have differential expression in patients with acute cellular rejection. The non-detection of the piRNAs and siRNAs biotypes stands out, as well as the absence of alteration in the scaRNAs biotype. We propose serum miscRNA levels as potential biomarkers of cardiac rejection. We highlight the role of RN7SL840P due to its excellent diagnostic capacity for RCA, and RN7SKP5 since it also allows the detection of mild rejection. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Carlos III European Regional Development Fund (ERDF)

Poke Not Prod: First Canadian Experience Using Donor-Derived Cell Free DNA to Replace Endomyocardial Biopsy During COVID-19

PurposeAfter a heart transplant (HT), non-invasive methods for rejection surveillance minimize the need for endomyocardial biopsies (EMBx). We describe the first experience with combined use of genetic expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) testing in Canada as part of a quality improvement project to minimize patient risk during the COVID pandemic.MethodsAdult outpatients at least 6 months after HT were screened from May 2021 to July 2021 to have their routine EMBx replaced by a combination of GEP and dd-cfDNA. Demographics, modification of immunosuppression (IS) and outcomes (hospital admission, rejection, and need for EMBx) were collected.ResultsAmong 90 patients, 31 (33%) were enrolled, and 37 non-invasive tests were performed. The median time after HT was 2 years and patients were predominantly Caucasian (52%) and male (68%). 53% had a history of acute cellular rejection during the first year and 32% had cardiac allograft vasculopathy. Of the tests performed, 23 (60%) were - GEP / - dd-cfDNA, 10 (27%) were + GEP / - dd-cfDNA, 4 (11%) were - GEP / + dd-cfDNA and none were + GEP / + dd-cfDNA. Being bridged with a VAD (OR = 5.5, p=0.034) and a history of a previously treated CMV (OR = 16.0, p=0.003) were associated with a positive GEP and a negative dd-cfDNA result. Having received a COVID vaccine in the last 3 months did not affect GEP results (GEP was positive in 23.8% after vaccination vs 33.3% in non-vaccinated patients, p=0.690; average GEP score 29.8 vs 30.7, p=0.673). The 4 patients with a + dd-cfDNA (range 0.19 - 0.81%) underwent an EMBx with no significant cellular or antibody mediated rejection, thus avoiding 89% of the EMBx. No unscheduled clinic visits, emergency department or hospital admissions were recorded. After non-invasive testing, the IS was reduced in 16 cases (43.2%). IS was reduced in in 59% of patients with negative concordant tests (- GEP / - dd-cfDNA), 30% in patients with + GEP / - dd-cfDNA and no reduction in IS occurred in those with + dd-cfDNA.ConclusionThe combination of GEP and dd-cfDNA for rejection surveillance allowed for a marked reduction in EMBx (89%) and for a personalized downtitration of IS without adverse events in the short term. The use of non-invasive rejection surveillance testing was an effective strategy to avoid hospital contact for HT recipients during the COVID-19 pandemic.

Enhancing knowledge and awareness of transthyretin cardiac amyloidosis and shared decision-making among cardiology team members in Colorado, USA via an online educational initiative

ABSTRACT Objectives Our project aimed to increase knowledge of noninvasive diagnostic modalities (including bone radiotracer scintigraphy), raise suspicion of transthyretin cardiac amyloidosis (ATTR-CA), and improve cardiology team member’s awareness and knowledge of shared decision-making (SDM), as well as the quality of SDM communication between cardiology team members and patients. Methods An online educational module and survey was developed and cardiology team members in Colorado, USA, were invited to participate. This online educational module included various important topics related to ATTR-CA (e.g., the cause of ATTR-CA, endomyocardial biopsy, and noninvasive methods to diagnose ATTR-CA) and SDM (e.g., benefits of SDM, the role of SDM in the diagnosis of ATTR-CA, implementation of SDM in cardiology practice, and the 3-talk model). Results There were 34 survey respondents, over one-third of whom were cardiologists. Most respondents agreed on the importance of diagnosing ATTR-CA at an early stage, and about three-quarters of the survey takers agreed that bone scintigraphy can reliably diagnose ATTR-CA without the need for endomyocardial biopsy. Concern over increased time commitment was the leading barrier to the implementation of SDM in respondents’ clinical practice. The majority of respondents identified the correct answer regarding ATTR-CA and SDM after reading the online educational module. This improvement in scores after exposure to the online educational module was statistically significant. Conclusion Baseline knowledge and awareness of various issues related to ATTR-CA was relatively low among cardiology team members. Participants’ knowledge was enhanced through our effective online educational program. Prospective educational projects focused on various methods of detecting ATTR-CA as well as other amyloid conditions in diverse clinical settings will remain important.

