Journal of Clinical Medicine Review Multimodality Cardiac Imaging in Cardiomyopathies: From Diagnosis to Prognosis Guillem Casas 1,2,3, * and José F. Rodríguez-Palomares 1,2,3, * 1 Cardiovascular Imaging Unit and Inherited Cardiovascular Diseases Unit, Cardiology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain 2 Department de Medicina, Universitat Autónoma de Barcelona, 08035 Barcelona, Spain 3 Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, 28029 Madrid, Spain * Correspondence: gcasas@vhebron.net (G.C.); jfrodriguez@vhebron.net (J.F.R.-P.) Abstract: Cardiomyopathies are a group of structural and/or functional myocardial disorders which encompasses hypertrophic, dilated, arrhythmogenic, restrictive, and other cardiomyopathies. Multi- modality cardiac imaging techniques are the cornerstone of cardiomyopathy diagnosis; transthoracic echocardiography should be the first-line imaging modality due to its availability, and diagnosis should be confirmed by cardiovascular magnetic resonance, which will provide more accurate mor- phologic and functional information, as well as extensive tissue characterization. Multimodality cardiac imaging techniques are also essential in assessing the prognosis of patients with cardiomy- opathies; left ventricular ejection fraction and late gadolinium enhancement are two of the main variables used for risk stratification, and they are incorporated into clinical practice guidelines. Finally, periodic testing with cardiac imaging techniques should also be performed due to the evolving and progressive natural history of most cardiomyopathies.   Keywords: cardiomyopathy; multimodality cardiac imaging techniques; diagnosis; prognosis; left Citation: Casas, G.; ventricular ejection fraction; late gadolinium enhancement Rodríguez-Palomares, J.F. Multimodality Cardiac Imaging in Cardiomyopathies: From Diagnosis to Prognosis. J. Clin. Med. 2022, 11, 1. Introduction 578. https://doi.org/10.3390/ Cardiomyopathies constitute a heterogeneous group of diseases that affect the muscle jcm11030578 of the heart and present a very diverse etiology. Classically, the European Society of Cardiol- Academic Editor: Andrea ogy (ESC) classifies these diseases as hypertrophic, dilated, arrhythmogenic, restrictive, or Igoren Guaricci other cardiomyopathies [1]. Additionally, all of them are subclassified as familial/genetic or non-familial/non-genetic. Cardiomyopathies present variable expressions and symptoms Received: 8 December 2021 Accepted: 17 January 2022 that can change over time. Thus, periodic evaluation using cardiac imaging techniques is Published: 24 January 2022 essential throughout follow-up. These techniques can help us to diagnose, guide treatment, and optimize patients’ prognosis. Publisher’s Note: MDPI stays neutral The patient evaluation includes anamnesis, physical examination, an electrocardio- with regard to jurisdictional claims in gram, and transthoracic echocardiography (TTE) that may raise suspicion of cardiomyopa- published maps and institutional affil- thy. This information is usually complemented with a cardiovascular magnetic resonance iations. (CMR) that provides more precise anatomic and functional evaluation, as well as excellent tissue characterization with prognostic implications. Additionally, some patients may require a nuclear medicine test or cardiovascular computed tomography (CT). Copyright: © 2022 by the authors. In this manuscript, we will review the information that the different imaging tech- Licensee MDPI, Basel, Switzerland. niques offer in the diagnosis and management of these patients. This article is an open access article distributed under the terms and 2. Hypertrophic Cardiomyopathy conditions of the Creative Commons Hypertrophic cardiomyopathy (HCM) is defined by an increase in left ventricular (LV) Attribution (CC BY) license (https:// wall thickness and/or LV mass, unexplained by LV loading conditions. HCM is the most creativecommons.org/licenses/by/ prevalent cardiomyopathy, affecting approximately 1:500 of the adult population, and is 4.0/). usually caused by mutations in sarcomeric genes [2,3]. J. Clin. Med. 2022, 11, 578. https://doi.org/10.3390/jcm11030578 https://www.mdpi.com/journal/jcm 2.2.Hypertrophic HypertrophicCardiomyopathy Cardiomyopathy Hypertrophiccardiomyopathy Hypertrophic cardiomyopathy (HCM) (HCM) is is defined definedby byan anincrease increaseininleft leftventricular ventricular J. Clin. Med. 2022, 11, 578 (LV) wall thickness and/or LV mass, unexplained by LV loading (LV) wall thickness and/or LV mass, unexplained by LV loading conditions. HCM conditions. HCM 2 of 30is is thethe most prevalent cardiomyopathy, affecting approximately 1:500 most prevalent cardiomyopathy, affecting approximately 1:500 of the adult population,of the adult population, andisisusually and usuallycaused causedby bymutations mutations in in sarcomeric sarcomericgenes genes[2,3]. [2,3]. TTE is TTE is the first‐line imaging modality for HCM evaluation:aa amaximal TTE the is first‐line the imaging first-line imaging modality modality for for HCM HCM evaluation: evaluation: maximal maximal wall wall thickness thick- wall thickness > 15ness mm>15(ormmhigher than two (or higher standard than deviations two standard fromfrom deviations normal corrected normal for age, corrected gender, for age, > 15 mm (or higher than two standard deviations from normal corrected for age, gender, andgender, height)andor height) asymmetricor asymmetric septal hypertrophy septal hypertrophy (septal/posterior (septal/posterior wall thickness) wall thickness) ratio > 1.3 and ratio height) or(orasymmetric >1.3 >1.5 in septal hypertrophy hypertensive patients) is (septal/posterior suggestive of HCM wall thickness) (Figure 1) [4]. A ratio > 1.3 wall (or > 1.5 in hypertensive patients) is suggestive of HCM (Figure 1) [4]. A wall thickness ≥ (or >thickness 1.5 in hypertensive ≥30 mm is patients) associated is suggestive with a higher riskofof HCM (Figure suddendeath cardiac 1) [4].(SCD) death A wall thickness ≥ 30 mm is associated with a higher risk of sudden cardiac (SCD) [2,3]. [2,3]. 30 mm is associated with a higher risk of sudden cardiac death (SCD) [2,3]. Figure 1. A parasternal long‐axis view of a patient with septal HCM. Note the marked increase in septal wall1.thickness Figure andlong-axis A parasternal the asymmetry view of compared to the a patient with posterior septal wall.the marked increase in HCM. Note Figure 1. A parasternal long‐axis view of a patient with septal HCM. Note the marked increase in septal wall thickness and the asymmetry compared to the posterior wall. septal wall thickness and the asymmetry compared to the posterior wall. TTE allows for localization of the hypertrophy and hence identification of different TTE allows for localization of the hypertrophy and hence identification of different phenotypes: septal, septal reverse, apical, or diffuse HCM, among others (Figure 2). In TTE allowsseptal, phenotypes: for localization of the septal reverse, hypertrophy apical, and hence or diffuse HCM, among identification others (Figure 2). of In different addition, patients addition, patients with HCM present ancillary signs that, although non‐specific, can help phenotypes: septal, with septalHCM presentapical, reverse, ancillary orsigns that,HCM, diffuse although non-specific, among otherscan help 2). In (Figure in the diagnosis: in the papillary diagnosis: papillary muscle muscle abnormalities abnormalities (hypertrophic, (hypertrophic, bifidorortrifid, bifid trifid, and and with an with addition, apical patients with HCM present ancillary signs that, although non‐specific, can help an apical insertion), false tendons, myocardial clefts or crypts, aneurysms, or mitral valvevalve insertion), false tendons, myocardial clefts or crypts, aneurysms, or mitral inand the diagnosis: subvalvular and papillary subvalvularstructure muscle abnormalities structure abnormalities (elongated abnormalities (elongated (hypertrophic, mitral mitral bifid leaflets leaflets or trifid, with/without with/without and with an systolic systolic apical insertion), anterior motion anterior false motion‐SAM‐) tendons, -SAM-)(Figure myocardial 3) [5]. (Figure 3) [5]. clefts or crypts, aneurysms, or mitral valve and subvalvular structure abnormalities (elongated mitral leaflets with/without systolic anterior motion ‐SAM‐) (Figure 3) [5]. Figure 2. Different Figure 2. Differenthypertrophic hypertrophic cardiomyopathy phenotypes. cardiomyopathy phenotypes. (A)(A) Septal Septal HCM. HCM. (B) Apical (B) Apical HCM.HCM. (C)(C) Diffuse HCM. Diffuse HCM. Figure 2. Different hypertrophic cardiomyopathy phenotypes. (A) Septal HCM. (B) Apical HCM. (C) Diffuse HCM. J. Clin. Med. 2022, 11, 578 3 of 30 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 3 of 32 Figure 3. Ancillary signs in HCM. (A) Myocardial crypts in the inferior wall. (B) Apical aneurysm Figure 3. Ancillary signs in HCM. (A) Myocardial crypts in the inferior wall. (B) Apical aneurysm in in a patient with apical HCM. (C) Apical insertion of the papillary muscles in a patient with septal aHCM. patient with apical HCM. (C) Apical insertion of the papillary muscles in a patient with septal HCM. (D) Outflow tract obstruction measured on Doppler CW, note the dagger‐shaped curve. (E) (D) SAM Outflow tract evidenced onobstruction M‐mode: seemeasured on Doppler the movement CW, note of the anterior the leaflet mitral dagger-shaped curve. towards the (E)inSAM septum evidenced systole. on M-mode: see the movement of the anterior mitral leaflet towards the septum in systole. Moreover, Moreover, the the presence presenceof ofLV LVoutflow outflowtract tractobstruction obstruction (LVOTO) (LVOTO) cancanbebe easily easily evalu- eval‐ ated uatedandandisisdefined definedas as aa peak gradienthigher peak gradient higherthanthan3030 mmmm HgHg at at restrest or after or after provocative provocative maneuvers (typicallyobserved maneuvers (typically observedasasa adagger‐shaped dagger-shaped curve curve on on continuous continuous wave wave Doppler, Doppler, Figure Figure 3D). LVOTO LVOTO differentiates differentiatesbetween betweenobstructive obstructive andand non-obstructive non‐obstructive HCM, HCM,withwith important important therapeutic therapeutic and prognostic implications implications [2,3].