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.

Abstract

HomeCirculation: Cardiovascular ImagingVol. 14, No. 7ASNC/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 Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBASNC/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 Sharmila Dorbala, MD, MPH, FASNC, Chair, Yukio Ando, MD, PhD, Sabahat Bokhari, MD, Angela Dispenzieri, MD, Rodney H. Falk, MD, Victor A. Ferrari, MD, Marianna Fontana, PhD, Olivier Gheysens, MD, PhD, Julian D. Gillmore, MD, PhD, Andor W. J. M. Glaudemans, MD, PhD, Mazen A. Hanna, MD, Bouke P. C. Hazenberg, MD, PhD, Arnt V. Kristen, MD, Raymond Y. Kwong, MD, MPH, Mathew S. Maurer, MD, Giampaolo Merlini, MD, Edward J. Miller, MD, PhD, James C. Moon, MD, Venkatesh L. Murthy, MD, PhD, C. Cristina Quarta, MD, PhD, Claudio Rapezzi, MD, Frederick L. Ruberg, MD, Sanjiv J. Shah, MD, Riemer H. J. A. Slart, MD, Hein J. Verberne, MD, PhD and Jamieson M. Bourque, MD, MHS, FASNC, Co-Chair Sharmila DorbalaSharmila Dorbala Search for more papers by this author , Yukio AndoYukio Ando Search for more papers by this author , Sabahat BokhariSabahat Bokhari Search for more papers by this author , Angela DispenzieriAngela Dispenzieri Search for more papers by this author , Rodney H. FalkRodney H. Falk Search for more papers by this author , Victor A. FerrariVictor A. Ferrari Search for more papers by this author , Marianna FontanaMarianna Fontana Search for more papers by this author , Olivier GheysensOlivier Gheysens Search for more papers by this author , Julian D. GillmoreJulian D. Gillmore Search for more papers by this author , Andor W. J. M. GlaudemansAndor W. J. M. Glaudemans Search for more papers by this author , Mazen A. HannaMazen A. Hanna Search for more papers by this author , Bouke P. C. HazenbergBouke P. C. Hazenberg Search for more papers by this author , Arnt V. KristenArnt V. Kristen Search for more papers by this author , Raymond Y. KwongRaymond Y. Kwong Search for more papers by this author , Mathew S. MaurerMathew S. Maurer Search for more papers by this author , Giampaolo MerliniGiampaolo Merlini Search for more papers by this author , Edward J. MillerEdward J. Miller Search for more papers by this author , James C. MoonJames C. Moon Search for more papers by this author , Venkatesh L. MurthyVenkatesh L. Murthy Search for more papers by this author , C. Cristina QuartaC. Cristina Quarta Search for more papers by this author , Claudio RapezziClaudio Rapezzi Search for more papers by this author , Frederick L. RubergFrederick L. Ruberg Search for more papers by this author , Sanjiv J. ShahSanjiv J. Shah Search for more papers by this author , Riemer H. J. A. SlartRiemer H. J. A. Slart Search for more papers by this author , Hein J. VerberneHein J. Verberne Search for more papers by this author and Jamieson M. BourqueJamieson M. Bourque Search for more papers by this author Originally published1 Jul 2021https://doi.org/10.1161/HCI.0000000000000029Circulation: Cardiovascular Imaging. 2021;14Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 1, 2021: Ahead of Print PreambleCardiac amyloidosis is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. Due to the relative rarity of cardiac amyloidosis, clinical and diagnostic expertise in the recognition and evaluation of individuals with suspected amyloidosis is mostly limited to a few expert centers. Electrocardiography, echocardiography, and radionuclide imaging have been used for the evaluation of cardiac amyloidosis for over 40 years.1-3 Although cardiovascular magnetic resonance (CMR) has also been in clinical practice for several decades, it was not applied to cardiac amyloidosis until the late 1990s. Despite an abundance of diagnostic imaging options, cardiac amyloidosis remains largely underrecognized or delayed in diagnosis.4 While advanced imaging options for noninvasive evaluation have substantially expanded, the evidence is predominately confined to single-center small studies or limited multicenter larger experiences, and there continues to be no clear consensus on standardized imaging pathways in cardiac amyloidosis. This lack of guidance is particularly problematic given that there are numerous emerging therapeutic options for this morbid disease, increasing the importance of accurate recognition at earlier stages. Imaging provides non-invasive tools for follow-up of disease remission/progression complementing clinical evaluation. Additional areas not defined include appropriate clinical indications for imaging, optimal imaging utilization by clinical presentation, accepted imaging methods, accurate image interpretation, and comprehensive and clear reporting. Prospective randomized clinical trial data for the diagnosis of amyloidosis and for imaging-based strategies for treatment are not available. A consensus of expert opinion is greatly needed