Advances in echocardiography for cardiac amyloidosis and restrictive cardiomyopathies.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.

Systemic amyloidosis is a relatively rare multisystem disease caused by the deposition of misfolded protein in various tissues and organs. It may present to almost any specialty, and diagnosis is frequently delayed.[1][1] Cardiac involvement is a leading cause of morbidity and mortality, especially

Left Atrial and Ventricular Strain Differentiates Cardiac Amyloidosis and Hypertensive Heart Disease: A Cardiac MR Feature Tracking Study

Introduction: Light chain cardiac amyloidosis (AL) has a variable but usually poor prognosis. Left ventricular (LV) function measures including LV strain imaging for global longitudinal strain (GLS) have shown clinically prognostic value in AL. However, the utility of novel left atrial (LA) strain imaging and its associations with LV disease remains unclear. Hypothesis: LA strain is of additive prognostic value to GLS in AL. Methods: We included 99 consecutive patients with AL. Cardiac amyloidosis either confirmed by endocardial biopsy (25%) or by non-cardiac tissue biopsy and imaging data supportive of cardiac amyloidosis. Peak LA reservoir strain was calculated as an average of peak longitudinal strain from apical 2- and 4-chamber views. GLS and apical sparing ratio were assessed using the 3 standard apical views. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic GLS and peak longitudinal LA strain were feasible in 96 (97%) and 86 (87%) of patients, respectively. There were 48 AL patients who died during follow-up. Patients with low GLS (GLS < median; 10.3% absolute values) had worse prognosis than patients with high GLS group (p<0.001). Although peak longitudinal LA strain was correlated with GLS (R=0.65 p<0.001), peak longitudinal LA strain had additive prognostic value. AL patients with low GLS and low Peak LA strain (<13.4%) had a 8.3-fold increase in mortality risk in comparison to patients with high GLS (95% confidence interval: 3.84-18.03; p<0.001). Multivariable analysis showed peak longitudinal LA strain was significantly and independently associated with survival after adjusting for clinical and echocardiographic covariates (p<0.01). Conclusions: Peak longitudinal LA strain was additive to LV GLS in predicting prognosis in patients with biopsy confirmed AL amyloidosis. LA strain imaging has potential clinical utility in patients with AL cardiac amyloidosis.

Reduced Diagnostic Accuracy of Apical-Sparing Strain Abnormality for Cardiac Amyloidosis in Patients with Chronic Kidney Disease

Introduction: In cardiac amyloidosis, supraventricular tachycardia is common. Probable mechanisms are left ventricular dysfunction resulting in left atrial disease, but also direct atrial amyloid infiltration. Although measurement of left ventricular global longitudinal strain is commonly used, the value of left atrial strain remains unclear. Hypothesis: Left atrial strain should be strongly associated with the occurrence of supraventricular tachycardia in cardiac amyloidosis patients. Methods: In 69 cardiac amyloidosis patients (75% male, mean age 65 years) in our Amyloidosis Expert Center, echocardiographic strain analysis was performed using EchoPAC (version 203, General Electric Healthcare) between March 2017 and May 2020. Results: Supraventricular tachycardia occurred in 34 (43%) cardiac amyloidosis patients, which were older (70±8 vs. 60±15 years, p=0.001) but had a similar left ventricular mass index and ejection fraction. Left atrial volume index was higher (56±21 vs. 45±18 ml/m 2 , p=0.02), left ventricular global longitudinal strain (11±4 vs. 14±4, p=0.004) and left atrial reservoir strain (12±9 vs. 23±16, p=0.001) were lower. Left atrial reservoir strain was associated with supraventricular tachycardia, independent of left ventricular global longitudinal strain or left atrial volume (B-value 0.88 (confidence interval 0.80 - 0.97), p=0.01). Conclusion: Low left atrial reservoir strain was associated with the occurrence of supraventricular tachycardia independent of left atrial volume and left ventricular global longitudinal strain and therefore a promising parameter in cardiac amyloidosis patients.