[2,3]. Assessment AssessmentofofLV LVsystolic systolicfunc‐ function tion or LVorejection LV ejection fraction fraction (LVEF)(LVEF) is also is also important important because because it remains it remains anan importantpredictor important pre‐ dictor of of events events [6]. Patients [6]. Patients withwith an LVEF an LVEF <50% <50% present present a apoor poorprognosis prognosis [7] [7] and and should should be be considered considered forfor prophylactic prophylactic implantablecardioverter-defibrillator implantable cardioverter‐defibrillator (ICD) (ICD) according according to the the recent American guidelines [3]. In addition, the anteroposterior recent American guidelines [3]. In addition, the anteroposterior left atrial diameter left atrial diametershould should be measured, and the diastolic function should be assessed. be measured, and the diastolic function should be assessed. The maximal wall thickness, The maximal wall thickness, the thediameter, left atrial left atrial and diameter, LVOTO and haveLVOTO been have been incorporated incorporated into the riskintoprediction the risk pre‐ model diction model of SCD [8] endorsed of SCD [8] endorsed by the ESC [2]. by the ESC [2]. Strain parameters Strain parameters fromfrom speckle‐tracking speckle-trackingTTE TTEconstitute constitutemarkers markersofofLV LVsystolic systolicfunc‐ function tionare and andmore are more sensitive sensitive thanthan LVEF LVEF to systolic to systolic impairment. impairment. An An abnormal abnormal global global longi‐ longitudinal tudinal(GLS) strain strainhas (GLS) beenhasassociated been associated with withworse worse outcomes outcomes in HCMin HCM [9],[9], even even thoughclear though clear cut‐off values are not available cut-off values are not available due to lack of standardization. Other techniques,such due to lack of standardization. Other techniques, such as as circumferential circumferential strain strain or LVor LV rotation rotation andand twist twist mechanics, mechanics, are not are not routinely routinely recom‐ recommended. mended. CMR has become the gold standard technique for HCM evaluation and should be CMR has become the gold standard technique for HCM evaluation and should be performed in all patients [4]. Beyond more accurate measurement of LV wall thickness and performed in all patients [4]. Beyond more accurate measurement of LV wall thickness LVEF, CMR allows for tissue characterization with late gadolinium enhancement (LGE) and LVEF, CMR allows for tissue characterization with late gadolinium enhancement sequences (Figure 4). Artificial intelligence and machine learning could further improve (LGE) sequences (Figure 4). Artificial intelligence and machine learning could further im‐ the accuracy of wall thickness measurements [10]. prove the accuracy of wall thickness measurements [10]. LGE is a frequent finding in HCM (about 60% of patients) [6,11–13], correlates with the presence of myocardial fibrosis [14], and usually affects the most hypertrophied segments with an intramural pattern. In addition, its location in areas of septal-free wall junctions is a common finding. The presence of LGE has been consistently associated with adverse outcomes and especially with SCD risk [11,15,16]. J. Clin. Med. J. Clin. 2022, Med. 11,11, 2022, 578x FOR PEER REVIEW 4 of432 of 30 Figure 4. CMR study of a patient with septal HCM. (A) Maximal wall thickness measured on the Figure 4. CMR study of a patient with septal HCM. (A) Maximal wall thickness measured on the short‐axis cine stack at end‐diastole. (B) Post‐contrast T1 sequences showing extensive basal and short-axis cine stack at end-diastole. (B) Post-contrast T1 sequences showing extensive basal and mid‐anteroseptal LGE with an intramyocardial pattern. mid-anteroseptal LGE with an intramyocardial pattern. LGE is a frequent finding in HCM (about 60% of patients) [6,11–13], correlates with Quantification of LGE, usually as the percentage of total LV mass using the five the presence of myocardial fibrosis [14], and usually affects the most hypertrophied seg‐ standard deviation method [17], has emerged as a powerful predictor of SCD, both in ments with an intramural pattern. In addition, its location in areas of septal‐free wall junc‐ obstructive and non-obstructive, tions is a common low- and finding. The presence of high-risk LGE has beenHCMconsistently [6,11–13,18]associated and withwithbetter predictive value than the ESC calculator [8]. adverse outcomes and especially with SCD risk [11,15,16]. An LGE >15% has been proposed as a risk marker for SCD [3,16,19]. Contrarily, outcomes of patients with Quantification of LGE, usually as the percentage of total LV mass using the fivea low LGE amount (<5%) are comparable standard to those deviation method without LGEemerged [17], has [6,12]. Progression as a powerful of predictor LGE extension of SCD, throughout both in follow-up has also been reported in HCM patients and has been obstructive and non‐obstructive, low‐ and high‐risk HCM [6,11–13,18] and with better related to adverse cardiac remodeling and worse predictive value than theprognosis [18]. Owing ESC calculator [8]. Anto the LGEstrong >15%evidence, “extensive” has been proposed as LGE a riskhas been incorporated marker as a parameter for SCD [3,16,19]. for prophylactic Contrarily, ICD implantation outcomes of patients with a lowinLGE the recent amount American (<5%) guidelines, are comparablewhichtoalso those recommend without LGEperforming a CMR every [6,12]. Progression 3–5 years of LGE to evaluate extension disease throughout progression [3]. follow‐up has also been reported in HCM patients and has been related to adverse cardiac Emerging remodeling andCMRworsesequences, suchOwing prognosis [18]. as T1 to andtheT2 mapping strong evidence,and“extensive” extracellularLGEvolume has (ECV), allow for quantitative analysis of tissue characteristics and been incorporated as a parameter for prophylactic ICD implantation in the recent Ameri‐ are more sensitive than LGE for the detection of myocardial fibrosis, especially in case can guidelines, which also recommend performing a CMR every 3–5 years to evaluate of diffuse interstitial fibrosis (Figure disease5) [20]. Further, progression [3]. T1 and T2 mapping are useful in the differential diagnosis of left ventricular Emerginghypertrophy [21]. Small CMR sequences, suchstudies as T1 have and T2 so mapping far reported andprognostic extracellularimplications volume of(ECV), T1 mapping allow for[22] and ECV [23] quantitative values. analysis However, of tissue further studies characteristics and areare needed more to validate sensitive than the LGE prognostic implications for the detection of mapping of myocardial sequences fibrosis, especially toinfully case incorporate them into of diffuse interstitial daily fibro‐ clinical practice. sis (Figure 5) [20]. Further, T1 and T2 mapping are useful in the differential diagnosis of Stress echocardiography left ventricular hypertrophy [21]. (SE)Small is another studies useful have technique in theprognostic so far reported assessment of HCM implica‐ because tions ofone-third T1 mapping of patients [22] and have ECVlatent [23] LVOTO. SE is safe and values. However, usually further performed studies in a semi- are needed to supine validateposition, while the the prognostic use of dobutamine implications of mappingissequences not recommended in HCM. them to fully incorporate LVOTO,intoLV daily clinical systolic functionpractice. (LVEF and GLS), LV diastolic function (E/E’), dynamic mitral regurgitation (usually secondary to SAM) and tricuspid regurgitation (TR) velocity should be evaluated at rest, at peak stress, and post-exercise (Figure 6) [24]. Exercise-induced significant LVOTO (>50 mmHg) is a marker of worse prognosis and can be used to guide treatment [2,3,24]. A diastolic stress test may also be performed; an increase in E/E’ > 14 and peak TR velocity >2.8 m/s has been invasively correlated with elevated LV filling pressures during exercise [25] and is a marker of poor exercise tolerance [24]. The role of SE in the detection of inducible ischaemia in HCM is controversial. In this scenario, stress CMR with vasodilators is usually preferred, and signs of microvascular dysfunction may be observed [4]. J. Clin. Med. 2022, 11, 578 5 of 30 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 5 of 32 A B C Figure 5. CMR study of a patient with septal HCM. (A,B) LGE sequences with heterogeneous J. Clin. Med. 2022, 11, x FOR PEER REVIEW contrast 6 ofan 32 Figure 5.uptake in the basal CMR study and mid-anteroseptal of a patient segments. with septal HCM. (C) Native (A,B) LGE T1 mapping sequences sequence with with heterogeneous con‐ increased native trast uptake T1 basal in the value and of 1108 ms in the basalsegments. mid‐anteroseptal anteroseptal (C)segment (reference Native T1 mappingrange 950–1050 sequence ms). with an increased native T1 value of 1108 ms in the basal anteroseptal segment (reference range 950–1050 ms). Stress echocardiography (SE) is another useful technique in the assessment of HCM because one‐third of patients have latent LVOTO. SE is safe and usually performed in a semi‐supine position, while the use of dobutamine is not recommended in HCM. LVOTO, LV systolic function (LVEF and GLS), LV diastolic function (E/E’), dynamic mitral regur‐ gitation (usually secondary to SAM) and tricuspid regurgitation (TR) velocity should be evaluated at rest, at peak stress, and post‐exercise (Figure 6) [24]. Exercise‐induced signif‐ icant LVOTO (>50 mmHg) is a marker of worse prognosis and can be used to guide treat‐ ment [2,3,24]. A diastolic stress test may also be performed; an increase in E/E’ >14 and peak TR velocity >2.8 m/s has been invasively correlated with elevated LV filling pres‐ sures during exercise [25] and is a marker of poor exercise tolerance [24]. The role of SE in the detection of inducible ischaemia in HCM is controversial. In this scenario, stress CMR with vasodilators is usually preferred, and signs of microvascular dysfunction may be observed [4]. Figure6.6. Stress Figure Stress echocardiography echocardiography in in aapatient patientwith withHCM. HCM.Note Notethethemarked markedincrease in in increase SAM SAM(B, white arrow) and the significant increase in LVOTO (D) at peak stress compared to the basal situa‐ (B, white arrow) and the significant increase in LVOTO (D) at peak stress compared to the basal tion (A,C). situation (A,C). Therole The roleofofcardiac cardiacCTCTin in HCM HCM is secondary is secondary andand may may be considered be considered to exclude to exclude coro‐ coronary nary artery artery disease. disease. Recently, Recently, assessment assessment of myocardial of myocardial fibrosis fibrosis by delayed by delayed enhanced enhanced CT hasCT has been been described described withwith an adequate an adequate agreement agreement withwith LGELGE by CMR by CMR [26].[26]. EvenEven though though data data is is still scarce, and no clinical implications should be attributed, it might become still scarce, and no clinical implications should be attributed, it might become an alternativean alter‐ native for thosefor those patients patients who have who have a contraindication a contraindication for CMR. for CMR. Table 1 describes the main imaging diagnostic and prognostic findings in HCM. Table 1. Summary of imaging findings in HCM. J. Clin. Med. 2022, 11, 578 6 of 30 Table 1 describes the main imaging diagnostic and prognostic findings in HCM. Table 1. Summary of imaging findings in HCM. Diagnostic Criteria Ancillary Signs Prognostic Markers Maximal wall thickness >15 mm Papillary muscle Maximal wall thickness (>13 mm in relatives of abnormalities (>30 mm) HCM patients) Asymmetric septal hypertrophy (ratio Mitral valve and subvalvular Left atrial size septal/posterior wall structure abnormalities (anteroposterior diameter) thickness >1.3 or >1.5 in hypertensive patients) Maximum LVOT gradient (at Myocardial clefts/crypts rest or induced by exercise) Aneurysms LVEF < 50% Abnormal GLS Presence, extension, and progression of LGE J. Clin. Med. 2022, 11, x FOR PEER REVIEW Increased T1/ECV values 7 of 32 3. Dilated Cardiomyopathy 3. Dilated Cardiomyopathy Dilated cardiomyopathy (DCM) is defined by LV (or biventricular) systolic dysfunction Dilated cardiomyopathy (DCM) is defined by LV (or biventricular) systolic dysfunc‐ (LVEF < 45%) and dilatation (LV end-diastolic volumes or diameters >2 standard deviations tion (LVEF < 45%) and dilatation (LV end‐diastolic volumes or diameters >2 standard de‐ from normal corrected by age, gender, and body surface area) not attributed to loading viations from normal corrected by age, gender, and body surface area) not attributed to conditions or coronary loadingartery disease conditions or (Figure coronary7). DCMdisease artery affects(Figure approximately 7). DCM 1:2500 affects adults, approximately can be both genetic and acquired, and is a leading cause of heart failure [27]. 