COVID-19 and Acute Myocardial Injury and Infarction: Related Mechanisms and Emerging Challenges.

In the era of the coronavirus disease 2019 (COVID-19) pandemic, acute cardiac injury (ACI), as reflected by elevated cardiac troponin above the 99th percentile, has been observed in 8%-62% of patients with COVID-19 infection with highest incidence and mortality recorded in patients with severe infection. Apart from the clinically and electrocardiographically discernible causes of ACI, such as acute myocardial infarction (MI), other cardiac causes need to be considered such as myocarditis, Takotsubo syndrome, and direct injury from COVID-19, together with noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis. Acute coronary syndromes (ACS) with normal or near-normal coronary arteries (ACS-NNOCA) appear to have a higher prevalence in both COVID-19 positive and negative patients in the pandemic compared to the pre-pandemic era. Echocardiography, coronary angiography, chest computed tomography and/or cardiac magnetic resonance imaging may render a correct diagnosis, obviating the need for endomyocardial biopsy. Importantly, a significant delay has been recorded in patients with ACS seeking advice for their symptoms, while their routine care has been sharply disrupted with fewer urgent coronary angiographies and/or primary percutaneous coronary interventions performed in the case of ST-elevation MI (STEMI) with an inappropriate shift toward thrombolysis, all contributing to a higher complication rate in these patients. Thus, new challenges have emerged in rendering a diagnosis and delivering treatment in patients with ACI/ACS in the pandemic era. These issues, the various mechanisms involved in the development of ACI/ACS, and relevant current guidelines are herein reviewed.

Practical recommendations for the diagnosis and management of transthyretin cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by accumulation in the heart interstitium of amyloid fibrils formed by misfolded proteins. Most common CA types are light chain amyloidosis (AL) caused by monoclonal immunoglobulin light chains and transthyretin amyloidosis (ATTR) caused by either mutated or wild-type transthyretin aggregates. Previously considered a rare disease, CA is increasingly recognized among patients who may be misdiagnosed as undifferentiated heart failure with preserved ejection fraction (HFPEF), paradoxical low-flow/low-gradient aortic stenosis, or otherwise unexplained left ventricular hypertrophy. Progress in diagnosis has been due to the refinement of cardiac echocardiographic techniques (speckle tracking imaging) and magnetic resonance (T1 mapping) and mostly due to the advent of bone scintigraphy that has enabled noninvasive diagnosis of ATTR, limiting the need for endomyocardial biopsy. Importantly, proper management of CA starts from early recognition of suspected cases among high prevalence populations, followed by advanced diagnostic evaluation to confirm diagnosis and typing, preferentially in experienced amyloidosis centers. Differentiating ATTR from other types of amyloidosis, especially AL, is critical. Emerging targeted ATTR therapies offer the potential to improve outcomes of these patients previously treated only palliatively.

Non-cardiac biopsy sites with high frequency of transthyretin amyloidosis.