A 74-year-old man presented with decreasing exercise tolerance and mild ankle edema. He was previously fit but was now breathless on climbing 2 flights of stairs. He had no history of angina, orthopnea, or paroxysmal nocturnal dyspnea. His medical history included non–insulin-dependent diabetes mellitus treated for 10 years and mild hypertension. Six years earlier he had been diagnosed with a monoclonal gammopathy of unknown significance. At that time, a bone marrow biopsy showed 30% overall cellularity with 5% to 10% plasmacytosis (normal <4%) and immunoglobulin light-chain restriction. Approximately 3 years ago, he developed deep vein thrombosis and was treated with low-molecular-weight heparin. A year later, leg swelling occurred and was attributed to venous insufficiency. The following year, he developed progressive fatigue on exertion, and an abnormal ECG (Figure 1) led to a treadmill test that was considered normal. An echocardiogram showed concentric wall thickening (Movie 1 in the Data Supplement), and the possibility of cardiac amyloidosis was raised. A fat pad biopsy was negative for amyloid deposits. The bone marrow biopsy performed in 2005 (when his monoclonal gammopathy of unknown significance was diagnosed) was restained and was negative for amyloid. At that time, serum-free λ light chains were 108.9 mg/L (normal range, 5.7–26.3) with κ light chains of 13 mg/L (normal, 3.3–19) and an abnormal ratio of 0.12 (normal, 0.26–1.65). His brain natriuretic peptide measured 275 pcg/mL. He was treated with oral diuretics, which improved leg swelling, but because of persistent symptoms, he sought medical care at our institution. On review of symptoms, he denied jaw claudication, symptoms of postural hypotension, easy bruising, or tongue swelling. He did give a history suggestive of neuropathy with a leathery feeling in his feet but no numbness in his hands. Medications included metformin 500 mg twice a day, aspirin 80 mg daily, lisinopril …

Hemodynamic Determinants of Left Atrial Strain in Symptomatic Patients With Significant Primary Mitral Regurgitation.

Role of Multimodal Cardiac Imaging in Low-Flow, Low-Gradient Aortic Stenosis

Background Patients with cardiac amyloidosis (CA) display an enlarged and dysfunctional left atrium (LA), because of the effects of left ventricular (LV) diastolic and then systolic dysfunction, as well as the amyloid infiltration of LA wall. A single study reported impaired LA strain in CA, but differences among amyloid light-chain (AL) and transthyretin (ATTR) CA and the correlates of reduced LA strain have not been characterized. Methods We evaluated 426 consecutive patients undergoing a screening for suspected CA in 2 tertiary referral centres. Among them, 262 (61%) were diagnosed with CA (n=117 AL-CA, n=145 ATTR-CA). We measured peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) from 4- and 2-chamber (4C, 2C) views, and correlated them with maximum and minimum LA volumes, E/e' ratio, and LV global longitudinal strain (GLS). Results LA strain was much more severely impaired in patients with ATTR-CA than those without CA, and to a lesser extent than those with AL-CA (Figure). LA volumes were larger in patients with ATTR-CA than those without CA (maximal LA volume, p=0.042; minimal LA volume, p&amp;lt;0.001), and those with AL-CA (both volumes, p&amp;lt;0.001). LA strain values were more closely correlated with minimal than maximal LA volumes, and patients with AL-CA displayed stronger correlations than those with ATTR-CA or without CA; for example, Spearman's rho values for 4C-PALS vs. minimal LA volume were 0.595, 0.481, and 0.462, respectively (all p&amp;lt;0.001). Furthermore, LA strain correlated with E/e' in patients with AL-CA, but not in those with ATTR-CA: 4C-PALS vs. E/e', rho 0.406, p=0.001 (AL-CA), p=0.401 (ATTR-CA), and p=0.097 (no CA). Finally, LA strain correlated most closely with LV GLS in patients with AL-CA: 4C-PALS vs. LV GLS, rho 0.431, p&amp;lt;0.001 (AL-CA), rho 0.401, p&amp;lt;0.001 (ATTR-CA), rho 0.219, p=0.042 (no CA). Conclusions LA volume increase and reduced LA strain is particularly prominent in patients with ATTR-CA. Patients with AL-CA seem to display closer relationships between LA strain, size and haemodynamic load, possibly reflecting the most acute disease course, and lower time for amyloid deposition in the LA wall. Funding Acknowledgement Type of funding sources: None.