1:2500 adults, can be both genetic and acquired, and is a leading cause of heart failure [27]. Figure 7. Transthoracic echocardiography of a patient with dilated cardiomyopathy, showing a Figure 7. Transthoracic echocardiography of a patient with dilated cardiomyopathy, showing a parasternal long‐axis view (A) and an apical 4‐chambers view (B). Note the marked dilatation of the parasternal long-axis left view (A)and ventricle andthe anspherical apical 4-chambers pattern. view (B). Note the marked dilatation of the left ventricle and the spherical pattern. TTE allows for both anatomical and functional assessment. Three‐dimensional trans‐ TTE allows for both echocardiography thoracic anatomical and functional (3D TTE) assessment. is increasinglyThree-dimensional transtho-in tech‐ used due to improvements racic echocardiography nology and(3Dautomated TTE) is increasingly software and used dueadvantage has the to improvements in technology of direct LV measurements with and automated software and assumptions no geometric has the advantage (Figureof 8).direct Most LV measurements importantly, 3D TTEwith no geomet- is more accurate and re‐ ric assumptions producible (Figure 8).than Mostconventional importantly, two‐dimensional 3D TTE is more (2D) TTE and accurate shows and better agreement reproducible than conventional with CMR values. However, two-dimensional (2D) TTE 3D and TTE shows dependsbetter on good image quality, agreement requires with CMR more ad‐ val- vanced technical skills, and normal values are less well ues. However, 3D TTE depends on good image quality, requires more advanced technical established [28]. skills, and normal values are less well established [28]. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 8 of 32 J. Clin. Med. 2022, 11, 578 7 of 30 A B C Figure 8. Three‐dimensional transthoracic echocardiography of the left ventricle. (A) Triplane view of the LV allows simultaneous and single‐beat acquisition of Figure 8. Three-dimensional the three transthoracic apical views. By tracing echocardiography the endocardial of the borders, the LV left ventricle. volume is obtained(A) Triplane (surface view ofbottom rendering, the LVright). allows(B)simultaneous and single-beat Real‐time single‐beat acquisition of the 3D acquisition three of apical the LVviews. from theByapical tracing the endocardial window. borders, Volume renders allowthe forLV volume offline is obtained(C) reconstructions. (surface rendering, Tomographic bottom multislice right).from obtained (B) aReal-time single-beat multiple‐beat 3D acquisition apical view. Wall of the motion LV from abnormalities the can beVolume apical window. assessedrenders with this technique. allow for offline reconstructions. (C) Tomographic multislice obtained from a multiple-beat apical view. Wall motion abnormalities can be assessed with this technique. x FOR PEER REVIEW 9 of 32 J. Clin. Med. 2022, 11, 578 8 of 30 LVEF remains the strongest predictor of events in DCM; thus, patients with an LVEF ≤35% must be considered for optimal medical treatment and prophylactic ICD (with/with‐ LVEF remains the strongest predictor of events in DCM; thus, patients with an out cardiac resynchronization therapy, CRT) [29,30]. However, an LVEF ≤35% has proven LVEF ≤35% must be considered for optimal medical treatment and prophylactic ICD to have a low sensibility and specificity (with/without for SCD prediction, cardiac resynchronization so additional therapy, CRT) predictors [29,30]. However, an LVEFare≤35% required. Strain parameters, has proven both GLS to have (Figure a low 9) and sensibility andglobal circumferential specificity strainso(GCS) for SCD prediction, additional predictors are required. Strain parameters, both GLS (Figure 9) have been associated with cardiovascular events and present an incremental prognostic and global circumferential strain (GCS) have been associated with cardiovascular events and present an incremental value over LVEF [31]. Myocardial work (MW) is a novel quantitative parameter that in‐ prognostic value over LVEF [31]. Myocardial work (MW) is a novel quantitative parameter corporates both strain and LV pressure that incorporates variables both strain and LV (Figure pressure 10) [32]. (Figure variables Initial 10) reports suggest [32]. Initial reports that not only MW is related to outcomes, but also has an additional prognostic role over role suggest that not only MW is related to outcomes, but also has an additional prognostic both LVEF and GLS in both over DCM [33]. LVEF and GLS in DCM [33]. Figure 9. Longitudinal strain Figure analysis of strain 9. Longitudinal a patient with analysis of aDCM: patient4with chambers DCM: 4(A), 2 chambers chambers (B), 3 (B), (A), 2 chambers chambers (C), and bull’s eye plot (D). Note the diffusely affected longitudinal strain, consistent with with 3 chambers (C), and bull’s eye plot (D). Note the diffusely affected longitudinal strain, consistent depressed LVEF, and positive depressed values LVEF, in the values and positive basal inseptum the basalsuggestive of dyskinesia septum suggestive in inthese of dyskinesia these seg‐ segments. ments. Stress echocardiography (SE) is also useful for risk stratification in DCM. Dobutamine is most often used, with either low or high-dose protocols (10 or 40 µg/kg/min), and the contractile response is assessed. An increase by ≥5% in LVEF at peak stress is defined as a contractile reserve and is associated with improved outcomes and reverse remodeling in DCM [24,34]. SE may also be used to exclude ischaemic etiology. CMR should be performed at least once in all DCM patients since it is the gold standard technique for the assessment of biventricular volumes, systolic function, and tissue characterization. LGE is common in DCM and traduces myocardial fibrosis [35,36], usually with a septal mid-wall pattern (Figure 11). LGE has been consistently described as a strong and independent predictor of outcomes in DCM [35–37], and specifically for SCD [35,37,38]. The absence of LGE is also associated with reverse remodeling [37], which confers improved survival in DCM. Of note, LGE shows incremental prognostic value over LVEF [39], even in patients with only mild or moderate systolic dysfunction [40]. The extension, localization, and pattern of LGE have also been associated with prog- nosis [41,42]; a higher burden of LGE, septal LGE, and multiple patterns (combined septal J. Clin. Med. 2022, 11, 578 9 of 30 and free-wall, epicardial, and transmural LGE) are related to higher mortality or SCD. The risk of adverse outcomes is also higher in patients with progression of LGE over time [43]. Considering the important prognostic role of LGE and the aforementioned limitations of LVEF, a combined algorithm has recently been proposed to enhance the identification of x FOR PEER REVIEW 10 of 32 patients at high risk for SCD who should be considered for prophylactic ICD [42]. However, clinical guidelines are only based on LVEF [29,30]. Figure 10. MyocardialFigure work10.analysis in awork Myocardial patient with analysis in aDCM. patient (A) with Strain—pressure loop. loop. DCM. (A) Strain—pressure (B) Com‐ (B) Compar- parison of constructive work (green) and wasted work (blue). (C) Bull’s eye plot of myocardial work work ison of constructive work (green) and wasted work (blue). (C) Bull’s eye plot of myocardial index (mmHg%). (D) index Bull’s(mmHg%). (D)myocardial eye plot of Bull’s eye plotwork of myocardial work efficiency efficiency (%). (%). Stress echocardiography (SE) is also useful for risk stratification in DCM. Dobuta‐ mine is most often used, with either low or high‐dose protocols (10 or 40 μg/kg/min), and the contractile response is assessed. An increase by ≥5% in LVEF at peak stress is defined as a contractile reserve and is associated with improved outcomes and reverse remodeling in DCM [24,34]. SE may also be used to exclude ischaemic etiology. CMR should be performed at least once in all DCM patients since it is the gold stand‐ ard technique for the assessment of biventricular volumes, systolic function, and tissue characterization. LGE is common in DCM and traduces myocardial fibrosis [35,36], usu‐ ally with a septal mid‐wall pattern (Figure 11). LGE has been consistently described as a strong and independent predictor of outcomes in DCM [35–37], and specifically for SCD [35,37,38]. The absence of LGE is also associated with reverse remodeling [37], which con‐ fers improved survival in DCM. Of note, LGE shows incremental prognostic value over LVEF [39], even in patients with only mild or moderate systolic dysfunction [40]. ard technique for the assessment of biventricular volumes, systolic function, and tissue characterization. LGE is common in DCM and traduces myocardial fibrosis [35,36], usu‐ ally with a septal mid‐wall pattern (Figure 11). LGE has been consistently described as a strong and independent predictor of outcomes in DCM [35–37], and specifically for SCD [35,37,38]. The absence of LGE is also associated with reverse remodeling [37], which con‐ J. Clin. Med. 2022, 11, 578 fers improved survival in DCM. Of note, LGE shows incremental prognostic value10over of 30 LVEF [39], even in patients with only mild or moderate systolic dysfunction [40]. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 11 of 32 Figure 11. CMR study of a patient with DCM. (A) Short‐axis cine stack. (B,C) Post‐contrast T1 se‐ quences showing a typical LGE pattern with a lineal mid‐septum uptake as well as a focal uptake in the septum‐free wall inferior junction. The extension, localization, and pattern of LGE have also been associated with prog‐ nosis [41,42]; a higher burden of LGE, septal LGE, and multiple patterns (combined septal and free‐wall, epicardial, and transmural LGE) are related to higher mortality or SCD. The risk of adverse outcomes is also higher in patients with progression of LGE over time [43]. Figure 11. CMR Considering thestudy of a patient important with DCM. prognostic role of(A) LGEShort-axis cine stack. (B,C) limitations and the aforementioned Post-contrast of T1 sequences showing a typical LGE pattern with a lineal mid-septum uptake as well LVEF, a combined algorithm has recently been proposed to enhance the identification of as a focal uptake inpatients the septum-free wall for at high risk inferior SCDjunction. who should be considered for prophylactic ICD [42]. How‐ ever, clinical guidelines are only based on LVEF [29,30]. GLS by CMR (Figure 12) has been shown to be associated with outcomes in DCM, and GLS by CMR (Figure 12) has been shown to be associated with outcomes in DCM, most importantly to improve risk classification beyond LVEF and LGE [44]. However, it and most importantly to improve risk classification beyond LVEF and LGE [44]. However, has not been standardized and no cut-off points have been proposed, so routine clinical it has not been standardized and no cut‐off points have been proposed, so routine clinical use is not yet recommended. Mapping techniques have also been evaluated in DCM; use is not yet recommended. Mapping techniques have also been evaluated in DCM; higher T1 and ECV values have been shown to have prognostic implications irrespective of higher T1 and ECV values have been shown to have prognostic implications irrespective LVEF of LVEFandandLGE [45]. LGE Furthermore, [45]. Furthermore, anan increased increasednative nativeT2T2value valueindicates indicatesthe thepresence presence of myocardial of myocardial edema, edema,which whichcould suggest could thethe suggest presence of inflammatory presence of inflammatory cardiomyopathy cardiomyopathy [46]. These [46]. These techniques offer promising new tools for risk stratification, but further valida‐ is techniques offer promising new tools for risk stratification, but further