to guide the appropriate clinical utilization of imaging in cardiac amyloidosis.IntroductionThe American Society of Nuclear Cardiology (ASNC) has assembled a writing group with expertise in cardiovascular imaging and amyloidosis, with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), the American Society of Echocardiography (ASE), the European Association of Nuclear Medicine (EANM), the Heart Failure Society of America (HFSA), the International Society of Amyloidosis (ISA), the Society for Cardiovascular Magnetic Resonance (SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This writing group has developed a joint expert consensus document on imaging cardiac amyloidosis, divided into two parts. Part 1 has the following aims:Perform and document a comprehensive review of existing evidence on the utility of echocardiography, CMR, and radionuclide imaging in screening, diagnosis, and management of cardiac amyloidosis.Define standardized technical protocols for the acquisition, interpretation, and reporting of these noninvasive imaging techniques in the evaluation of cardiac amyloidosis.Part 2 of this expert consensus statement addresses the development of consensus diagnostic criteria for cardiac amyloidosis, identifies consensus clinical indications, and provides ratings on appropriate utilization in these clinical scenarios.Purpose of the Expert Consensus DocumentThe overall goal of this multi-societal expert consensus document on noninvasive cardiovascular imaging in cardiac amyloidosis is to standardize the selection and performance of echocardiography, CMR, and radionuclide imaging in the evaluation of this highly morbid condition, and thereby improve healthcare quality and outcomes of individuals with known or suspected cardiac amyloidosis. We hope that research generated to validate the recommendations of this consensus document will form the basis for evidence-based guidelines on cardiac amyloidosis imaging within the next few years.Overview of Cardiac AmyloidosisCardiac amyloidosis is a cardiomyopathy that results in restrictive physiology from the myocardial accumulation of misfolded protein deposits, termed amyloid fibrils, causing a clinically diverse spectrum of systemic diseases. Most cases of cardiac amyloidosis result from two protein precursors: amyloid immunoglobulin light chain (AL), in which the misfolded protein is a monoclonal immunoglobulin light chain typically produced by bone marrow plasma cells, and amyloid transthyretin (ATTR) amyloidosis, in which the misfolded protein is transthyretin (TTR), a serum transport protein for thyroid hormone and retinol that is synthesized primarily by the liver.3 ATTR amyloidosis is further subtyped by the sequence of the TTR protein into wild-type (ATTRwt) or hereditary (ATTRv), the latter resulting from genetic variants in the TTR gene.5,6 Cardiac involvement in systemic AL amyloidosis is common (up to 75%, depending on diagnostic criteria),7 and in the case of ATTRwt amyloidosis, is the dominant clinical feature seen in all cases.The different types of cardiac amyloidosis display significant heterogeneity in clinical course, prognosis, and treatment approach.8 AL amyloidosis is characterized by a rapidly progressive clinical course, and if untreated, the median survival is less than 6 months. ATTRv amyloidosis follows a varied clinical course depending upon the specific mutation inherited with either cardiomyopathy and/or sensory/autonomic polyneuropathy.9 Furthermore, ATTR amyloidosis (both wild-type and hereditary) is characterized by an age-dependent penetrance, with the clinical phenotype developing as age advances.The diagnosis of cardiac amyloidosis remains challenging owing to a number of factors, which include the relative rarity of the disease, clinical overlap with more common diseases that result in thickening of the myocardium (ie, hypertension, chronic renal failure, hypertrophic cardiomyopathy, aortic stenosis), unfamiliarity with the proper diagnostic algorithm, and a perceived lack of definitive treatment. While systemic AL amyloidosis is indeed a rare disease affecting approximately 8 to 1210,11 per million person years, and as high as 40.5 per million person years in 2015,12 ATTRwt cardiac amyloidosis appears quite common, with recent reports using contemporary diagnostic strategies that place the prevalence in as many as 10% to 16% of older patients with heart failure or with aortic stenosis.13-15 In addition, the most common mutation associated with ATTRv amyloidosis has been reproducibly demonstrated in 3.4% of African Americans.16 While the penetrance remains disputed, this suggests there are approximately 2 million people in the United States who are carriers of an amyloidogenic mutation and are at risk for cardiac amyloidosis. It is clear both ATTRv and ATTRwt cardiac amyloidosis are underrecognized, yet