Observing mitral or tricuspid valve disease in an athlete raises many considerations for the clinician. Initially, the etiology must be clarified, with causes differing depending on whether the athlete is young or a master. Notably, vigorous training in competitive athletes leads to a constellation of structural and functional adaptations involving cardiac chambers and atrioventricular valve systems. In addition, a proper evaluation of the athlete with valve disease is necessary to evaluate the eligibility for competitive sports and identify those requiring more follow-up. Indeed, some valve pathologies are associated with an increased risk of severe arrhythmias and potentially sudden cardiac death. Traditional and advanced imaging modalities help clarify clinical doubts, allowing essential information about the athlete’s physiology and differentiating between primary valve diseases from those secondary to training-related cardiac adaptations. Remarkably, another application of multimodality imaging is evaluating athletes with valve diseases during exercise to reproduce the sport setting and better characterize the etiology and valve defect mechanism. This review aims to analyze the possible causes of atrioventricular valve diseases in athletes, focusing primarily on imaging applications in diagnosis and risk stratification. Mitral valve (MV) and tricuspid valve (TV) diseases can be commonly observed in athletes . HoweverPrimary valvular heart diseases (VHDs) show similar prevalence in athletes and the general population; however, athletes are more likely to experience secondary  mitral regurgitation (MR) and tricuspid regurgitation (TR) . This obVHD can reduce athletes’ performance depending on the severity degree. Generally, right-sided valvular abnormalities are better tolerated than left-sided valvular abnormalities, and regurgitant lesions are better tolerated than stenotic lesions . AnotherIn this complex scenario, traditional and advanced imaging modalities, including echocardiography, cardiac computed tomography (CCT), and cardiac magnetic resonance (CMR), are helpful in non-invasively differentiating several etiologies and better identifying athletes at risk of arrhythmias and indicating whether the athlete needs a particular treatment and if they can engage in a specific competitive sport.p < 0.001). In particular, MR prevalence was 69% vs. 27%, while TR prevalence was 76% vs. 15% [Remarkably, it has been demonstrated that athletes with structurally normal valves without a known cardiac disease have an overall higher statistically significant prevalence of functional valve regurgitation rate than non-athlete controls , heart rate (HR), blood pressure (BP), peripheral vascular resistance, LV afterload, cardiac chambers remodeling, and sympathetic/parasympathetic balance ,10,13,14sumption ,16. Indesumption ,11.Therefore, a balanced adaptation of the cardiac chambers is a characteristic and unmistakable feature of an athlete’s heart. However, although ventricular and atrial dilation can significantly affect atrioventricular annular geometry and related valvular competency in various pathological states, less is known about the EICR alterations in the shape and function of the mitral annulus (MA) and tricuspid annulus (TA) in CAs ,17.The MA and TA are elliptical, saddle-shaped, and dynamic structures that connect the leaflets with the ventricular and atrial myocardium. Elite athletes have a significant dilatation of the MA and TA dimensions and an increase in the tenting of both atrioventricular valves compared to non-athlete counterparts,  indicatiTherefore, adaptation to exercise determines several changes, including atrioventricular remodeling, with endurance athletes demonstrating the highest increase in cardiac chambers and atrioventricular remodeling. However, the abrupt surge in BP characteristically associated with a burst of muscle contraction in power sports may also contribute to atrioventricular valve disease. Nevertheless, several characteristics of the athlete’s heart could be related to the higher prevalence of regurgitation in the atrial and ventricular functional remodeling, cardiac chamber size increase, slower HR, increased SV, and altered RV and LV inflow patterns .Despite the ventricular functional regurgitation, it is now widely known that there is a type of atrioventricular regurgitation in patients with structurally intact leaflets, normal geometry and function of the ventricles, and dilated atria, called atrial functional regurgitation ,19. ManyAs claimed before, in isometrically conditioned athletes, there is a significantly greater degree of ventricular hypertrophy, i.e., a greater relative wall thickness (RWT) and less outward displacement of the papillary muscles (PMs). Furthermore, this LV response to exercise is less likely to tether the MV and less likely to cause significant MR . These fThe described physiological or pathological features can be appropriately identified by several imaging modalities, including different echocardiographic