validation still tionrequired. is still required. Figure 12. Strain analysis by CMR obtained with feature‐tracking software in a patient with DCM. Figure 12. Strain analysis by CMR obtained with feature-tracking software in a patient with DCM. Endocardial and epicardial segmentation of short and long‐axis is required, both at end‐diastole Endocardial and epicardial segmentation of short and long-axis is required, both at end-diastole and end- and end‐systole. Thus, longitudinal (A), radial (B), and circumferential (C) strain are simultaneously systole. Thus, longitudinal (A), radial (B), and circumferential (C) strain are simultaneously acquired. acquired. Assessment of right ventricle (RV) size and systolic function is recommended in all Assessment of right ventricle (RV) size and systolic function is recommended in all patients since RV systolic dysfunction is a common finding and an independent predictor of patients since RV systolic dysfunction is a common finding and an independent predictor poor outcome [47]. Different techniques may be applied: fractional area change [48], peak of poor outcome [47]. Different techniques may be applied: fractional area change [48], longitudinal strain of peak longitudinal RV free strain of RVwall [49] free by [49] wall TTE,byorTTE, RV ejection fractionfraction or RV ejection (RVEF) by CMRby (RVEF) [47]. The CMR [47]. The same advantages and limitations previously mentioned in 3D TTE alsoRV; same advantages and limitations previously mentioned in 3D TTE also apply to the specifically, apply to theglobal chamber including RV; specifically, RV inflow global chamber and outflow including tracts RV inflow andand apicaltracts outflow regionsandcan only be assessed by 3D TTE and not 2D TTE (Figure 13) [28]. Secondary (functional) apical regions can only be assessed by 3D TTE and not 2D TTE (Figure 13) [28]. Secondary mitral regurgitation and diastolic dysfunction should also be evaluated since they are associated (functional) mitral regurgitation and diastolic dysfunction should also be evaluated since they are associated with cardiovascular events [50]. LV GLS [51], left atrial strain [52] and MW [53,54] by TTE, as well as septal viability on CMR [54], have been identified as pre‐ dictors of response to CRT. J. Clin. Med. 2022, 11, 578 11 of 30 with cardiovascular events [50]. LV GLS [51], left atrial strain [52] and MW [53,54] by TTE, as well as septal viability on CMR [54], have been identified as predictors of response to CRT. Other imaging modalities are rarely used in DCM. Nuclear imaging can analyze car- diac sympathetic innervation, which has been associated with ventricular arrhythmias and adverse prognosis [55]. Cardiac CT is commonly used to exclude coronary artery disease. Recent studies have shown the ability of delayed enhancement CT to detect myocardial fibrosis, with comparable performance to LGE by CMR [56]. However, results are still preliminary, and no clinical studies are available, so routine use is not recommended. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 12 of 32 J. Clin. Med. 2022, 11, 578 12 of 30 A B C Figure 13. Three-dimensional transthoracic echocardiography of the right ventricle. (A) By tracing the endocardial RV borders (top and bottom left), a 3D volume of the RV (top right) is obtained throughout the cardiac cycle (bottom right) and 3D RVEF is calculated. Note the RV inflow and outflow tract in the 3D model. Figure 13. Three‐dimensional transthoracic echocardiography of the right ventricle. (A) By tracing the endocardial RV borders (top and bottom left), a 3D volume (B) Real-time single-beat 3D acquisition of the RV from the dedicated apical window. (C) Tomographic multislice obtained from a multiple-beat apical view. of the RV (top right) is obtained throughout the cardiac cycle (bottom right) and 3D RVEF is calculated. Note the RV inflow and outflow tract in the 3D model. (B) Real‐time single‐beat 3D acquisition of the RV from the dedicated apical window. (C) Tomographic multislice obtained from a multiple‐beat apical view. J. Clin. Med. 2022, 11, 578 13 of 30 Table 2 describes the main imaging prognostic findings in DCM. Table 2. Summary of prognostic imaging markers in DCM. LVEF ≤ 35% RV systolic dysfunction (RVEF < 45%) Significant (secondary) mitral regurgitation Advanced diastolic dysfunction Abnormal strain and myocardial work values Presence, extension, pattern, and progression of LGE Increased T1 and ECV values 4. Restrictive Cardiomyopathies Restrictive cardiomyopathies (RCM) account for less than 5% of all cardiomyopathies and have a highly varied etiology (Table 3). Table 3. Classification of restrictive cardiomyopathies. Restrictive Cardiomyopathy Non-Infiltrative Disorders Infiltrative Disorders Storage Diseases Endomyocardial Diseases • Anderson–Fabry disease • Carcinoid • Idiopathic • Amyloidosis • Danon disease • Endomyocardial fibrosis • Hereditary (sarcomere • Sarcoidosis • Pompe disease • Endocardial mutations . . . ) • Hereditary • Gaucher disease fibroelastosis • Systemic sclerosis hyperoxaluria • Iron overload • Metastatic tumor • Hereditary • Chemotherapy hemochromatosis • Radiation therapy RCM is characterized by a marked alteration of myocardial compliance: severe di- astolic dysfunction and a preserved systolic function (at least in early stages). The initial diagnosis is performed by TTE showing a normal/increased LV wall thickness (generally with a concentric/symmetric distribution), a restrictive pattern by Doppler, absence of left ventricular dilatation, preserved LVEF, and a marked biatrial dilatation [57]. However, although TTE is crucial for the initial approach and raising diagnostic suspicions, its role is limited when establishing the differential diagnosis, in which case CMR is highly relevant. 4.1. Idiopathic Restrictive Cardiomyopathy Idiopathic restrictive cardiomyopathy is a very uncommon disease affecting predomi- nantly children and young adults with a familial pattern. It is characterized by the presence of a restrictive diastolic filling pattern (increased left ventricular end-diastolic pressure), normal left ventricular dimensions, absence of an increased left ventricular mass, nor- mal left and right ventricular function, and absence of any other cardiac or pericardial diseases [58]. 4.2. Cardiac Amyloidosis Cardiac amyloidosis (CA) is an infiltrative disease caused by an extracellular accu- mulation of amyloid fibers. Most patients are affected by light chains (primary or AL amyloidosis) or by transthyretin (ATTR amyloidosis), either the hereditary form (ATTRm) or the wild type (ATTRwt) [59]. Among the main TTE findings, the following “red flags” should raise suspicion of CA [60]: left ventricular wall thickness > 12 mm, myocardial sparkling (Figure 14), increased valvular thickness, thick interatrial septum, low stroke volume, paradoxical low-flow low- gradient aortic stenosis, restrictive filling pattern by Doppler, and apical sparing pattern on strain analysis (a reduced global longitudinal strain with an apical to basal deformation ratio >2.1) (Figure 14), abnormal left atrial strain and pleural or pericardial effusion. creasedAmong valvularthethickness, main TTE thick findings, the following interatrial septum, “red flags” low should stroke raise paradoxical volume, suspicion of low‐ CA [60]: left ventricular wall thickness > 12 mm, myocardial sparkling (Figure 14), in‐ flow low‐gradient aortic stenosis, restrictive filling pattern by Doppler, and apical sparing creased valvular thickness, thick interatrial septum, low stroke volume, paradoxical low‐ pattern on strain analysis (a reduced global longitudinal strain with an apical to basal flow low‐gradient aortic stenosis, restrictive filling pattern by Doppler, and apical sparing deformation pattern on ratio strain >2.1) (Figure analysis 14), abnormal (a reduced left atrial strain global longitudinal strain with and an pleural apicalor topericardial basal J. Clin. Med. 2022, 11, 578 14 of 30 effusion. deformation ratio >2.1) (Figure 14), abnormal left atrial strain and pleural or pericardial effusion. A B C D A B C D Figure 14.14. Figure Apical Apical4‐chamber 4‐chamber (A), 3‐chamber(B), (A), 3‐chamber (B),and and 2‐chamber 2‐chamber (C)(C) views views in a in a patient patient with cardiac with cardiac amyloidosis Figure 14. Apical (left 4-chamber ventricular (A), wall 3-chamber thickness (B), and and 2-chamber sparkling). (C) On views the bull’sin a patient eye with strain cardiac images amyloidosis (left ventricular wall thickness and sparkling). On the bull’s eye strain images (D), (D), the the apical sparing amyloidosis apical sparingpattern (left isisdisplayed ventricular pattern (rightimage). wall thickness displayed (right image). and sparkling). On the bull’s eye strain images (D), the apical sparing pattern is displayed (right image). The Thepresence presenceofofaareduced reduced GLS GLSpresents presentsprognostic prognostic implications; implications; a GLS a GLS >−14.8% >−14.8% has has been The presence associated of aanreduced with increaseGLSin presents prognostic implications; theaapical −14.8%pat‐ GLS >sparing has been associated with an increase inglobal globalmortality mortality [61]. [61].Although Although the apical sparing pat‐ been tern associated with is quitesuggestive an increase suggestive of CA, CA, thisin global pattern mortality may [61]. not bebe Although present the in patientsapical sparing withwith pat- concomi‐ tern is quite tern is quite suggestive of thispattern of CA, this patternmaymay not not present be present in patients in patients concomi‐ with concomitant tant significant tantsignificant significant aortic aortic stenosis stenosis [62]. [62]. aortic stenosis [62]. CMR provides high‐resolution structural and functional information, allows tissue CMR CMR provides provideshigh‐resolution structuraland high-resolution structural and functional functional information, information, allows allows tissuetissue characterization [60], and permits diagnosis at early stages compared to TTE [63]. The characterization characterization[60], andpermits [60], and permits diagnosis diagnosis at early at early stagesstages comparedcompared to TTE to TTE [63]. [63]. The The main main findings, in addition to those described by TTE, are the difficulty to null the myo‐ findings, main findings,in addition to those described by TTE, are the difficulty to null the myocardial cardial signal in addition in LGE to those sequences, described a global by LGE, or diffuse TTE, andare athe difficulty marked to null increase the myo‐ in native signalsignal cardial in LGE in sequences, LGE a globalaor sequences, diffuse global orLGE, andLGE, diffuse a markedand increase a marked in native increaseT1 in and native T1 and ECV values (>40%) (Figure 15) [60,63,64]. ECV values (>40%) (Figure 15) [60,63,64]. T1 and ECV values (>40%) (Figure 15) [60,63,64]. Figure 15. CMR findings in a patient with CA: left ventricular concentric hypertrophy (left), in‐ creased native T1 mapping values (red color in the central image), and diffuse LGE (right image). Figure 15. CMR findings in a patient with CA: left ventricular concentric hypertrophy (left), in‐ Figure 15. CMR findings in a patient with CA: left ventricular concentric hypertrophy (left), increased creased As the T1 native disease progresses, mapping therecolor values (red is aninincrease in LGE the central uptake, image), and which diffuseisLGEinitially (rightsub‐ image). native T1 mapping values (red color in the central image), and diffuse LGE endocardial and progressively becomes transmural (which is associated with an increase(right image). in As overall thethemortality disease regardless there of theistype of amyloidosis) [65]. Additionally, is ainitially recent sub‐ As diseaseprogresses, progresses, there is anan increase increase in LGE in LGE uptake, uptake, whichwhich is initially suben- meta‐analysis showed that ECV is the strongest diagnostic and prognostic imaging bi‐ endocardial docardial andandprogressively progressively becomes becomes transmural transmural (which(which is associated is associated with anwith an increase increase in omarker overall in CA mortality[66], and an regardless ECVof >58% the type is associated of with amyloidosis) increased [65]. mortality Additionally, in a ATTR recent [67]. meta- in overall mortality regardless of the type of amyloidosis) [65]. Additionally, a recent CMR cannot analysis distinguish showed that ECV ATTR theand isECV AL forms, strongest but there diagnostic andare characteristically‐associated prognostic imaging biomarker meta‐analysis signs showed that is the strongest diagnostic and prognostic imaging bi‐ in CA(Table 4) [64,65,67,68]. [66], and an ECV >58% is associated with increased mortality in ATTR [67]. CMR omarker in CA [66], and an ECV >58% is associated with increased mortality in ATTR [67]. cannot distinguish ATTR and AL forms, but there are characteristically-associated signs CMR cannot distinguish ATTR and AL forms, but there are characteristically‐associated (Table 4) [64,65,67,68]. signs (Table Either4) [64,65,67,68]. 