INTRODUCTION Transthyretin amyloid cardiomyopathy (ATTR-CM) is an elusive, underdiagnosed condition, as its clinical presentation may be similar to many other cardiac and non-cardiac conditions, such as signs and symptoms of congestive heart failure or arrhythmias. A high degree of clinical suspicion of this condition with the appropriate diagnostic tools will allow early diagnosis and treatment, which can improve outcomes for patients diagnosed with ATTR-CM. Our case study below illustrates this condition. CASE PRESENTATION A 56-year-old Chinese man with a past history of hyperlipidaemia and bilateral carpal tunnel syndrome presented with a 2-week history of decreased effort tolerance, breathlessness and bilateral lower limb swelling. He did not have orthopnoea, paroxysmal nocturnal dyspnoea or chest pain. Vital signs on admission were heart rate 66 beats per minute, blood pressure 119/78 mmHg and oxygen saturation 98% on room air. His jugular venous pulse was elevated and there were no added heart sounds or murmurs. Auscultation of the lungs revealed bilateral basal crackles. He had pitting oedema up to his knees. Initial blood tests showed a haemoglobin level of 12.7 g/L (normal range [NR] 13.1–16.6 g/L) and creatinine level of 76 mg/L (NR 60–107 mg/L). Serial troponin-I levels were 67.9 ng/L, 88.8 ng/L and 91.3 ng/L (NR 0.0–17.4 ng/L). Electrocardiogram (ECG) on admission demonstrated sinus rhythm, PR interval 182 ms, normal QRS complex voltages and QRS duration 112 ms [Figure 1]. Serial ECGs showed an absence of dynamic ST segment-T wave changes. Chest radiograph revealed pulmonary congestion.Figure 1: 12-lead electrocardiogram on admission.Transthoracic echocardiography (TTE) demonstrated a marked symmetrical increase in left ventricular wall thickness on the parasternal long axis [Figure 2a] and apical 4-chamber view [Figure 2b], with a small pericardial effusion. The left ventricular wall thickness was measured to be maximally 22 mm during diastole (normal <10 mm). TTE also demonstrated a preserved left ventricular ejection fraction of 58% and mild valvular regurgitations. Strain imaging on TTE showed impaired global longitudinal strain (GLS) of −11.5% predominantly affecting the basal and mid-ventricular myocardial segments, with sparing of the apical segments ('cherry on top' pattern) [Figure 2c]. Given the TTE findings and the clinical presentation of heart failure, the working diagnosis was noted to be cardiac amyloidosis.Figure 2: (a) Transthoracic echocardiogram, parasternal long axis view. (b) Transthoracic echocardiogram, apical 4 chamber view, focused view of the left ventricle. (c) Transthoracic echocardiogram with speckle tracking, longitudinal strain map.Coronary angiogram demonstrated the absence of significant coronary artery disease. Screening for serum light chains was negative for monoclonal bands and free kappa/lambda ratio was within normal limits. The patient underwent endomyocardial biopsy (EMB), which confirmed the presence of Congo red-positive amyloid deposits. Histology images showed staining of the myocardium with haematoxylin and eosin (H&E) [Figure 3a] and immunoperoxidase [Figure 3b]. Liquid chromatography tandem mass spectrometry was performed and it detected a peptide profile consistent with transthyretin (TTR) amyloid deposition.Figure 3: Histology specimen from endomyocardial biopsy. (a) Photomicrograph shows myocardium with extracellular accumulation of hyalinised material (arrow) in between cardiomyocytes (H&E stain, x200). (b) Photomicrograph shows extracellular material that is immunoreactive for amyloid P protein (arrow) (immunoperoxidase, x200).He was reviewed by the neurology team and diagnosed with autonomic dysfunction, sensorimotor peripheral neuropathy and carpal tunnel syndrome, which were likely associated with systemic amyloidosis. There was no evidence of ocular manifestations of amyloidosis. He was counselled and subsequently underwent genetic testing. He was found to be heterozygous for a pathogenic variant in the TTR gene c.349G>T (p.Ala117Ser) associated with hereditary ATTR-CM (hATTR-CM).