AimsCardiac scintigraphy, a non‐invasive technique for diagnosing ATTR cardiac amyloidosis, lacks specificity in patients with concomitant monoclonal gammopathy (up to 40% of cases). For these patients, amyloid type is often established by endomyocardial biopsy (EMB), which has clinical risk. This study aimed to investigate the frequency of ATTR in amyloid‐positive tendon/synovium, urinary bladder, and prostate biopsies, sites for which prior biopsy specimens might exist for patients suspected of having cardiac amyloidosis, and, when available, determine the amyloid type concordance rate with other anatomic sites and provide clinical data regarding subsequent development of cardiac amyloidosis.Methods and resultsWe queried our reference laboratory database of 19,298 amyloid specimens from myriad anatomic sites typed by mass spectrometry‐based proteomics (LC‐MS/MS) to investigate the frequency of ATTR amyloid in tendon/synovium, urinary bladder, and prostate. The amyloid type was ATTR in 104/138 (75.4%) tendon/synovium, 173/453 (38.0%) urinary bladder, and 27/81 (33.3%) prostate samples. Of 62 patients with available clinical data, 12 (19%) had bona fide ATTR cardiac amyloidosis prior to/concomitant with the non‐cardiac site biopsy. Of the remaining 14 with follow‐up, 8 developed bona fide and 2 probable cardiac amyloidosis; at last follow‐up 4 had no evidence of cardiac amyloidosis. Fourteen of 16 patients (87.5%) for whom we typed both non‐cardiac and cardiac sites had concordant amyloid types. There were 2 discordant cases (prostate = ASem1/heart = AL and urinary bladder = AL/heart = ATTR); only the latter is potentially clinically consequential.ConclusionsIn patients suspected of having cardiac amyloidosis based on cardiac scintigraphy, LC‐MS/MS typing of Congophilic deposits in pre‐existing biopsy specimens from non‐cardiac sites may help establish the cardiac amyloid type, obviating the need for EMB. However, if the amyloid type identified in the non‐cardiac site is not in keeping with other clinical features, then EMB for typing the cardiac amyloid might be indicated.

Abstract 15703: Cardiac Magnetic Resonance Imaging Can Non-invasively Detect Rejection in Pediatric Heart Transplant Recipients

Introduction: Pediatric heart transplant recipients (PHTx) undergo frequent surveillance endomyocardial biopsies (EMB). Non-invasive screening for acute rejection (AR) could decrease morbidity, improve quality of life, and decrease healthcare costs. Hypothesis: We hypothesized that cardiac magnetic resonance (CMR) extracellular volume (ECV), native T1, and T2 mapping can detect AR in PHTx. Methods: PHTx (n=29) were prospectively enrolled at two sites at time of surveillance EMB or EMB for AR. AR was defined as a clinical change or positive EMB requiring intensification of immunosuppression. Subjects with cardiac allograft vasculopathy (n=3) were excluded; ECV was not measured in 2 subjects without rejection (no IV, poor breathholds). CMR without sedation included standard volumetrics, modified Look-Locker inversion recovery before and after contrast, and T2 mapping. A Wilcoxon rank sum was used to assess for a difference between groups. Results: Median age was 17 y/o (range 9-19). There were 9 subjects with and 17 subjects without AR. Base ECV, mid ECV, 4-ch ECV, and average ECV were increased in AR vs non-rejection (Table 1, Fig 1). Native T1 and T2 times were also increased in patients with AR (Table 1). A cut-off of 29% for mid ECV and 1070ms for mid native T1 identifies all patients with rejection with 6 false positive results in non-rejection (Fig 1) and could potentially decrease the need for EMB by 65%. Conclusions: ECV, native T1, and T2 mapping can non-invasively distinguish between PHTx with and without AR and have potential to decrease the required number of surveillance EMBs.

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation

Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx. This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0RS1 → 2RS2` → 0RS3). Relative expression (2-∆Cq) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx. A total of 21 ACR episodes (0RS1 → 2RS2 → 0RS3) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2-∆Cq) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%. miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

Incidence and risk factors for biopsy-proven heart allograft rejection during the first-year post heart transplantation