99m technetium diphosphonate (Tc-DPD) or pyrophosphate (Tc-PYP) scintig- raphy play a relevant role in diagnosing ATTR amyloidosis and allow early detection of cardiac involvement before TTE and CMR, however, false positives can be present [69]. Results are evaluated based on the Perugini scale: a grade 2 or 3 uptake (cardiac uptake similar to or greater than the ribs with/without a reduction in the bone uptake) has a positive predictive value around 100% [70]. Another means of quantification is the assess- ment of cardiac uptake compared to the contralateral chest (C/CL): a ratio ≥1.5 suggests the diagnosis of ATTR [68,70]. Prognostic implications of scintigraphy are still limited, however, a C/CL uptake >1.6 [71] or an apical sparing pattern [72] are associated with lower survival. J. Clin. Med. 2022, 11, 578 15 of 30 Table 4. Main differences between ATTR and AL amyloidosis. ATTR AL Left ventricular wall thickness and LV mass ++++ ++ Asymmetrical septal hypertrophy 79% 14% Transmural LGE 63% 27% Subendocardial LGE 24% 39% Native T1 elevation ++ ++++ Native T2 relaxation time ++ ++++ ECV ++++ ++ ++ Mildly abnormal. ++++ Severely abnormal. Table 5 describes the main imaging findings that should raise suspicion of cardiac amyloidosis. Table 5. Main imaging red flags in cardiac amyloidosis. Echocardiography CMR Scintigraphy • Left ventricular wall thickness > 12 mm. • Myocardial sparkling • Increased LV wall thickness. • Pleural/pericardial effusion • Increased myocardial LV mass • Increased valvular thickness • Bi-auricular enlargement • Thick interatrial septum. • Difficulty to null the myocardial signal • Grade 2 or 3 uptakes in the Perugini scale. • Low stroke volume. • Global or diffuse LGE, • C/CL uptake ≥ 1.5 • Paradoxical low-flow low-gradient aortic stenosis. • Marked increase in native T1 values • Restrictive filling pattern. • Elevated extracellular volume (> 40%) • Apical sparing pattern. • Presence of pleural or pericardial effusion • Abnormal left atrial strain. 4.3. Fabry Disease Anderson–Fabry disease (FD) is a rare (approximate incidence 1:40,000) genetic lyso- somal storage disorder caused by a mutation in the alpha-galactosidase A (GLA) gene with an X-linked inheritance. The presence of concentric left-ventricular hypertrophy (LVH) is the most common finding in FD, however, other patterns have also been described: septal, asymmetric, or apical [73]. LVH is higher in men than in women, and it tends to appear at younger ages. Another common finding is the presence of a binary septum: a hyperechoic endocardium adjacent to a hypoechoic subendocardium (Figure 16A). Prominent papillary muscles have also been described, as well as RV hypertrophy. There is also dilation and left atrial dysfunction (systolic and early diastolic strain) that is associated with a higher incidence J. Clin. Med. 2022, 11, x FOR PEER REVIEW of 16 of 32 supraventricular arrhythmias. Mitral and aortic valvular thickening are also frequent. Figure 16. Echocardiographic signs in Fabry disease. (A) Binary septum (arrows), (B) concentric Figure 16. Echocardiographic hypertrophy,signs in Fabry fibrosis and inferolateral disease. (A)abnormal (*), (C) Binarylongitudinal septum (arrows), strain more(B) concentric pronounced in the hypertrophy, and inferolateral inferolateralfibrosis wall (blue(*), (C)correlated area) abnormal withlongitudinal the fibrosis. strain more pronounced in the inferolateral wall (blue area) correlated with the fibrosis. Generally, the biventricular systolic function is preserved until advanced stages of the disease, at least in terms of LVEF. However, FD patients show reduced values of GLS Generally, theandbiventricular systolic function is preserved until advanced stages of GCS compared to controls, which are more reduced in those with inferolateral LGE the disease, at least(Figure in terms of LVEF. However, longitudinal 16C); thus, an inferolateral FD patients show strain peakreduced values value <−12.5% of GLS suggests the presence of fibrosis with a sensitivity of 90% and a specificity of 97% [74]. Table 6 describes the main imaging findings in Fabry disease. Table 6. Main echocardiographic findings in Fabry disease. J. Clin. Med. 2022, 11, 578 16 of 30 and GCS compared to controls, which are more reduced in those with inferolateral LGE (Figure 16C); thus, an inferolateral longitudinal strain peak value <−12.5% suggests the presence of fibrosis with a sensitivity of 90% and a specificity of 97% [74]. Table 6 describes the main imaging findings in Fabry disease. Table 6. Main echocardiographic findings in Fabry disease. CARDIAC STRUCTURE FINDINGS Left ventricle Concentric left ventricular hypertrophy Binary septum (low sensitivity and specificity for FD) Prominent papillary muscles Preserved LV function until end-stages Diastolic dysfunction Abnormal global longitudinal or radial strain, even in the absence of LVH Right ventricle Right ventricular hypertrophy Preserved RV function until end-stages Abnormal global longitudinal strain even with preserved EF Atrium J. Clin. Med. 2022, 11, x FOR PEER REVIEW Biauricular dilation 17 of 32 Increased end-diastolic pressure Reduced auricular strain Valves Increase in mitral and aortic valve thickness Valvular regurgitation (generally, mild) Valvular regurgitation (generally, mild) Aorta Aorta Dilation of the Dilation of aortic root the aortic and root the and theascending aorta(not ascending aorta (notdescending aorta) descending aorta) The most common finding in CMR is also the presence of concentric LVH. The typical The most common LGE pattern is an intramyocardial finding uptake in CMR at the basalisLV alsoinferolateral the presence of concentric wall, whichLVH. The typical is present in up to 50% of patients [75], and may progress to transmural extension together with ais pre‐ LGE pattern is an intramyocardial uptake at the basal LV inferolateral wall, which marked thinningsent in up of the to 50% of patients myocardial [75], and17). wall (Figure may progress to transmural extension together with a marked thinning of the myocardial wall (Figure 17). Figure 17. Late gadolinium enhancement pattern in a patient with Fabry disease. (A) Presence of Figure 17. Late gadolinium enhancement pattern in a patient with Fabry disease. (A) Presence of LGE LGE in the inferolateral wall. (B) Evolution of the same patient 5 years later, the presence of a thin‐ in the inferolateralning wall.of(B) the Evolution wall, a moreofextensive the same patient and 5 years transmural LGElater, theispresence pattern observed.of a thinning of the wall, a more extensive and transmural LGE pattern is observed. The presence of LGE is indicative of irreversible myocardial damage; tfhus, clinical The presence of LGE practice is indicative guidelines recommendof irreversible myocardial starting treatment with adamage; tfhus, clinical class I indication when there is practice guidelines no or minimal fibrosis recommend [76]. treatment starting The presence of LGE with is associated a class with when I indication a poorer response there is to medical treatment and an increased risk of cardiovascular events including SCD [74]. For this reason, some authors have suggested an ICD implantation in patients with a signifi‐ cant LGE mass; however, there are no available guidelines. T1 and T2 mapping techniques may identify the presence of early myocardial dam‐ age before the onset of myocardial fibrosis. Given that the degree of myocardial infiltra‐ tion is diffuse, it is recommended to assess the value of native T1 in all myocardial seg‐ J. Clin. Med. 2022, 11, 578 17 of 30 no or minimal fibrosis [76]. The presence of LGE is associated with a poorer response to medical treatment and an increased risk of cardiovascular events including SCD [74]. For this reason, some authors have suggested an ICD implantation in patients with a significant LGE mass; however, there are no available guidelines. T1 and T2 mapping techniques may identify the presence of early myocardial damage before the onset of myocardial fibrosis. Given that the degree of myocardial infiltration is diffuse, it is recommended to assess the value of native T1 in all myocardial segments (Figure 18) [77]. Native T1 time has been inversely correlated with wall thickness, so that, the more hypertrophy the lower T1. Additionally, patients with ECG abnormalities present shorter J. Clin. Med. 2022, 11, x FOR PEER REVIEWT1 [77]. In the early stages, ECV is normal, suggesting that LVH is due 18 toofmyocyte 32 hypertrophy and not to extracellular fibrosis. Figure 18. CMR findings in a patient with Fabry disease: (Left panel) presence of concentric left Figure 18. CMR ventricular findingswith hypertrophy in ano patient with Fabry LGE. (Central panel)disease: (Left T1 mapping panel) image presence of the of concentric same patient. (Right left ventricular hypertrophy panel) bull’s with no of eye representation LGE. (Central the T1 mapping panel) T1 mapping showing image a short native T1of in the same patient. the septum (glyco‐ (Right sphingolipid panel) bull’s eyeaccumulation) representation ofathe and long T1T1 value in showing mapping the inferolateral a shortwall (diffuse native T1 infibrosis). T1 map‐ the septum (glycosph- ping abnormalities appear earlier than LGE. ingolipid accumulation) and a long T1 value in the inferolateral wall (diffuse fibrosis). T1 mapping abnormalities appear earlier than LGE. FD must also be considered a chronic inflammatory disease. Thus, unlike patients with HCM, the presence of high native T2 values suggest FD, initially affecting the infer‐ FD must also be considered a chronic inflammatory disease. Thus, unlike patients olateral wall and becoming progressively diffuse. Using 18F‐fluorodeoxyglucose positron with HCM, the presence of high native T2 values suggest FD, initially affecting the infero- emission tomography (PET), an increase in the uptake of the tracer has also been de‐ lateral wallconfirming scribed, and becoming progressively the presence diffuse. of myocardial Using 18F-fluorodeoxyglucose inflammation [78]. Finally, patients withpositron emission tomography (PET), an increase in the uptake of the tracer has FD also present a reduction in sympathetic activity, and 123I‐meta‐iodobenzylguanidine also been