important causes of diastolic heart failure.17Treatment options are rapidly expanding. Anti-plasma cell therapeutics have extended median survival in AL amyloidosis beyond 5 years, 7 with increasing survival beyond 10 years. We are potentially nearing a similar sea change in the management of ATTR amyloidosis. ATTR amyloidosis was previously only treated by solid-organ transplantation, as conventional highly effective heart-failure therapy is poorly tolerated and contraindicated in advanced cardiac amyloidosis. Although early clinical trials of amyloid specific antibodies have been unsuccessful to date,18-20 one remains under study in a Phase I clinical trial.21 Novel therapeutics that suppress TTR expression have been studied in Phase 3 clinical trials and received FDA approval18,19 for ATTRv with polyneuropathy. Additionally, a randomized clinical trial of TTR stabilizer therapy demonstrated a reduction in all-cause mortality in ATTR cardiomyopathy22; this agent has recently received FDA approval for ATTR cardiomyopathy. As these exciting prospects move into the clinical realm, it is evident early diagnosis will be essential to afford the most effective treatment options for both AL and ATTR cardiac amyloidosis.Biomarkers and Biopsy in Cardiac AmyloidosisDespite these advances in treatment, the challenge persists to increase recognition and achieve effective, timely diagnosis. In the past, a diagnosis of cardiac amyloidosis required an endomyocardial biopsy, which remains the gold standard, as it is virtually 100% accurate, assuming appropriate sampling, for the detection of amyloid deposits.23 Specific identification of the precursor protein can be accomplished from the tissue specimen through immunohistochemistry, albeit with limitations,24 or laser-capture tandem mass spectrometry (LC/MS/MS). This latter technique is considered the definitive test for precursor protein identification.25 While ATTR cardiac amyloidosis can now be diagnosed accurately without the need of cardiac biopsy,3 AL amyloidosis requires demonstration of light-chain amyloid fibrils in tissue (although not necessarily the heart) prior to administration of chemotherapy. Even for ATTR cardiac amyloidosis, a cardiac biopsy remains necessary in the context of equivocal imaging or the co-existence of a monoclonal gammopathy.Clinical suspicion of cardiac amyloidosis can be raised by the constellation of clinical signs and symptoms, specific demographics (ie, age, race, country of family origin), electrocardiography, and suggestive non-invasive imaging findings. Endomyocardial biopsy, although highly sensitive (100%),23 is impractical as a screening test for cardiac amyloidosis, given its inherent risk and requirement of pathologic expertise, which is limited to a few academic centers. Other limitations of endomyocardial biopsy include: inability to quantify whole-heart amyloid burden, inability to evaluate systemic disease burden, and, for these same reasons, limited assessment of response to therapy. Thus, contemporary imaging techniques, including CMR, radionuclide imaging with bone-avid radiotracers, and echocardiography with longitudinal strain quantification, have evolved as the principal means for diagnosis and management of cardiac amyloidosis.The current diagnostic approach for cardiac amyloidosis involves the use of one or more of these imaging modalities in conjunction with assessment of a plasma-cell disorder (Figure 1).3 Serum plasma electrophoresis is an insensitive test for AL amyloidosis and thus is unreliable for diagnosing AL amyloidosis. Serum and urine immunofixation and the measurement of serum free light chains (FLC) are necessary for the diagnosis of AL amyloidosis. In cases of confirmed ATTR amyloidosis, TTR gene sequencing is performed to establish ATTRwt vs ATTRv. In AL amyloidosis, the concentration of the affected FLC, in conjunction with serum N-terminal-pro brain natriuretic peptide (NT-proBNP) and cardiac troponin T or I, can be utilized to assign a disease stage that confers highly reproducible prognostic information.26 Furthermore, a cardiac staging system based on NT-proBNP and cardiac troponins (along with differential FLC levels) allows the stratification of patients into stages widely used in clinical practice for modulating the therapy intensity in AL amyloidosis.26 A European study identified a stage 3b subgroup with very advanced cardiac involvement; these patients had high concentrations of NT-proBNP (>8500 ng/L) and a very poor prognosis, which warrants further study.27 Furthermore, a reduction in FLC following anti-plasma cell treatment, termed a hematologic response, is typically followed within 6 to 12 months by a reduction in NT-pro-BNP and troponin, termed an organ-specific response, which is associated with improved symptoms of heart failure and extended survival.28 