applications, CCT, and CMR ,22,23. IImaging is pivotal in evaluating athletes with valve diseases and identifying those at increased CV risk when exercising . Indeed,Accordingly, accurately interpreting cardiac imaging in an athlete, explicitly differentiating EICR from pathologic hypertrophy, requires careful consideration of a specific athlete’s predominant sporting discipline ,24. AnotThe classical ventricular type of functional regurgitation is mainly characterized by increased leaflet tenting, whereas a notably enlarged annulus refers to atrial functional regurgitation. Notably, the athlete’s heart shares several features of both types of functional regurgitation; in addition, pronounced ventricular and atrial dilation may exaggerate their impact on annular geometry and valvular function. Thus, a mixed type of functional regurgitation can be assumed in athletes with MR or TR . AlthougFurthermore, the sport may trigger life-threatening ventricular arrhythmias (VAs) and sudden cardiac death (SCD) in predisposed patients with structural or electrical abnormalities; hence, the differentiation of physiological from pathological remodeling by imaging is a fundamental step . AlthougA broad spectrum of imaging modalities is available to evaluate the athletes, allowing the clinician to adopt a step-by-step and comprehensive approach .Transthoracic echocardiography (TTE) is the CV imaging method of choice in the athletic population by its widespread availability, relatively low cost, and safety.In most cases, in athletes, TTE is a second-level examination following a physical examination and a 12-lead electrocardiogram. Different echocardiography applications are available, from traditional two-dimensional echocardiography (2DE) to three-dimensional echocardiography (3DE).Indeed, in most athletes, the low acoustic impedance of the chest makes it possible to obtain high-quality images and assess all the cardiac structures . In partEICR is the term used to describe the unique modifications in heart structure and function that result from regular physical activity, with dichotomous LV remodeling patterns described by Morganroth et al. . General2 as the maximum expected value for LA indexed volume in CA and the mean + 2 deviation standards to distinguish from pathological values [Early echocardiographic results reported that CAs, especially endurance athletes, frequently have an enlarged left atrium (LA), with LA diameter being larger than 4.6 mm in endurance CA, 3.5 mm in mixed strength and endurance CA, and 2.9 mm in just strength trained CAs when compared to inactive controls . LA sizeIn addition, recent evidence claims a higher end-systolic wall stress for the RV than the LV due to a higher relative increase in systolic PAP (sPAP) compared to systolic arterial BP during endurance exercise, which is associated with pressure and volume load . Indeed,2/m2 for the RA area and 2.9 cm/m2 for the RA minor axis [Recent data confirm that atrial adaptation on exercise also involves the right atrium (RA). It has been shown that athletes have larger RA dimensions than non-athletes, with RA area being even more significant among those athletes who present TR than athletes without . Since Rnor axis . Regardinor axis ,42. In anor axis .All these anatomic and functional cardiac chamber modifications can be the cause, or the consequence, representing an additional echocardiographic challenge in evaluating valve abnormalities. Therefore, in patients where TTE is inconclusive or technically challenging or when surgical intervention is considered, knowledge of the specific MV and TV anatomy is necessary, which can be obtained with trans-esophageal echocardiography .Mitral valve prolapse (MVP) at echocardiography, in parasternal long axis or apical 3-chamber view, is characterized by a systolic billowing of any portion of the mitral leaflets more than 2 mm past the mitral annular plane . Moreove2, regurgitant volume (RVol) ≥ 60 mL, and a regurgitant fraction (RF) ≥ 50% [2 in an elliptical regurgitant orifice area and RVol ≥ 45 mL in low flow conditions [Regarding MR, as mentioned, echocardiography is crucial in determining etiology, morphology, and mechanism, especially in secondary or functional origin cases. Therefore, many echocardiographic methods should be considered to quantify MR ,50,51,52F) ≥ 50% . Similarnditions . Howevernditions  and COAPnditions  trials, 2, 3D VC area or quantitative EROA 95–114 mm2) and “torrential” TR  [TTE also allows a comprehensive evaluation of TR severity , as repo115 mm2) . In addi115 mm2) .Exercise stress echocardiography (ESE) is a non-invasive diagnostic test that is trustworthy, secure, and can help identify cardiac pathologic conditions among athletes by reproducing sports practiced .For example, athletes with LV hypertrophy reporting symptoms such as dyspnea or syncope with echocardiographic LVOT gradient higher than 50 mmHg during or right after exercise can be affected by HCM . ESE is In general, exercise produces no significant change or a mild decrease in the RF