described, confirming the presence (MIBG) scintigraphy of myocardial studies inflammation can differentiate [78].disease stages of the Finally, patients [79]. with FD The absence of also present a reduction myocardial in sympathetic denervation could play aactivity, relevant and 123I-meta-iodobenzylguanidine role in assessing the risk of developing ven‐ (MIBG) scintigraphy studies can tricular arrhythmias and differentiate SCD. stages of the disease [79]. The absence of myocar- dial denervation could play a relevant role in assessing the risk of developing ventricular 4.4. Iron Overload arrhythmias Cardiomyopathy and SCD. Iron overload cardiomyopathy (IOC) is a secondary form of cardiomyopathy result‐ 4.4.ing Iron Overload from Cardiomyopathy iron accumulation in the myocardium mainly because of genetically‐determined iron Ironmetabolism overload disorders or multiple cardiomyopathy transfusions (IOC) [80]. It has is a secondary formbeen described as a dilated of cardiomyopathy resulting cardiomyopathy, characterized by LV remodeling with chamber from iron accumulation in the myocardium mainly because of genetically-determined dilatation and reduced iron LVEF. However, primary hemochromatosis, a genetically determined condition leading metabolism disorders or multiple transfusions [80]. It has been described as a dilated to iron overload, is classically categorized as an infiltrative cause of restrictive cardiomy‐ cardiomyopathy, characterized by LV remodeling with chamber dilatation and reduced opathy. Moreover, secondary hemochromatosis may lead to severe diastolic LV dysfunc‐ LVEF. tionHowever, in the earlyprimary stages ofhemochromatosis, a genetically the disease, before LVEF is affecteddetermined [80]. condition leading to iron overload, is classically categorized as an infiltrative cause of IOC can be very difficult to diagnose by TTE, therefore, CMR T2* imaging restrictive cardiomyopathy. is consid‐ Moreover, ered the secondary hemochromatosis reference standard for detectingmayand lead to severe quantifying diastoliciron myocardial LV overload. dysfunctionAb‐ in the early stages ofinthe normalities CMRdisease, T2* canbefore LVEF is occur before theaffected [80]. of systolic or diastolic dysfunc‐ development IOC tion andcan be very may difficult be used to diagnose to guide by TTE, iron chelation therefore, therapy CMRheart to prevent T2* imaging failure oris death considered the[81]. reference standard for detecting and quantifying myocardial iron overload. Abnormali- For easy ties in CMR T2*classification into different can occur before IOC risk groups, the development the following of systolic classification or diastolic has and dysfunction may been be adopted using airon used to guide 1.5 Tesla MR scanner: chelation therapypatients with T2* to prevent heart>20failure ms areorregarded as not death [81]. having cardiac iron overload, between 10–20 ms have mild to moderate cardiac iron load and those <10 ms are considered to have a heavy cardiac iron load [82]. 4.5. Cardiac Sarcoidosis Sarcoidosis is an inflammatory granulomatous disease that can involve any organ, J. Clin. Med. 2022, 11, 578 18 of 30 For easy classification into different IOC risk groups, the following classification has been adopted using a 1.5 Tesla MR scanner: patients with T2* >20 ms are regarded as not having cardiac iron overload, between 10–20 ms have mild to moderate cardiac iron load and those <10 ms are considered to have a heavy cardiac iron load [82]. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 4.5. Cardiac Sarcoidosis 19 of 32 Sarcoidosis is an inflammatory granulomatous disease that can involve any organ, with cardiac involvement (cardiac sarcoidosis, CS) in a quarter of patients. Clinical manifes- festations tations include include heart heart block, block, atrial atrial andand ventricular ventricular arrhythmias, arrhythmias, and and heartheart failure. failure. Diag‐ Diagnosis nosis can be challenging but with the increased availability of advanced can be challenging but with the increased availability of advanced cardiac imaging, more cardiac imaging, more are cases cases are being being identified. identified. sensitivity and specificity TTE has limited sensitivity specificity for for the diagnosis diagnosis of CS, however, however, it it is often the initial initial imaging imagingstudy. study.TheTheTTETTEmain main findings findings include include ventricular ventricularhypertrophy, hypertrophy, diastolic dias‐ dysfunction/restrictive tolic dysfunction/restrictive filling pattern, filling wallwall pattern, motion motion abnormalities abnormalities withwith a non-coronary a non‐coro‐ distribution, nary distribution,aneurysms, and LV aneurysms, and orLVRVor systolic dysfunction RV systolic [83]. CS dysfunction patients [83]. who need CS patients who pacing and have an LVEF <50% should be considered for need pacing and have an LVEF <50% should be considered for CRT with ICD accordingCRT with ICD according to the recent ESC guidelines [84]. to the recent ESC guidelines [84]. CMR CMR plays playsananimportant importantrole roleininthe thediagnosis diagnosis and andrisk stratification risk of patients stratification of patients withwith CS. Although CS. Although the presence of LGE the presence maymay of LGE be non-specific, be non‐specific, the subepicardial the subepicardial location, multifocal location, multi‐ distribution, high high focal distribution, signal intensity, signal andand intensity, contiguous contiguous extension extension from fromthetheleft lefttotothe the right right ventricle may increase the specificity of this finding for the diagnosis ventricle may increase the specificity of this finding for the diagnosis of CS [85]. Many of CS [85]. Many studies studies have have also also demonstrated demonstrated its its prognostic prognostic value;value; LGELGE is is associated associated with with anan increased increased risk of ventricular arrhythmias and all-cause risk of ventricular arrhythmias and all‐cause mortality [85].mortality [85]. Cardiac Cardiac PETPET using using 18F-FDG 18F‐FDG has has emerged emerged as as aa cornerstone cornerstone in in the the clinical clinical diagnosis, diagnosis, prognostic prognostic evaluation, evaluation, and monitoring of and monitoring of therapy therapy in inCS. CS.FDG‐PET/CT FDG-PET/CThas hasa fair a fair diagnos- diagnostic tic accuracy for CS [86]. The classic pattern is one of ‘perfusion–metabolism’ accuracy for CS [86]. The classic pattern is one of ‘perfusion–metabolism’ mismatch, in mismatch, in which which areas areas of 18F-FDG of 18F‐FDG uptake uptake correspond correspond to areas to areas of reduced of reduced or absent or absent perfusion. perfusion. FDG‐ FDG-PET/CT has a fair diagnostic accuracy for CS with a sensitivity PET/CT has a fair diagnostic accuracy for CS with a sensitivity of 89% and specificity of 89% and specificity of of 78% 78% [86]. [86]. AnAn abnormal abnormal FDG FDG uptake uptake is associated is associated withwith increased increased rates rates of ventricular of ventricular ar‐ arrhythmias rhythmias and anddeath, death,especially especiallywhenwhenlocated locatedin inthe theright right ventricle ventricle [87] [87] (Figure (Figure 19). 19). Serial Serial PET imaging is useful in monitoring disease activity and response to immunosuppres- PET imaging is useful in monitoring disease activity and response to immunosuppressive sive therapy. Additionally, hybrid CMR-PET imaging has shown incremental value in therapy. Additionally, hybrid CMR‐PET imaging has shown incremental value in deter‐ determining disease activity and pattern [88]. mining disease activity and pattern [88]. Figure 19. (A) Patchy LGE distribution in the septum (arrows) and (B) subepicardial LGE (arrows) Figure 19. (A) Patchy LGE distribution in the septum (arrows) and (B) subepicardial LGE (arrows) in in a patient with sarcoidosis. (C) 18F‐FDG uptake in a patient with sarcoidosis (arrow). (D) Perfu‐ a patient with sarcoidosis. (C) 18F-FDG uptake in a patient with sarcoidosis (arrow). (D) Perfusion- sion‐metabolism mismatch in a patient with sarcoidosis (perfusion defect in the upper image, me‐ metabolism mismatch tabolism uptake in theinmid a patient image,with and sarcoidosis mismatch in(perfusion the lowerdefect in the upper image, metabolism image). uptake in the mid image, and mismatch in the lower image). 4.6. Endomyocardial 4.6. Endomyocardial Fibrosis Fibrosis Endomyocardial fibrosis Endomyocardial fibrosis (EMF) (EMF) is is aa rare rare form form ofof RCM RCM characterized characterized by by an an abnormal abnormal thickening of the endocardium due to fibrous tissue deposit [89] secondary thickening of the endocardium due to fibrous tissue deposit [89] secondary to infections to infections (typically in (typically in the the tropical tropical regions), regions),inflammation, inflammation,or ortoxic toxicagents agentsamong amongothers. others.Echocardi‐ Echocar- ographic findings include apical obliteration due to endocardial thickening, diographic findings include apical obliteration due to endocardial thickening, a small a small ven‐ tricular cavity, and a marked restrictive diastolic pattern. EMF may affect ventricular cavity, and a marked restrictive diastolic pattern. EMF may affect primar- primarily the left ventricle, both left and right ventricles (in approximately half of the cases), or predom‐ inantly the right ventricle [90]. Apical thrombus is also a common finding and echocardi‐ ographic contrast may be used to differentiate them from the thickened myocardium (Fig‐ ure 20). J. Clin. Med. 2022, 11, 578 19 of 30 ily the left ventricle, both left and right ventricles (in approximately half of the cases), or predominantly the right ventricle [90]. Apical thrombus is also a common finding J. Clin. Med. 2022, 11, x FOR PEER REVIEW and echocardiographic contrast may be used to differentiate them from the thickened 20 of 32 myocardium (Figure 20). Figure 20. Figure 20. Transthoracic Transthoracic echocardiography echocardiography (A,B) (A,B) and and cardiac cardiac magnetic magnetic resonance resonance (C,D) (C,D) of of patients patients with endomyocardial fibrosis. Note the marked endocardial thickening of the mid and apical seg‐ with endomyocardial fibrosis. Note the marked endocardial thickening of the mid and apical ments and apical obliteration of the left ventricle (A,B), the apical thrombus (C,D), and the endo‐ segments and apical obliteration of the left ventricle (A,B), the apical thrombus (C,D), and the myocardial fibrosis on LGE sequences (D). endomyocardial fibrosis on LGE sequences (D). CMR is CMR is the thegold goldstandard standardforforEMF EMFevaluation evaluationandandspecifically specificallyfor forlocalization, localization, char‐ charac- acterization, and quantification of fibrous tissue by LGE sequences. LGE strongly terization, and quantification of fibrous tissue by LGE sequences. LGE strongly correlates corre‐ lates histopathological with with histopathological findings findings and and its its extension extension is associated is associated with with increased increased mor‐ mortality tality risk riskCMR [91]. [91]. may CMRalso mayidentify also identify apical apical thrombus thrombus or calcifications. or calcifications. 