The FLC-based and NT-proBNP-based hematology and cardiac responses have been extensively validated in AL amyloidosis.29 In ATTR cardiac amyloidosis, NT-pro-BNP, cardiac troponin, and estimated glomerular filtration rate have also been validated as diagnostic markers in different risk-prediction models,30-32 with changes in NT pro-BNP useful to follow disease progression.18,22 Biomarker evaluation is an integral part of the management of patients with AL and ATTR cardiac amyloidosis.Download figureDownload PowerPointFigure 1. Systematic evaluation of cardiac amyloidosis. A comprehensive evaluation of cardiac amyloidosis includes consideration of clinical symptoms, evaluation of cardiac involvement (biomarkers and cardiac imaging), evaluation of systemic amyloidosis (serum, urine testing, and biopsy), followed by typing of amyloid deposits into AL or ATTR, and documentation of mutations in patients with ATTR amyloidosis. *Clinical symptoms: heart failure, peripheral/autonomic neuropathy, macroglossia, carpal tunnel syndrome, periorbital bruising, stroke, atrial fibrillation, postural hypotension, fatigue, weight loss, pedal edema, renal dysfunction, diarrhea, constipation. †Evaluation for cardiac amyloidosis: ECG, ECHO, CMR, EMB, 99mTc-PYP/DPD/HMDP/123I-mIBG/PET, NT-proBNP, troponin T. ‡Evaluation for systemic amyloidosis: AL: detect plasma cell clone: serum and urine immunofixation, serum FLC assay and immunoglobulin analysis; AL: detect systemic organ involvement: 24-hour urine protein, Alkaline phosphatase, eGFR, cardiac biomarkers (NT-proBNP, troponins); Tissue biopsy: EMB/Fatpad/ Bone marrow/Other with Congo red staining. §Confirm Amyloidosis Type: ATTR: IHC and MS of Biopsy or 99mTc- PYP/DPD/HMDP Grade 2 or 3 if a clonal process is excluded; AL: MS or IHC of Biopsy. ¥Confirm TTR Mutation in Patients with ATTR amyloidosis: genetic testing for TTR mutations. AL, amyloid light chain; ATTR, amyloid transthyretin; CMR, cardiac magnetic resonance imaging; DPD, -3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram; EMB, endomyocardial biopsy; ECHO, echocardiogram; eGFR, estimated glomerular filtration rate; HMDP, hydroxymethylenediphosphonate; IHC, immunohistochemistry; mIBG, meta-iodobenzylguanidine; MS, mass spectroscopy; v, hereditary; PYP, pyrophosphate; Tc, technetium; wt, wild-type.Evolution of Imaging in Cardiac AmyloidosisDespite the widespread utilization of serum biomarkers for risk assessment of cardiac amyloidosis, biomarkers themselves are non-specific for the diagnosis of amyloidosis. This lack of specificity is primarily due to confounding by renal function and overlap with other cardiomyopathies that also result in abnormalities of NT-pro BNP and troponin. For this reason, imaging remains a requisite component of the diagnostic algorithm for cardiac amyloidosis. In addition, imaging alone captures the cardiac functional impairment caused by amyloid infiltration and affords insight into hemodynamics. Finally, imaging has the potential to directly visualize cardiac remodeling that may result from both FLC reduction, TTR stabilization/suppression, and/or the anti-amyloid specific therapies in development. This consensus document serves as means to summarize the interpretation and application of multimodal imaging in cardiac amyloidosis.The first descriptions of echocardiographic findings in cardiac amyloidosis were reported more than 40 years ago.1,33 Since that time, echocardiography has become a standard part of the diagnostic assessment in patients with suspected or confirmed cardiac amyloidosis.34-37 The initial studies of echocardiography in cardiac amyloidosis occurred when only M-mode echocardiography was routinely available and predated the advent of clinical 2D and Doppler echocardiography. Nevertheless, these early studies recognized many of the findings of cardiac amyloidosis still used today in clinical practice,34-41 along with more recent advances as discussed in subsequent sections.1,33 Echocardiography has the advantage of portability, bedside availability, conspicuous presence, and superior diastolic function assessment. Thus, while echocardiography is not sufficient by itself, to make the diagnosis of cardiac amyloidosis, it is an essential part of the diagnostic evaluation and ongoing management of patients with this disorder.Cardiovascular magnetic resonance in cardiac amyloidosis provides structural and functional information that complements echocardiography.42 Cardiovascular magnetic resonance may have advantages when acoustic windows are poor, for characterization of the right ventricle, tissue characterization based on the contrast-enhanced patterns of myocardial infiltration, and precise quantification of cardiac chamber volumes and ventricular mass. However, CMR with late gadolinium enhancement (LGE) may be relatively contraindicated in patients