because of reduced systemic vascular resistance. However, patients with elevation of HR (increased systolic ejection time per minute) or BP with exercise may manifest marked increases in Rvol and pulmonary capillary pressures .In patients with asymptomatic mitral stenosis (MS), exercise testing can be beneficial by revealing latent symptoms. In addition, ESE helps determine whether symptomatic patients with only mild or moderate MS have provoked high transvalvular gradients or inducible pulmonary hypertension (PH) by Doppler echocardiography assessment, determining how much exercise is permissible . For exaMoreover, ESE gives essential information in patients with valve prostheses because it detects hemodynamic changes when the mean transvalvular gradient increases disproportionately during exercise , which may indicate severe prosthesis stenosis or a significant patient-prosthesis mismatch .2 and RVol ≥ 15 mL) can be found in nearly 30% of the patients, with a magnitude associated with variation of exercise-induced sPAP [2; sPAP > 60 mmHg), moderate MR before surgical revascularization, persistent PH following surgery [On the other hand, the role of ESE in patients with MVP founds place, primarily when associated with primary MR. Elevated sPAP (>60 mmHg) during activity could be significant in CA with severe primary MR that is not showing any symptoms. In addition, failure of LVEF to improve regularly with exercise indicates poorer postoperative LV function . Furtherced sPAP . In addiced sPAP . Furtherced sPAP , and ESE surgery .Moreover, ESE may be used to evaluate the TV to uncover latent symptoms, discover inducible ischemia, and evaluate for latent or progressive valve dysfunction . In part3DE enhances the diagnostic power of cardiac ultrasound in athletes with valve disease as it helps evaluate the cardiac chambers’ size and anatomy, ventricular function, valvular morphology and dynamics, and blood flow velocity . Indeed,Regarding MVP, the techniques of 3DE, such as simultaneous multiplane mode, real-time 3DE, and ECG-triggered multi-beat 3DE (zoom and full volume mode), assist in identifying MV billowing and prolapse, identification of the etiology process and determination of the prolapsing or flail scallops . Further2, and PISA-EROA ≥ 0.34 cm [Nowadays, the role of 3DE is becoming more critical in evaluating MR and TR. Indeed, it provides a more comprehensive evaluation of both MV and TV apparatus compared to 2DE. In addition, the total amount of the LA volume may not be captured by 2DE computations, and 3DE has more precision for LA assessment than 2DE . Similar 0.34 cm . Further 0.34 cm .All the described factors contribute to the differentiation between physiological and pathological modifications. For instance, athletes with MR displayed a more prominent MA enlargement, and this subgroup also revealed a more prominent TA remodeling, according to Fábián et al. . In addiNewer echocardiographic applications include the MW assessment, which seems to be a more reliable measure of myocardial contractility and contractile reserve in athletes than traditional echocardiographic measurements ,80,81.Indeed, studies evaluating 2D-derived GLS measured in endurance athletes at rest provided contrasting results, showing in some studies higher values, in others lower ones, or no differences with non-athletes . This diIn addition, to exceed the load dependency and other limits of GLS, the MW has emerged as an alternative instrument for evaluating myocardial function . MW can Therefore, in the currently available echocardiographic software, after calculating GLS in two-, three-, and four-chamber views, the values of brachial blood pressure and the time of valvular events, it is possible to obtain PSL and more precise information about myocardial contraction during the different phases of the cardiac cycle .In particular, the determinants of MW indices that are produced by the software include global work index (GWI), global constructive work (GCW), global wasted work , and global work efficiency  ,81.GWI, expressed as mmHg%, is the amount of MW performed by the LV during systole obtained with the area of the PSL from MV closure to MV opening. GCW, expressed as mmHg%, is the positive work performed during myocardial shortening in systole and negative work during lengthening in isovolumic relaxation. GWW, expressed as mmHg%, is the negative work performed during lengthening in systole and positive work performed during myocardial shortening in isovolumic relaxation. Finally, GWE, expressed as %, is the relationship between constructive work and the sum of constructive and wasted work ,81.It was recently reported that LV adaptation in endurance athletes resulted in preserved GWE and GWW, even though with decreased values of GLS. In addition, GWE at rest can predict better than LVEF, functional capacity, and pulmonary or hemodynamic congestion individuated at peak exercise .Therefore, the utility of MW indices is to provide a comprehensive insight into myocardial contraction, adding