[1] Thus, a diagnosis of hATTR-CM was made. The patient was initially started on frusemide and spironolactone and achieved a good diuretic response. When EMB confirmed the diagnosis of cardiac amyloidosis, he was commenced on treatment with doxycycline and tauroursodeoxycholic acid. He remained well during clinic follow-up and was in New York Heart Association (NYHA) Class I. Given his diagnosis of hATTR-CM, his two children, a 22-year-old daughter and a 21-year-old son, were counselled for genetic testing. The same pathogenic variant in the TTR gene c.349G>T (p.Ala117Ser) was detected in both his children. To date, they are both pre-symptomatic and are planned for serial screening ECGs and TTEs with speckle tracking. DISCUSSION Our patient presented with heart failure along with neurological features of sensorimotor peripheral neuropathies and carpal tunnel syndrome. These clinical clues should prompt investigation of systemic amyloidosis, a family of disorders characterised by misfolded precursor proteins that form b-sheet-rich amyloid fibrils that are deposited extracellularly in several tissues, including cardiomyocytes.[2] About 95% of cardiac amyloidosis is the result of two culprit proteins — monoclonal immunoglobulin light chains secreted by clonal plasma cells, or TTR, a protein produced primarily by the liver in transthyretin amyloidosis (ATTR).[2] Light chain (AL) amyloid cardiomyopathy (CM) typically presents with rapidly progressive heart failure with a median survival of 6 months from the onset of heart failure if untreated. AL-CM is treated predominantly with chemotherapy and immunotherapeutics.[3] ATTR-CM, however, tends to present as a slow progressive disease, and patients without treatment can survive from years to decades.[3] Distinguishing ATTR-CM from AL-CM is hence important for management and prognostication. ATTR is classified into wild-type (wtATTR) or hereditary (hATTR), in which the mutant TTR gene is transmitted in an autosomal-dominant manner with variable penetrance.[2] The TTR gene is found on chromosome 18.[2] In hATTR, there are single amino acid mutations that destabilise the hetero-tetramer, leading to misfolding and aggregation in tissues.[2] TTR amyloid protein can infiltrate organs, primarily the heart and autonomic and peripheral nervous systems.[4] Cardiac infiltration of these rigid amyloid fibrils leads to stiffness and dysfunction.[2] The presence and extent of cardiac involvement is a major determinant of prognosis for patients with ATTR. ATTR-CM remains an elusive, underdiagnosed condition, as its clinical presentation may be similar to many other cardiac and non-cardiac conditions. Patients with ATTR-CM may experience symptoms and signs of heart failure, including exertional dyspnoea and decreased functional capacity, lung crackles, hepatomegaly, ascites and lower extremity oedema.[5,6] They may subsequently develop arrhythmias and conduction system disease.[5] Patients may also present with primary peripheral and autonomic neuropathy, spinal canal stenosis, biceps tendon rupture and vitreous opacities.[5] Laboratory findings include elevated NT-proBNP and troponin levels.[5] ECGs may demonstrate low voltages that are classically described in cardiac amyloidosis; however, this finding is less commonly seen in ATTR-CM compared to AL-CM (refer to our patient's ECG in Figure 1 which did not show low voltages).[4] Echocardiography is a cost-effect imaging modality that is often used in the initial evaluation of suspected cardiac amyloidosis.[5] TTE classically demonstrates global left ventricular wall thickening because of increased extracellular deposition of amyloid protein [Figures 2a and b].[4] The thick and dense myocardium is also often described as having a sparkling or speckled appearance.[4] There may be bi-atrial enlargement, thickened valves and pericardial and pleural effusions.[4,6,7] In the later stages of the disease, there may be diastolic dysfunction with restrictive left ventricular filling pattern.[4] There is reduced longitudinal systolic strain and a distinctive pattern of apical sparing in which the left ventricular apical region shows preserved strain compared with the mid and basal regions [Figure 2c].[4,6] A ratio of mean apical to mean basal plus mid-longitudinal strain of >1.0 has been found to be 93% sensitive and 82% specific for cardiac amyloidosis.[7,8] GLS has been shown to be an effective marker of cardiovascular mortality and morbidity — advanced ATTR with GLS <17% has a 100% 5-year mortality rate.