with suspected cardiac amyloidosis and concomitant renal failure—a frequent occurrence. Moreover, in centers where CMR scanning in patients with pacemakers is not yet routine, echocardiography may be the only option for imaging cardiac structure and function. Although both the echocardiographic and CMR assessment of structure and function alone may be non-specific, some features provide more specificity, including biventricular long axis function impairment, apical sparing, reduced stroke volume index, pericardial effusion, marked biatrial enlargement, atrial appendage thrombus in sinus rhythm, sparkling texture of the myocardium, and/or disproportionate increase in left ventricular (LV) mass for electrocardiogram (ECG) voltages. Given the limitations of assessment of structure and function alone (by echo or CMR), tissue characterization by CMR adds high value, as discussed in subsequent sections.Radionuclide imaging provides critical information on amyloid type that complements cardiac structural and functional characterization by echocardiography and CMR. It has long been appreciated that there is a unique myocardial uptake pattern in amyloid by scintigraphy with 99mTechnetium (Tc)-bisphosphonate derivatives (99mTc-pyrophosphate [PYP], 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), 99mTc hydroxymethylene- diphosphonate [99mTc-HMDP]). Many studies dating from the 1970s and 80s suggested 99mTc-PYP could assist in diagnosing amyloidosis.2,43-48 However, there was variable diagnostic accuracy, which limited early use of the technique, owing to the study of mixed patients populations with undifferentiated ATTR and AL subtypes. Subsequent studies comparing 99mTc-bisphosphonate scintigraphy to gold standard endomyocardial biopsy discovered that ATTR cardiac amyloidosis has avidity for bone radiotracers, whereas AL cardiac amyloidosis has minimal or no avidity for these tracers. Therefore, bone-avid radiotracers can definitively diagnose amyloid type when a plasma cell dyscrasia is excluded. Recognition of preferential ATTR binding to bone-avid 99mTc-bisphosphonate-based radiotracers resulted in renewed interest and greater clinical application of cardiac scintigraphy with 99mTc-PYP, 99mTc-DPD, and 99mTc-HMDP. Although there is no direct comparison between these tracers, the information available suggests they can be used interchangeably. This is fortunate, given that there is limited access to 99mTc-DPD and 99mTc-HDMP in the United States and 99mTc-PYP in Europe.Evidence Base for Cardiac Amyloidosis ImagingDiagnosisCardiac amyloidosis is substantially underdiagnosed due to varied clinical manifestations, especially in the early stages of disease. An ideal non-invasive diagnostic method would identify cardiac involvement in amyloidosis and would also confirm the etiologic subtype. No existing diagnostic tools can provide this information individually, necessitating a multimodality cardiac imaging approach.EchocardiographyEchocardiography plays a major role in the non-invasive diagnosis of cardiac amyloidosis due to its assessment of structure and function and its pervasive use in patients with concerning cardiac symptoms. The evaluation of cardiac amyloidosis using echocardiography focuses on morphological findings related to amyloid infiltration, in particular, thickened LV walls >1.2 cm in the absence of any other plausible causes of LV hypertrophy (Figure 2).28 Although increased LV mass in the setting of low voltage ECG is suggestive of cardiac amyloidosis, a definitive distinction by echocardiography of amyloidosis from hypertrophic cardiomyopathy or other causes of LV hypertrophy is challenging.49 Other echocardiographic findings that suggest infiltrative disease include normal to small LV cavity size; biatrial enlargement and dysfunction41; left atrial and left atrial appendage stasis and thrombi; thickened valves; right ventricular and interatrial septal thickening; pericardial effusion; and a restrictive transmitral Doppler filling pattern.50-54 Several of these features, including an overt restrictive mitral inflow pattern are uncommon until late in the disease process.34,51 However, reduced LV systolic thickening, filling pressures, cardiac output,38 early diastolic dysfunction,39,40 and signs of raised filling pressures are commonly seen.34,52 A granular sparkling appearance of the myocardial walls may be appreciated, but it is not considered a highly specific finding and can be seen in other conditions, such as end-stage renal disease. The echocardiographic shift from fundamental to harmonic imaging has confounded this phenotype.Download figureDownload PowerPointFigure 2. Characteristic appearance of cardiac amyloidosis on echocardiography. (A)-(D) 2D echocardiography. (A) (parasternal long axis) and (B) (parasternal short axis) demonstrate increased LV wall thickness with