The diagnosis of cardiac allograft rejection is based on the histological analysis of a myocardial tissue sample obtained by endomyocardial biopsy (EMB), an invasive procedure at risk of complications. Our aim is to enable the shift from a protocol biopsy approach, to a precision medicine approach, in which the need for EMB is tailored to each patient's individual risk. To analyze the incidence and the risk factors for biopsy-proven rejections following heart transplantation in a large cohort of highly phenotyped heart-transplant recipients. We performed a multicenter, retrospective, observational study (Pitié-Salpêtrière, HEGP, 2004–2016). We included all patients with ≥ 1 EMB during the first year ( n = 1050 patients, 13677 EMB). All EMB performed before 2012 were retrospectively reviewed and graded according to ISHLT guidelines. Rejections were defined as acute cellular rejection (ACR) ≥ 1R1B and/or antibody-mediated rejections (AMR) ≥ pAMR1. Pre-formed DSA were evaluated using Luminex Single Antigen Assay (MFI ≥ 500). Risk factors for rejection were identified using Cox proportional hazard model. Biopsy-proven rejections were diagnosed in 489 patients (46.4%) representing 1009 EMB (7.3%, mostly low-grade rejections: ACR 1R1B or 1R2: n = 724, see Fig. 1 ). Risk factors for rejection included recipient's age (HR = 0.988 per 1-year increment, P = 0.002), type of transplantation (combined heart-kidney and heart-liver compared to isolated heart: HR = 0.336 and 0.204 respectively, P < 0.001), pre-formed DSA (HR = 1.422, P < 0.001), HLA A-B-DR mismatches (HR = 1.129 per 1-mismatch increment, P = 0.02) and the type of induction (basiliximab compared to anti-thymocyte globulins: HR = 1.725, P = 0.008). We identified five independent risk factors for biopsy-proven rejection during the first-year post-heart transplantation. Our findings might help clinicians to customize post-transplant endomyocardial biopsies monitoring.

Comparison of different techniques to identify cardiac involvement in immunoglobulin light chain (AL) amyloidosis

AbstractWe retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%), respectively. Among cohort 2 (n = 342), 259 (76%) had an elevated NT-proBNP, of whom 237 (92%) had an abnormality detected on TTE. Of 83 patients with normal NT-proBNP <300 pg/mL, 27 (33%) had an abnormality on TTE (all with borderline strain rate −18% to −15%). Only 5/27 patients were considered to have possible early cardiac involvement and none had any other diagnostic or classical features of amyloidosis on TTE. The combination of NT-proBNP and comprehensive echocardiographic evaluation can diagnose cardiac amyloidosis negating the need for endomyocardial biopsy. A negative NT-proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis.

Advances in the diagnosis and treatment of transthyretin amyloidosis with cardiac involvement.

Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils constituted by misfolded proteins, which can modify tissue anatomy and hinder the function of multiple organs including the heart. Amyloidosis that can affect the heart includes mostly systemic amyloidosis (amyloid light chain, AL) and transthyretin amyloidosis (ATTR). The latter can be acquired in elderly patients (ATTRwt), or be inherited in younger individuals (ATTRm). The diagnosis is demanding given the high phenotypic heterogeneity of the disease. Therefore, "red flags," which are suggestive features giving support to diagnostic suspicion, are extremely valuable. However, the lack of broad awareness among clinicians represents a major obstacle for early diagnosis and treatment of ATTR. Furthermore, recent implementation of noninvasive diagnostic techniques has revisited the need for endomyocardial biopsy (EMB). In fact, unlike AL amyloidosis, which requires tissue confirmation and typing for diagnosis, ATTR can now be diagnosed noninvasively with the combination of bone scintigraphy and the absence of a monoclonal protein. Securing the correct diagnosis is pivotal for the newly available therapeutic options targeting both ATTRm and ATTRwt, and are directed to either stabilization of the abnormal protein or the reduction of the production of transthyretin. The purpose of this article is to review the contemporary aspects of diagnosis and management of transthyretin amyloidosis with cardiac involvement, summarizing also the recent therapeutic advances with tafamidis, patisiran, and inotersen.

Indications and diagnostic yield of endomyocardial biopsies for unexplained cardiomyopathy, a single center experience

Background: Endomyocardial biopsies (EMBs) remain the golden standard to diagnose underlying pathophysiologic process in heart failure (HF), when potential therapeutic decisions cannot be made by non-invasive techniques. However, changes in the field of non-invasive diagnostic testing might have an impact on the need for performing an EMB in certain scenarios.Methods: We performed a retrospective analysis of consecutive EMBs performed in a single, non-academic, tertiary-care centre. EMBs were performed between February 2009 and March 2018. Baseline characteristics including non-invasive imaging and hemodynamic profile were assessed. Indications of EMBs were analysed in accordance with the 2007-AHA/ACC/ESC-scientific statement on EMBs.Results: A total of 57 patients (74% male) were included. The overall diagnostic yield was 58%, with a trend towards a higher yield in left-side (64%) versus right-side EMBs (45%; p = .346). The majority of patients (88%) underwent EMBs for a class IIa-recommendation, 9% for a class-I recommendation and the remaining patients for a class IIb-indication. Of the EMBs for a class IIa indication, 82% (n = 47) was for an unexplained restrictive cardiomyopathy, in which 53% (n = 25) revealed a diagnosis (of whom n = 23 patients had amyloidosis). Subtyping of the EMBs with a pathologic diagnosis of amyloidosis revealed that 52% (n = 12) had transthyretin amyloidosis (ATTR) and 43% (n = 10) had light-chain amyloidosis (AL). Overall one major (1.7%) and one minor (1.7%) complication occurred following the EMB-procedure.Conclusions: When following the AHA/ACC/ESC-scientific statement on EMBs, the performance of EMBs had a high diagnostic yield, with acceptable complication rates. However, in patients presenting with an unexplained restricted cardiomyopathy, technetium-labelled bone scanning could offer a non-invasive approach to establishing the diagnosis of ATTR, mitigating the need for EMBs in a subset of patients.