[9] Cardiac MR imaging (CMR) provides detailed information about systolic function and cardiac function, and enables tissue characterisation.[5] As compared to echocardiography, CMR imaging has superior spatial resolution and provides reproducible measure of radial and longitudinal systolic function. Cine images may suggest a diagnosis of cardiac amyloidosis through MR imaging parameters such as global left ventricular and right ventricular thickening, as well as alterations in systolic and diastolic function measures, including strain pattern, mitral and tricuspid annular plain excursion and pericardial effusions.[10,11] Late gadolinium enhancement (LGE) imaging in CMR imaging can distinguish cardiac amyloidosis from other causes of left ventricular hypertrophy such as hypertension and hypertrophic cardiomyopathy.[12] LGE imaging is challenging in amyloidosis, as amyloid infiltration within the interstitium of the heart reduces the differences in contrast signal between blood and myocardium; this may cause the two compartments to null together or reverse, due to the high uptake of gadolinium in the expanded interstitial of amyloidotic hearts.[12] The global subendocardial pattern of LGE has traditionally been considered virtually diagnostic of the disease [Figure 4]. However, the pattern of LGE can be atypical and patchy, especially in early disease.[12] LGE may be inadequate for detecting cardiac amyloidosis in cases of diffuse and symmetrical disease without normal myocardium as a point of visual reference.[12] Quantitative parameters such as extracellular volume (ECV) and T1 mapping can also be employed for evaluation of cardiac amyloidosis in patients with diffuse disease and to identify the presence of early disease.[12] Extensive infiltration of the interstitium by the amyloid matrix would lead to increased ECV and native myocardial T1.[13] Extracellular expansion in cardiac amyloidosis is significant with an average ECV of 54% in ATTR and 51% in AL amyloidosis; in contrast, ECV in healthy subjects is about 20%–26%, and this is elevated to 27%–31% in diffuse fibrotic conditions and rarely goes beyond 40%.[14]Figure 4: MR images of a patient with transthyretin amyloid cardiomyopathy show a diffuse subendocardial late gadolinium enhancement pattern in the mid to basal regions of the left ventricle (arrows).Although useful for differentiating amyloidosis from other non-amyloid diseases, neither echocardiography nor cardiac MR imaging alone is considered sufficient in the diagnosis of cardiac amyloidosis.[4] Furthermore, both modalities are unable to reliably differentiate ATTR-CM from AL-CM.[4] Histopathological diagnosis with EMB is nearly 100% sensitive and specific for cardiac amyloidosis if the biopsy specimens are collected from multiple sites and tested for amyloid deposits with Congo red staining.[2] Identification of misfolded precursor proteins with immunohistochemistry or tandem mass spectrometry analysis can determine the amyloid subtype.[2] Extracardiac biopsy has varied sensitivity and unclear diagnostic reliability.[4] EMB, however, is invasive and is not routinely available at all centres. With the advent of nuclear scintigraphy using bone-avid radiotracers, diagnosis of ATTR-CM is now increasingly made through non-invasive imaging without the need for invasive cardiac biopsy and its attendant risks.[2] Myocardial scintigraphy with bone-avid tracers — Tc-99m-PYP (pyrophosphate), Tc-99m-DPD (diphosphono-1,2-propanodicarboxylic acid) and Tc-99m-HMDP (hydroxymethylene diphosphonate) — have high sensitivity and specificity for ATTR-CM, and may be useful for early diagnosis of ATTR-CM, even before the onset of increased wall thickness on TTE.[5] Studies using Tc-99m-PYP scan demonstrated that AL-CM and ATTR-CM can often be differentiated using quantitative or semiquantitative approaches; TTR amyloidosis has been shown to have high avidity for these radiotracers, while AL amyloidosis has low avidity.[9] However, it is prudent to concurrently screen for monoclonal proteins in the serum and urine using protein electrophoresis and immunofixation, as AL cardiac amyloidosis can uncommonly have grade 1 or higher grades of cardiac uptake on bone scintigraphy or there may be co-existence of an unrelated monoclonal gammopathy in ATTR-CM.