a sparkling texture of the myocardium (yellow arrows) in a patient with primary (AL) cardiac amyloidosis. Also, note the small pericardial effusion (white arrows), which is often seen in patients with cardiac amyloidosis. (C) (apical 4-chamber view) demonstrates increased biventricular wall thickness, biatrial enlargement, and increased thickening of the interatrial septum (yellow arrow) and mitral valve leaflets (white arrow) in a patient with wild-type transthyretin cardiac amyloidosis. (D) Tissue Doppler imaging (TDI) tracing taken at the septal mitral annulus in a patient with ATTR cardiac amyloidosis. The TDI tracings shows the ‘‘5-5-5’’ sign (s’ [systolic], e’ [early diastolic], and a’ [late (atrial) diastolic] tissue velocities are all <5 cm/s), which is seen in patients with more advanced cardiac amyloidosis. The dotted lines denote the 5 cm/s cut-off for systolic and diastolic tissue velocities. In addition to the decreased tissue velocities, isovolumic contraction and relaxation times (IVCT and IVRT, respectively) are increased and ejection time (ET) is decreased, findings also seen in patients with cardiac amyloidosis especially as the disease becomes more advanced.Tissue Doppler imaging (TDI) and speckle-tracking echocardiography (STE) refine the non-invasive recognition of cardiac amyloidosis by quantitating longitudinal systolic function.51,55,56 A pattern of reduced longitudinal shortening with preserved LV ejection fraction and radial shortening is characteristic of cardiac amyloidosis and can differentiate it from other causes of increased LV wall thickness. Longitudinal systolic function is commonly impaired, even in the earlier phases of the disease, when radial thickening and circumferential shortening are still preserved.34,51,57-62 Both AL and ATTR cardiac amyloidosis patients demonstrate a typical pattern of distribution of STE-derived longitudinal strain in which basal LV segments are severely impaired while apical segments are relatively spared (Figure 3).51,63 Conversely, patients with other causes of LV hypertrophy (ie, aortic stenosis, hypertrophic cardiomyopathy) typically show reduced LV longitudinal strain in the regions of maximal hypertrophy.63,64Download figureDownload PowerPointFigure 3. Left ventricular longitudinal strain abnormalities. (A) (apical 4-chamber view), (B) (apical 2-chamber view), (C) (apical 3-chamber view) all show abnormal longitudinal strain in the basal and mid segments with relative preservation in the apical segments (purple and green curves, white arrows) in a patient with ATTRv cardiac amyloidosis. (D) shows the corresponding bullseye map of the longitudinal strain pattern throughout the left ventricle with the ‘‘cherry-on-the-top’’ sign (red denotes normal longitudinal strain at the apex and pink/blue denotes abnormal longitudinal strain at the mid/basal left ventricle).Another abnormal quantitative measure of LV contractility in cardiac amyloidosis is the myocardial contraction fraction (MCF), the ratio of stroke volume to myocardial volume. The MCF is an index of the volumetric shortening of the myocardium that is independent of chamber size and geometry and highly correlated with LV longitudinal strain.65-67 Abnormalities beyond the left ventricle can also suggest cardiac amyloidosis. Recently, it has been reported that the stroke volume index has a prognostic performance similar to LV strain in predicting survival in AL cardiac amyloidosis, independently of biomarker staging. Because the stroke volume index is routinely calculated and widely available, it could serve as the preferred echocardiographic measure to predict outcomes in AL cardiac amyloidosis patients. Left atrial reservoir and pump functions measured by strain are frequently impaired, irrespective of left atrial size, suggesting that both raised LV filling pressures and direct atrial amyloid infiltration (as documented by CMR studies) contribute to left atrial dysfunction.41,68 This dysfunction may result in the formation of atrial and atrial appendage thrombi, even in the setting of normal sinus rhythm, exposing patients to higher relative risk for embolic strokes. Although data are not available, clinical experience from major amyloidosis centers suggest the highly thrombogenic milieu of the left atrium increases cardioembolic risk in these patients.69 The right ventricle is often affected due to a combination of increased afterload from pulmonary hypertension and intrinsic right ventricular amyloid infiltration, resulting in reduced tricuspid annular plane systolic excursion, tissue Doppler systolic velocity, and longitudinal strain.70As echocardiographic findings lack the tissue characterization provided by CMR, echocardiographic diagnosis of cardiac amyloidosis relies on the presence of highly suggestive findings that can confirm diagnostic suspicion.34,71Ta