The Changing Face of Amyloidosis Referrals at a Tertiary Center over the Past 3 Decades

▪Amyloidosis is an increasingly recognized group of disorders, characterized by the deposition of misfolded protein aggregates in various tissues and organs. For over 50 years, the Amyloidosis Center at Boston University Medical Center (BUMC) has taken lead in the comprehensive evaluation and treatment of patients with this disease. The center serves as a tertiary referral site both nationally and globally, with patients visiting from 18 countries in recent years. Historically, immunoglobulin light chain (AL) amyloidosis associated with a plasma cell dyscrasia has had the greatest prevalence at our center. Other forms of amyloidosis, such as the hereditary mutant transthyretin (ATTRm) and age-related wild type transthyretin (ATTRwt) amyloidoses, have been seen less commonly due in part to underdiagnosis and a perceived paucity of effective treatments.We report here the spectrum of referrals at the Amyloidosis Center at BUMC from 1990 to 2017. We used data from a prospectively maintained database of consented patients. Of the 3084 patients seen for an initial evaluation at our center during this period, patients with AL amyloidosis decreased from 86% to 79% to 65% in the first, second and third decade, respectively. In the same time intervals, ATTRm amyloidosis cases increased from 12% to 14% to 19% of the total patients; an even steeper increase, from 2% to 7% to 16%, was seen in patients with ATTRwt amyloidosis.There is a marked trend towards more referrals of ATTR amyloidosis at BUMC. We believe this reflects increasing awareness and advancements in the diagnostic and therapeutic landscape of ATTR amyloidosis. In the early 2000s, the potential for misdiagnosis of hereditary ATTR as AL amyloidosis was recognized (Lachmann, et al. N Engl J Med. 2002). Accordingly, biochemical analysis by immunogold electron microscopy or laser capture tandem mass spectrometry has become a standard for more accurate typing of amyloid protein. Availability and utilization of these specific pathological modalities may in part explain the growing proportion of ATTR amyloidosis seen at our center.Perhaps an even more significant factor is the development of nuclear cardiac imaging techniques, which accurately diagnose ATTR cardiac amyloidosis without the need for endomyocardial biopsy. In the last decade, technetium associated bone-avid tracers, such as pyrophosphate (PYP), have been found to be highly sensitive and specific in identifying ATTR cardiac amyloidosis among patients with heart failure (Gillmore, et al. Circulation. 2016). Ease of performance and interpretation, availability and standardization have spurred widespread adaptation of this imaging modality, thereby allowing for recognition of ATTR cases that were undiagnosed in prior decades.A recent surge in diagnosis of ATTR amyloidosis is coincident with an evolving therapeutic landscape. There have been a number of clinical trials for ATTR amyloidosis, investigating transthyretin protein suppression and stabilization, as well as fibril clearance. Three therapies have completed phase III trials and are pending US regulatory review and registration. Publicity surrounding these trials has led physicians and patients to seek referral to tertiary centers for evaluation for novel treatments. The rise in new ATTR referrals at BUMC is countered by a decline in AL amyloidosis referrals, from a former average of 102 new cases per year to 91 per year in the last decade. We believe this to be largely owed to increasing experience with and adoption by community hematologists of the therapeutic options for AL amyloidosis, which are derived from treatments for multiple myeloma.In conclusion, once thought to be exceedingly rare, ATTR is becoming an increasingly prevalent form of amyloidosis at tertiary centers, comprising nearly 1 of every 3 new referrals at BUMC in the past decade. We anticipate that this proportion will rise further as PYP nuclear imaging becomes incorporated into screening algorithms for heart failure and awareness spreads about the anticipated approval of new pharmaceuticals for ATTR amyloidosis. DisclosuresBerk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator.