[2] Semiquantitative grading using the Perugini visual scoring system in which the heart-to-rib uptake is compared can confer 97% specificity for ATTR-CM when grade 2 or 3 uptake is seen [Figure 5a].[9] A quantitative approach with heart-to-contralateral-chest ratio uptake of >1.5 is diagnostic of ATTR-CM, with 97% sensitivity and 100% specificity [Figure 5b], in the absence of monoclonal proteins.[9]Figure 5: Tc-99m-PYP scintigraphy images of a patient with transthyretin amyloid cardiomyopathy. Delayed planar and single photon emission chest CT images up to 3 hours were obtained following intravenous administration of Tc-99m-PYP. (a) There was diffuse, moderately intense radiotracer uptake of the myocardium, in particular the left ventricular wall. Overall, the uptake intensity was slightly higher than that of the adjacent ribs (indicating grade 3 myocardial PYP-uptake). (b) The calculated heart uptake: contralateral chest uptake ratio at 1-hour post-radiotracer administration was approximately 2.34 (>1.5), which was highly suggestive of transthyretin cardiac amyloidosis.Treatment of ATTR-CM is broadly divided into management of heart failure, treatment of arrhythmias and commencement of disease-modifying therapies. ATTR-CM exhibits a similar clinical phenotype as heart failure with preserved ejection fraction.[7] Diuretics are the first-line treatment for congestion, along with mineralocorticoid receptor antagonists.[7] Treatment of atrial fibrillation, which is common in ATTR-CM, is often challenging; rate control agents using beta-blockers and calcium-channel blockers may have negative inotropic effect and reduce cardiac output.[7] Disease-modifying targets include TTR silencing (target TTR hepatic synthesis), TTR stabilisation (prevent TTR tetramer misfolding) and TTR disruption (target clearance of amyloid fibrils from tissues).[15] Tafamidis, a TTR stabiliser, in its landmark trial ATTR-ACT in 2018, has demonstrated lower all-cause mortality and cardiovascular-related hospitalisation after 30 months.[16] It is now indicated in patients with ATTR-CM that having NYHA Class I-III symptoms and early initiation may slow disease progression.[6] Doxycycline and tauroursodeoxycholic acid are TTR disruptors; there are ongoing studies to elucidate their efficacy in ATTR-CM.[7] Patisiran, a small interfering RNA that blocks expression of TTR in the liver, is a TTR silencer that has demonstrated improvement in neurological status in patients with ATTR and polyneuropathy in the phase 3 trial APOLLO; studies are ongoing to evaluate its efficacy in ATTR-CM.[15] Genetic testing should be advised in all patients with confirmed ATTR-CM to look for pathologic TTR gene variants, regardless of patient age, because of the potential significant impact on their family members.[2,17] Hereditary ATTR is inherited in an autosomal-dominant manner, in which each child of the affected person has a 50% chance of carrying the pathogenic TTR variant. The advent of effective ATTR therapies in the past decade to treat the disease, especially in its early stages, has contributed to a shift in the perception of genetic testing. Genetic testing of asymptomatic family members of patients with ATTR is recommended, which allows early identification of individuals with the pathologic TTR variant.[18] By identifying at-risk individuals early, physicians can offer them close monitoring and prompt treatment once early signs of disease are detected.[17] There are founder mutations for TTR among families in Japan, Taiwan and elsewhere, with differing dominance between neurological and cardiac signs, but the TTR mutation spectrum has not yet been analysed in detail in Singapore.[19,20] Genetic counselling should be conducted to provide applicants with information about the disease, allowing them to understand the medical, psychological and familial implications of the genetic test results.[18] Penetrance of the disease varies among variants, with some individuals developing symptoms early in adulthood, while some remain asymptomatic throughout their lives.[18] Recommendations on the frequency of interval follow-up, appropriate modalities for surveillance and treatment options for pre-symptomatic carriers are not yet clearly delineated in current guidelines.