5. Arrhythmogenic 5. Arrhythmogenic Cardiomyopathy Cardiomyopathy Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder pre‐ Arrhythmogenic pre- disposing to SCD, particularly disposing particularly in inyoung youngpatients patientsand andathletes. athletes.It is It aiscell‐to‐cell junction a cell-to-cell junc- cardiomyopathy, tion cardiomyopathy, typically caused typically causedbybygenetically‐determined genetically-determinedabnormalities abnormalities of cardiac of cardiac desmosomes. Pathological features include loss of myocytes desmosomes. myocytes andand fibrofatty fibrofatty replacement replacement of right of right or or left left ventricular ventricular myocardium. myocardium. ACM diagnosis does not rely on on aa single single gold gold standardtest standard testbut butisisclassically classically achieved achieved using using a scoring a scoring system, system, which which encompasses encompasses fa‐ familial milial and and genetic genetic factors,factors, ECG abnormalities, ECG abnormalities, arrhythmias, arrhythmias, and structural/functional and structural/functional ven‐ ventricular alterations [92]. The[92]. tricular alterations score was The recently score updatedupdated was recently and simplified [93]. and simplified [93]. TTE TTE is is the the initial initial diagnostic diagnostic approach approach in in ACM ACM patients. patients. A A thorough thorough RV RV assessment assessment with with dedicated RV planes is recommended if clinical suspicion is high (Figure 21). dedicated RV planes is recommended if clinical suspicion is high (Figure 21). The The presence of regional RV akinesia, dyskinesia, or aneurysms and either presence of regional RV akinesia, dyskinesia, or aneurysms and either RV dilatation RV dilatation or RVor systolic dysfunction RV systolic dysfunctionare considered are considereddiagnostic criteria diagnostic on the criteria on2010 Task Task the 2010 ForceForce Criteria, with Criteria, different cut-offcut‐off with different pointspoints for TTEforand TTECMR majormajor and CMR or minor criteria or minor (Table(Table criteria 7) [92].7)These were [92]. These were changed slightly in the Padua criteria [93], where RV dilatation and systolic dysfunc‐ tion were defined according to nomograms, with no specific cut‐off points. J. Clin. Med. 2022, 11, 578 20 of 30 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 21 of 32 changed slightly in the Padua criteria [93], where RV dilatation and systolic dysfunction were defined according to nomograms, with no specific cut-off points. Figure 21. Transthoracic echocardiography of a patient with right ventricular arrhythmogenic car‐ Figure 21. Transthoracic echocardiography of a patient with right ventricular arrhythmogenic diomyopathy. (A) RV dedicated apical 4‐chamber view shows severe dilatation of the RV. RV ded‐ cardiomyopathy. (A) RV dedicated apical 4-chamber view shows severe dilatation of the RV. RV icated apical 4‐chamber view (B) and subcostal view (C) show the presence of aneurysms in the RV dedicated apical 4-chamber view (B) and subcostal view (C) show the presence of aneurysms in the free wall (arrow). RV free wall (arrow). Table 7. 2010 Task Force Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Cardiomy‐ opathy. Table 2010 Taskfrom 7. Adapted Force[92]. Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Cardiomy- opathy. Adapted from [92]. Global and/or Regional Dysfunction and Structural Alterations By 2D TTE: regionalGlobal RV akinesia, dyskinesia, and/or Regional or aneurysm Dysfunction and 1 of the and Structural following (end diastole): Alterations  PLAX RVOT ≥ 32 By 2D mm TTE: (corrected regional for body RV akinesia, size [PLAX/BSA] dyskinesia, or aneurysm ≥ 19 mm/m and 2) 1 of the following (end diastole): Major  PSAX RVOT≥ • 36 mmRVOT PLAX (corrected ≥ 32 mmfor(corrected body sizefor [PSAX/BSA] body size ≥ 21 mm/m≥)19 mm/m2 ) [PLAX/BSA] 2 Major  Or fractional • areaPSAXchange RVOT≤ ≥33% 36 mm (corrected for body size [PSAX/BSA] ≥ 21 mm/m2 ) By CMR: regional •RV akinesia or dyskinesia Or fractional area changeor ≤dyssynchronous 33% RV contraction and 1 of the following:  Ratio of RV end‐diastolic volume to BSA ≥ 110 mL/m 2 (male) or ≥100 mL/m2 (female) By CMR: regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of  Or RV ejection fraction ≤ 40% the following: By RV angiography: • regional Ratio ofRV RV akinesia, dyskinesia, end-diastolic volume toor ≥ 110 mL/m2 (male) or ≥100 mL/m2 (female) aneurysm BSA • Or RV ejection fraction ≤ 40% By 2D‐TTE: regional RV akinesia or dyskinesia and 1 of the following (end‐diastole):  PLAX RVOT ≥ 29 By RV to <32 mm regional angiography: (correctedRV for bodydyskinesia, akinesia, size [PLAX/BSA] ≥ 16 to <19 mm/m2) or aneurysm Minor  PSAX RVOT ≥ 32 to <36 By 2D-TTE: mm RV regional (corrected akinesia for body sizeand or dyskinesia [PSAX/BSA] ≥ 18 to(end-diastole): 1 of the following <21 mm/m2)  Or fractional Minor • areaPLAXchange ≥ 29 to RVOT>33% to<32 mm (corrected for body size [PLAX/BSA] ≥ 16 to <19 mm/m2 ) ≤40% By CMR: regional •RV akinesia PSAX RVOT ≥ 32 to <36or or dyskinesia mm (corrected for body dyssynchronous RVsize [PSAX/BSA] contraction and≥118 oftothe <21 mm/m2 ) following: • Or fractional area change >33% to ≤40%  Ratio of RV end‐diastolic volume to BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 mL/m2 (female)  Or RV ejection By CMR: regional fraction RV akinesia >40% to ≤45%or dyskinesia or dyssynchronous RV contraction and 1 of the following • Ratio of RV end-diastolic volume to BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 2 (female) LVmL/m involvement is identified in more than half of patients with ACM, and biventric‐ • ular Oras RV ejection fraction well as predominant to ≤ACM >40%LV 45% forms may occur [94], which are associated with a worse prognosis [95]. Specific diagnostic criteria for LV ACM were recently proposed: global LVLV systolic dysfunction involvement is identified(either in moreLVEF or GLS) than half with or of patients without with ACM, LVand dilatation, or biventricular regional LV hypokinesia/akinesia of the LV free wall or septum are considered as well as predominant LV ACM forms may occur [94], which are associated with a worse minor cri‐ teria [93]. [95]. Specific diagnostic criteria for LV ACM were recently proposed: global LV prognosis Emerging systolic TTE parameters dysfunction (either LVEFin the evaluation or GLS) with orof without patients with suspectedor LV dilatation, orregional established LV hypokinesia/akinesia of the LV free wall or septum are considered minor criteria [93]. RV ACM include the measurement of tricuspid annular plane systolic excursion (TAPSE), basalEmerging diameter,TTEGLSparameters (RV and LV), mechanical in the evaluationdispersion (RV of patients withand LV), andor suspected the use of 3D established TTE. In particular, RV GLS is affected in early ACM phases [96], TAPSE ACM include the measurement of tricuspid annular plane systolic excursion (TAPSE), (as well as frac‐ RV basal diameter, GLS (RV and LV), mechanical dispersion (RV and LV), and the usedisper‐ tional area change) are associated with worse outcomes [97], and RV mechanical of 3D sion correlates with ventricular arrhythmias risk [98]. Besides, LVEF has an incremental prognostic role over RV systolic function [99]. Altogether, an international consensus pro‐ posed that prophylactic ICD implantation should be indicated in case of severe RV/LV J. Clin. Med. 2022, 11, 578 21 of 30 TTE. In particular, RV GLS is affected in early ACM phases [96], TAPSE (as well as frac- J. Clin. Med. 2022, 11, x FOR PEER REVIEW 22 of 32 tional area change) are associated with worse outcomes [97], and RV mechanical dispersion correlates with ventricular arrhythmias risk [98]. Besides, LVEF has an incremental prog- nostic role over RV systolic function [99]. Altogether, an international consensus proposed that prophylactic systolic dysfunction ICDandimplantation should be indicated should be considered if there is in case of severe moderate RV or LV RV/LV systolic impairment dysfunction and should be considered if there is moderate RV or LV impairment [100]. [100]. Due to Due to the the limitations limitations of of TTE TTE in in RV RV evaluation, evaluation, CMRCMR has has become become an an integral integral part part of of the diagnostic evaluation in ACM. Beyond determining the presence the diagnostic evaluation in ACM. Beyond determining the presence of morpho‐func‐ of morpho-functional ventricular tional abnormalities, ventricular CMR provides abnormalities, CMR provides information on the presence, information morphology, on the presence, and morphol‐ ogy, and wall distribution of myocardial fibrofatty scar by LGE or fat‐saturation T1The wall distribution of myocardial fibrofatty scar by LGE or fat-saturation T1 sequences. se‐ same criteria quences. previously The same criteriadescribed previouslyfor TTE apply described to CMR for TTE applywith corresponding to CMR cut-off with correspond‐ points ing andpoints cut‐off nomograms (Table 7) [92,93]. and nomograms (Table 7)RVEF by RVEF [92,93]. CMR hasby CMRbeenhas incorporated into the been incorporated risk prediction model of ventricular arrhythmias [101]. The presence of into the risk prediction model of ventricular arrhythmias [101]. The presence of transmu‐ transmural LGE of ≥ 1 RV region or LV LGE of the free wall (subepicardial or intramyocardial) ral LGE of ≥1 RV region or LV LGE of the free wall (subepicardial or intramyocardial) or or septum are considered septum major criteria are considered [93]. Typically, major criteria the LGE [93]. Typically, pattern the LGE shows pattern showslarge amounts large amounts of contrast uptake in the LV with a non-ischaemic pattern, predominantly of contrast uptake in the LV with a non‐ischaemic pattern, predominantly involving the involving the subepicardial layers subepicardial layers ofof the the inferior inferior and and the the inferolateral inferolateral regions regions (Figure (Figure 22). 22). The The presence presence of a subepicardial annular (ring-like pattern) is also suggestive of ACM. of a subepicardial annular (ring‐like pattern) is also suggestive of ACM. Figure 22. CMR findings in a patient with ACM. (A) RV aneurysms (arrows) in cine images. (B) CMR findings Figure 22. infiltration Fibrofatty in a patient with in T1‐weighted ACM. turbo (A) RVsequences spin‐echo aneurysms(arrow). (arrows)(C)in cine images. Right (B) Fibro- ventricular en‐ fatty infiltration largement in T1-weighted and left turbothinning ventricular wall spin-echo sequences (arrow). (subepicardial (C) Right ventricular fatty infiltration) enlargement (arrows) in a 3‐cham‐ andview ber left ventricular wall thinningLGE cine. (D) Subepicardial (subepicardial fatty (arrows) and (E)infiltration) subepicardial(arrows) in a(arrows) annular 3-chamber view cine. patterns. (D) Subepicardial LGE (arrows) and (E) subepicardial annular (arrows) patterns. In cases where CMR is contraindicated, CT can be an alternative for the evaluation of RVInand cases LVwhere CMR volumes andis EF, contraindicated, CT can beinfiltration, aneurysms, fibrofatty an alternative andfor themotion wall evaluation of abnor‐ RV and LV volumes and EF, aneurysms, fibrofatty infiltration, and wall motion abnormali- malities. Although generally not used in clinical practice for this purpose, angiography ties. Although may generally be an alternative in not used in clinical the evaluation practice of these for this purpose, angiography may be patients. an alternative in the evaluation of these patients. 