Comparison of Different Techniques to Identify Cardiac Involvement in Immunoglobulin Light Chain Amyloidosis

▪Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function.Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis.Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent.Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1.Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE.Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. [Display omitted] DisclosuresDispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Identifying Non-invasive Tools to Distinguish Acute Myocarditis from Dilated Cardiomyopathy in Children.

There is often a diagnostic dilemma in pediatric patients presenting with depressed ventricular function, as myocarditis and dilated cardiomyopathy (DCM) of other etiologies can appear very similar. Accurate identification is critical to guide treatment and to provide families with the most accurate expectation of long-term outcomes. The objective of this study was to identify patterns of clinical presentation and to assess non-invasive measures to differentiate patients with acute myocarditis from other forms of DCM. We identified all children (< 18years) from our institution with a diagnosis of idiopathic DCM or myocarditis based on endomyocardial biopsy or explant pathology (1996-2015). Characteristics at the time of presentation were compared between patients with a definite diagnosis of myocarditis and those with idiopathic DCM. Data collected included clinical and laboratory data, radiography, echocardiography, and cardiac catheterization data. A total of 58 patients were included in the study; 46 (79%) with idiopathic DCM and 12 (21%) with acute myocarditis. Findings favoring a diagnosis of myocarditis included a history of fever (58 vs. 15%, p = 0.002), arrhythmia (17 vs. 0%, p = 0.003), higher degree of cardiac enzyme elevation, absence of left ventricular dilation (42 vs. 7%, p = 0.002), segmental wall motion abnormalities (58 vs. 13%, p = 0.001), lower left ventricular dimension z-score (3.7 vs. 5.2, p = 0.031), and less severe depression of left ventricular systolic function. There are notable differences between patients with myocarditis and other forms of DCM that can be detected non-invasively at the time of presentation without the need for endomyocardial biopsy. These data suggest that it may be possible to develop a predictive model to differentiate myocarditis from other forms of DCM using non-invasive measures.

Gene expression profiling scores in dual organ transplant patients are similar to those in heart-only recipients

BackgroundSerial gene expression profiling (GEP) may reduce the need for endomyocardial biopsies for detecting acute cellular rejection (ACR) after transplantation, but its performance in dual organ transplant recipients is currently unknown. MethodsWe analyzed 18 months of follow-up in a national cohort of 27 dual organ recipients (18 heart-kidney, 8 heart-liver, 1 heart-lung) matched to 54 heart-only recipients for gender, age, and time to first GEP (AlloMap®) test. ACR, antibody-mediated rejection (AMR), cytomegalovirus infections, biopsies, and longitudinal GEP scores were evaluated. ResultsDuring the first 90 days post-transplant, the mean GEP score for dual organ recipients was 25.2 ± 9.1, vs. 23.5 ± 7.7 for heart-only recipients (P = 0.48), with final GEP scores being 29.1 ± 6.1 and 32.3 ± 3.4, respectively (P = 0.34). GEP scores increased over time (P < 0.001) at a similar rate (P = 0.33) for both groups. One heart-only recipient had treated ACR (GEP score = 17). Fourteen subjects had cytomegalovirus infection, 8 of whom were dual-organ. During follow-up, mean GEP score among patients with cytomegalovirus infection was 32.3, compared to 26.7 (p < 0.001) in patients without cytomegalovirus. Only 4 (2%) of 233 biopsies were positive for mild AMR; all occurring in 2 heart-only recipients (GEP scores = 18–33). ConclusionsThis largest cohort to date suggests that dual organ transplantation alone should not be reason to omit GEP testing from post-transplant medical management, as the two groups' scores did not differ significantly. Confirming that GEP scores increase over time for heart-only and dual organ recipients and in the presence of cytomegalovirus infection, our work shows promise for the use of serial GEP testing in dual organ recipients.