[18] Several groups have suggested regular monitoring 10 years before the predicted age of onset of symptomatic disease, estimated through the involved mutation, typical age of onset and age of onset in affected family members.[18] Regular cardiac and neurological assessments are recommended and ECG, TTE, CMR and scintigraphy with bone tracers may be employed.[17,18] The diagnosis of ATTR-CM can be challenging and relies on the integration of information derived from a range of imaging modalities. Management of these patients requires a multidisciplinary approach and longitudinal follow-up. Acknowledgements We would like to thank Professor Tan Kong Bing for reviewing and providing the histology slides for our patient. Financial support and sponsorship Nil. Conflicts of interest Foo SY is a member of the SMJ Editorial Board. SMC CATEGORY 3B CME PROGRAMME Online Quiz: https://www.sma.org.sg/cme-programme Deadline for submission: 6 pm, 28 February 2023

Although impaired left ventricular (LV) global longitudinal strain (GLS) with apical sparing is a feature of cardiac amyloidosis (CA), its diagnostic accuracy has varied across studies. We aimed to determine the ability of apical sparing ratio (ASR) and most common echocardiographic parameters to differentiate patients with confirmed CA from those with clinical and/or echocardiographic suspicion of CA but with this diagnosis ruled out. We identified 544 patients with confirmed CA and 200 controls (CTRLs) as defined above (CTRL patients). Measurements from transthoracic echocardiograms were performed using artificial intelligence software (Us2.AI, Singapore) and audited by an experienced echocardiographer. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance and optimal cut-offs for the differentiation of CA patients from CTRL patients. Additionally, a group of 174 healthy subjects (healthy CTRL) was included to provide insight on how patients and healthy CTRLs differed echocardiographically. LV GLS was more impaired (-13.9 ± 4.6% vs. -15.9 ± 2.7%, P < 0.0005), and ASR was higher (2.4 ± 1.2 vs. 1.7 ± 0.9, P < 0.0005) in the CA group vs. CTRL patients. Relative wall thickness and ASR were the most accurate parameters for differentiating CA from CTRL patients [area under the curve (AUC): 0.77 and 0.74, respectively]. However, even with the optimal cut-off of 1.67, ASR was only 72% sensitive and 66% specific for CA, indicating the presence of apical sparing in 32% of CTRL patients and even in 6% healthy subjects. Apical sparing did not prove to be a CA-specific biomarker for accurate identification of CA, when compared with clinically similar CTRLs with no CA.

Aims: The present study aims to evaluate magnetic-resonance-imaging (MRI)-assessed left atrial strain (LAS) and left atrial strain rate (LASR) as potential parameters for the diagnosis of cardiac amyloidosis (CA), the distinction of clinical subtypes and differentiation from other cardiomyopathies. Methods and results: LAS and LASR were assessed by MRI feature tracking in patients with biopsy-proven CA. LAS and LASR of patients with CA were compared to healthy subjects and patients with hypertrophic cardiomyopathy. LAS and LASR were also analyzed concerning differences between patients with transthyretin (ATTR) and light chain amyloidosis (AL). A total of 44 patients with biopsy-proven CA, 19 patients with hypertrophic cardiomyopathy and 24 healthy subjects were included. In 22 CA patients (50%), histological examination identified ATTR as CA subtype and AL in the remaining patients. No significant difference was observed for reservoir, conduit or booster LAS in patients with AL or ATTR. Reservoir LAS, conduit LAS and booster LAS were significantly reduced in patients with CA and HCM as compared to healthy subjects (p < 0.001). Reservoir LAS and booster LAS were significantly reduced in CA as compared to HCM patients (p < 0.001). A linear correlation was observed between LA global reservoir strain and LA-EF (p < 0.001, r = 0.5), conduit strain and global longitudinal LV strain (p < 0.001, r = 0.5), global booster strain rate and LA-EF (p < 0.001, r = 0.6) and between global booster strain rate and LA area at LVED (p < 0.0001, 0.5). Conclusions: LAS and LASR are severely impaired in patients with CA. The MRI-based assessment of LAS and LASR might allow non-invasive diagnosis and categorization of CA and its distinct differentiation from other hypertrophic phenotypes.