6. Left Ventricular Noncompaction 6. Left Ventricular Noncompaction Left ventricular noncompaction (LVNC) is a heterogeneous entity characterized by Left ventricular noncompaction (LVNC) is a heterogeneous entity characterized by prominent LV trabeculae, deep intertrabecular recesses, and a thin compacted (C) myo‐ prominent LV trabeculae, deep intertrabecular recesses, and a thin compacted (C) myocar- cardial layer dial layer [102] [102] (Figure (Figure 23).23). Hypertrabeculation Hypertrabeculation maymay occur occur associated associated with with LVLV dilata‐ dilatation tion (DCM) or hypertrophy (HCM), and both acquired and genetic LVNC forms (DCM) or hypertrophy (HCM), and both acquired and genetic LVNC forms may occur.oc‐ may cur. Different diagnostic criteria have been described for LVNC (Figures 24 and 25). By TTE, the distance from the epicardial surface to the trough of the trabeculae (X) and the distance from the epicardial surface to the peak of the trabeculae (Y) can be measured on short-axis views. A ratio of X/Y ≤0.5 at end-diastole is diagnostic of LVNC [103]. Alternatively, a ratio of NC/C layers >2 measured on the short-axis at end-systole is also suggestive of LVNC [104]. By CMR, a ratio of NC/C layers >2.3 measured on long-axis views [105], a trabeculated mass >20% of the total LV mass [106], or a fractal dimension >1.30 [107] are diagnostic of LVNC (all measured at end-diastole). Fulfillment of LVNC morphologic criteria per se has not been associated with LV remodeling [108] or clinical events [109] throughout follow-up. However, the extension of the trabeculae has been recently related to outcomes: patients presenting hypertrabeculation from the apex to the base have been found to have higher mortality [110]. 6. Left Ventricular Noncompaction Left ventricular noncompaction (LVNC) is a heterogeneous entity characterized by prominent LV trabeculae, deep intertrabecular recesses, and a thin compacted (C) myo‐ cardial layer [102] (Figure 23). Hypertrabeculation may occur associated with LV dilata‐ J. Clin. Med. 2022, 11, 578 22 of 30 tion (DCM) or hypertrophy (HCM), and both acquired and genetic LVNC forms may oc‐ cur. J. Clin. Med. 2022, 11, x FOR PEER REVIEW 23 of 32 Figure 23. TTE (A) and CMR (B) images of patients with left ventricular noncompaction showing marked hypertrabeculation and deep intertrabecular recesses. Different diagnostic criteria have been described for LVNC (Figures 24 and 25). By TTE, the distance from the epicardial surface to the trough of the trabeculae (X) and the distance from the epicardial surface to the peak of the trabeculae (Y) can be measured on short‐axis views. A ratio of X/Y ≤0.5 at end‐diastole is diagnostic of LVNC [103]. Alterna‐ tively, a ratio of NC/C layers >2 measured on the short‐axis at end‐systole is also sugges‐ tive of LVNC [104]. By CMR, a ratio of NC/C layers >2.3 measured on long‐axis views [105], a trabeculated mass >20% of the total LV mass [106], or a fractal dimension >1.30 [107] are diagnostic of LVNC (all measured at end‐diastole). Fulfillment of LVNC mor‐ phologic criteria per se has not been associated with LV remodeling [108] or clinical events [109] throughout follow‐up. However, the extension of the trabeculae has been recently Figure 23. TTE (A) and CMR (B) images of patients with left ventricular noncompaction showing related to outcomes: patients presenting hypertrabeculation from the apex to the base marked hypertrabeculation have beenand deep found tointertrabecular recesses. have higher mortality [110]. Figure 24. TTE parasternal short‐axis mid‐ventricular view of a patient with LVNC (A). Measure‐ Figure 24. TTE parasternal short-axis ment of the compactedmid-ventricular viewatof and non‐compacted layers a patientafter end‐diastole with LVNC (A). echocontrast Measure- administration, ment of the compacted and non-compacted fulfilling layers LVNC diagnostic criteria (B).at end-diastole after echocontrast administration, fulfilling LVNC diagnostic criteria (B). TTE is the first-line imaging technique for both quantification and localization of the trabeculae: the apex and lateral segments are the most frequently involved. Contrast echocardiography may be used to enhance trabeculation measurement and exclude the presence of intertrabecular thrombi (Figure 24B). Assessment of LVEF is mandatory since it is one of the strongest predictors of outcomes [110–112]. Strain analysis by TTE may detect subclinical myocardial dysfunction [113] and different studies have shown the diagnostic value of strain to differentiate LVNC from healthy controls [113] and DCM [114]. However, no consistent data is available on its prognostic implications. CMR should be performed in all LVNC patients. The presence of LV dilatation [111,115] and a thinned compacted myocardial layer [115] has been associated with negative out- comes. Although LGE seems to be less frequent in LVNC compared to DCM or HCM [111], and not always related to the most hypertrabeculated segments, it is a powerful and inde- pendent predictor of outcomes, with added prognostic implications over LVEF [111,112,116]. Of note, patients with preserved LVEF and negative LGE have an excellent prognosis, while those with positive LGE are at increased risk irrespective of LVEF [116]. LGE has also been associated with SCD risk, even in the absence of severe systolic dysfunction [112]. Mapping techniques have been studied in LVNC; a small report has described worse outcomes with higher ECV values [117]. In addition, feature-tracking strain analysis may be used J. Clin. Med. 2022, 11, 578 23 of 30 to differentiate LVNC from the general population [118] and DCM [119]. However, it J. Clin. Med. 2022, 11, x FOR PEER REVIEW 24 of 32 is not recommended in routine practice due to lack of standardization and unvalidated association with clinical events. Figure25. Figure 25.CMR CMR4-chambers 4‐chambers view view of of aa patient patient with withLVNC LVNC(A). (A).Measurement Measurementofofthe thecompacted and compacted and non‐compacted layers at end‐diastole on a long‐axis view (Petersen criteria, B). Measurement non-compacted layers at end-diastole on a long-axis view (Petersen criteria, B). Measurement of of thethe trabeculated mass on a short‐axis view (Jacquier criteria, C). trabeculated mass on a short-axis view (Jacquier criteria, C). TTE is the Finally, first‐line cardiac CT isimaging technique rarely used for both in LVNC, quantification with and localization its main objective of the being to exclude trabeculae: the apex and lateral segments are the most frequently involved. coronary artery disease. However, a large population study has demonstrated that Contrast echo‐the cardiography may be used to enhance trabeculation measurement and exclude the pres‐ degree of hypertrabeculation measured by CT was independently related to outcomes [120]. ence of intertrabecular thrombi (Figure 24B). Assessment of LVEF is mandatory since it is Therefore, cardiac CT may be considered in patients with contraindications for CMR. one of the strongest predictors of outcomes [110–112]. Strain analysis by TTE may detect subclinical 7. Conclusions myocardial dysfunction [113] and different studies have shown the diagnostic value of strain to differentiate LVNC from healthy controls [113] and DCM [114]. How‐ Cardiac imaging techniques are an essential tool in the study of cardiomyopathies, ever, no consistent data is available on its prognostic implications. and they provide both diagnostic and prognostic relevant information. Transthoracic CMR should be performed in all LVNC patients. The presence of LV dilatation echocardiography should always be the first technique used due to its availability and cost, [111,115] and a thinned compacted myocardial layer [115] has been associated with nega‐ as well as the possibility of periodic testing. Cardiovascular magnetic resonance should also tive outcomes. Although LGE seems to be less frequent in LVNC compared to DCM or be performed in all patients due to its additional anatomical and functional information as HCM [111], and not always related to the most hypertrabeculated segments, it is a pow‐ well as thorough tissue characterization, with important prognostic implications. Other erful and independent predictor of outcomes, with added prognostic implications over techniques (e.g., CT, PET-CT, LVEF [111,112,116]. Of note,scintigraphy, patients with among others) preserved may and LVEF be applied negativein selected LGE have entities an while excellent prognosis, while those with positive LGE are at increased risk irrespective offer more advanced imaging analysis (e.g., strain, myocardial work, mapping, etc.) of promising LVEF [116].butLGE stillhas preliminary also beenresults. Altogether, associated with SCDmultimodality risk, even in thecardiac absenceimaging plays of severe ansystolic important role in clinical dysfunction decision-making [112]. Mapping techniques andhave helps to improve been studied inpatients’ LVNC; management a small re‐ and outcomes. port has described worse outcomes with higher ECV values [117]. In addition, feature‐ tracking strain analysis may be used to differentiate LVNC from the general population Author Contributions: G.C. and J.F.R.-P. have equally contributed to manuscript preparation, writing [118] and DCM [119]. However, it is not recommended in routine practice due to lack of and revision. All authors have read and agreed to the published version of the manuscript. standardization and unvalidated association with clinical events. Finally, Funding: cardiacreceived The authors CT is rarely used in no financial LVNC,for support with its main objective the publication being to exclude of this article. coronary artery disease. However, a large population study has demonstrated that the Institutional Review Board Statement: Not applicable. degree of hypertrabeculation measured by CT was independently related to outcomes Informed Consent Statement: [120]. Therefore, cardiac CT Not mayapplicable. be considered in patients with contraindications for CMR. Data Availability Statement: See references. Conflicts of Interest: The authors declare no conflict of interest. 7. Conclusions Cardiac imaging techniques are an essential tool in the study of cardiomyopathies, and they provide both diagnostic and prognostic relevant information. Transthoracic echocardiography should always be the first technique used due to its availability and cost, as well as the possibility of periodic testing. Cardiovascular magnetic resonance should also be performed in all patients due to its additional anatomical and functional information as well as thorough tissue characterization, with important prognostic impli‐ cations. Other techniques (e.g., CT, PET‐CT, scintigraphy, among others) may be applied in selected entities while more advanced imaging analysis (e.g., strain, myocardial work, J. Clin. Med. 2022, 11, 578 24 of 30 Abbreviations 2D Two-dimensional 3D Three-dimensional ACM arrhythmogenic cardiomyopathy AL primary amyloidosis ATTR transthyretin amyloidosis C/CL cardiac compared to the contralateral chest CA cardiac amyloidosis CMR cardiovascular magnetic resonance CRT cardiac resynchronization therapy CS cardiac sarcoidosis CT computed tomography DCM dilated cardiomyopathy ECG electrocardiogram ECV extracellular volume EMF endomyocardial fibrosis ESC European Society of Cardiology FD Anderson–Fabry disease FDG 18F-fluorodeoxyglucose GCS global circumferential strain GLS global longitudinal strain HCM hypertrophic cardiomyopathy ICD implantable cardioverter-defibrillator IOC iron overload cardiomyopathy LGE late gadolinium enhancement LV left ventricle LVEF left ventricular ejection fraction LVH left ventricular hypertrophy LVNC left ventricular noncompaction LVOTO left ventricular outflow tract obstruction MIBG 123I-meta-iodobenzylguanidine MW myocardial work PET positron emission tomography RCM restrictive cardiomyopathies RV right ventricle RVEF right ventricle ejection fraction SAM systolic anterior motion SCD sudden cardiac death TAPSE tricuspid annular plane systolic excursion TTE transthoracic echocardiography References 1. 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