Funding Acknowledgements Type of funding sources: None. Background Despite the increasing number of studies concerning Left Atrial Strain (LAS), few data are available comparing LAS patients with cardiac amyloidosis (CA) and sarcomeric hypertrophic cardiomyopathies (HCM). Purposes We aimed to perform a comparative multimodal imaging analysis of LAS of a prospective cohort of patients with CA and HCM. Methods For each enrolled patient, we performed same-day two and three-dimension echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) to blindly measure the peak atrial longitudinal strain (PALS) and the peak atrial contraction strain (PACS). Patients with acute atrial fibrillation were excluded. Results Between January 2020 and July 2021, 67 patients were included: 31 patients with CA (age 75.1 ± 10 years, left ventricular ejection fraction 60.6 ± 10.4%, maximum left ventricular thickness 17.8 ± 3.9 mm) and 36 with HCM (age 50.8 ± 15.5 years, left ventricular ejection fraction 66.1 ± 9.8%, maximum left ventricular thickness 20.7 ± 4.5 mm). Left atrial volume was similar in the 2 groups (42.5 ± 15.6 mL/m2 in HCM vs 47.9 ± 15 in CA, P = 0.1557). Concerning PALS, its values for CA and for CMH were on 2D TTE manual (10.9 ± 5.8% vs 21.4 ± 9.4%, P &amp;lt; 0.001), 2D TTE automatic (11.5 ± 7.3% vs 22.9 ± 10.2%, P &amp;lt; 0.001), 3D TTE (10 ± 6.8% vs 18.1 ± 6.7%, P &amp;lt; 0.001), and CMR (11.3 ± 8 vs 24.4 ± 17.1, P &amp;lt; 0.001) respectively. Concerning PACS, its values for CA and for CMH were on 2D TTE manual (5.2 ± 3.4% vs 10 ± 4%, P &amp;lt; 0.001), 2D TTE automatic (4.9 ± 3.9% vs 10.2 ± 5.1%, P &amp;lt; 0.001), 3D TTE (3.6 ± 3.8% vs 7.9 ± 4%, P = 0.001) and CMR (6.2 ± 5.8% vs 11.9 ± 9%, P = 0.004) respectively. Multivariate analysis adjusted on main factors influencing LAS (left ventricular (LV) mass, LV ejection fraction, LV global longitudinal strain, renal function and history of hypertension) found that the differences between the two groups remained significant for PALS and PACS for almost all technics. Furthermore, although concordance between the 3 echocardiographic technics was excellent (the interclass correlation coefficient (ICC) was higher than 0.80 between each TTE methods), ICC was poor between TTE and CMR technics: 0.40 (0.18-0.59) for manual 2D TTE and CMR, 0.46 (0.24-0.63) for auto 2D TTE and CMR, 0.40 (0.14-0.60) for 3D TTE and CMR. Conclusion Our study is the first to describe and compare, both on TTE and CMR, LAS on a prospective cohort of patients with CA and HCM. Although they have same mean left atrial volume, we found significant differences on PALS and PACS between these two groups of patients on all the studied technics. These findings may be used in future multi-modality imaging studies dealing with diagnosis or prognosis of these hypertrophic cardiopathies. Abstract Figure. LAS 2D TTE manual Abstract Figure. LAS comparison between CA and HCM

Echocardiographic diagnosis of cardiac amyloidosis: Does the masquerader require only a "cherry on top"?