essential information to differentiate between physiological remodeling or pathological remodeling, for example, due to valve regurgitation. In this context, MW indices are pivotal in the clinical decision-making process of selecting patients that need valve surgery. For example, in the MVP, energy demand and oxidative stress are increased due to localized hypercontractility and recurrent segmental myocardial traction, which also causes localized myocyte hypertrophy and fibrous tissue repair . For thep = 0.005) despite the comparable values of LVEF and GLS [Nevertheless, Ermakov et al. demonstrated an increase in mechanical dispersion in patients with MVP, especially in the arrhythmic MVP, compared with controls  is a new marker used to quantitatively assess RV function by incorporating the RV GLS (RVGLS), PAP, and tricuspid and pulmonic valvular events . Wu et aCMR is the most useful imaging technique for differentiating between physiology and pathology in athletes ,24,93. CAn athlete’s heart can be distinguished from cardiomyopathy using recent techniques such as LGE, native T1, extracellular volume (ECV) mapping, and T2 mapping .As reported above, some MV or TV diseases are associated with increased SCD; therefore, CMR has a primary role in MV and TV evaluation, identifying myocardial subvalvular scarring and other factors related to increased risk of SCD and requiring preventive strategies such as specific management or appropriate sports restriction .p < 0.001), and it is associated with a higher arrhythmic event rate [For example, in patients with MVP, fibrosis of the PMs and inferobasal LV wall, suggesting a myocardial stretch by the prolapsing leaflet, is the structural hallmark and correlates with VAs origin . In partent rate .In MVP patients, the most frequently individuated non-ischemic fibrosis pattern was mid-wall striae and patchy pattern of the basal inferolateral wall (31.1%), followed by the inferior basal wall (10.7%). These patterns differ from the typical LGE sub-endocardial or transmural distribution in patients with coronary artery disease . MoreoveAlthough CMR is not ideally suited to evaluating VHD, it can be used to evaluate valve defects comprehensively. The main strength of CMR lies in the highly accurate and reproducible assessment of ventricular volumes and function in patients with left- or right-sided valve disease ,102. In Indeed, phase-contrast (PC) CMR velocity encoding is used for velocity measurements based on the accumulated phase of moving protons. Therefore, it is used to quantify the severity of valvular regurgitation and stenosis.Even though CMR has long been the gold standard for determining chamber volumes, assessing their functionality, and evaluating the effects of severe MS , studies have repeatedly shown that the relatively low temporal resolution of CMR causes mitral velocities to be considerably lower than those obtained from TTE . In caseIn the setting of MR, besides the precise quantification of LV and LA volumes, CMR has benefits in terms of precision and reproducibility for assessing the extent of LV remodeling and its impact on MV tethering, as well as for quantifying the grade of local or diffuse LV fibrosis and LV deformation or strain ,106. In Similarly, in patients with TR, CMR also helps in tissue characterization, providing information about myocardial impairment and RV fibrotic remodeling  . In addiCCT is another diagnostic method that can be used to evaluate CAs. CCT is more frequently applied to athletes at risk for SCD when there is a suspicion of coronary artery abnormalities . In addiIn addition, CCT utility in valve disease assessment has been widely studied and has some specific applications. For example, in the case of MS, the CCT provides a clear depiction of MV leaflet thickening and calcification (because of high X-ray attenuation), evaluation of the extent of mitral annular calcification (which is rare in athletes), and accurate annular sizing . FurtherHowever, CCT, despite a lower temporal resolution than CRM, can analyze MR, provide precise volumetric measurements of chamber dimensions, and evaluate the MV and MA geometry. Moreover, pre-procedural planning using CCT is crucial for percutaneous MV replacement operations .CCT can also provide morphological information about the TV considering its optimal spatial resolution and ability for multiplanar reconstructing . The strIn 1963, Barlow first described the MVP, reporting the common association of mid–late systolic clicks with late-systolic murmurs ,117. MVPHistologically, MVP is characterized by fibro-myxomatous changes in the MV leaflets . The conMVP is one of the most challenging valve abnormalities in the athlete population. In 1966, Hancock et al. described that features associated with MVP were predominantly female sex, low or inverted T waves in leads II, III, and aVF, prolonged Q-T interval, syncope, or SCD .Although most patients have a benign natural history, a small proportion may develop numerous cardiac complications, including severe MR due to degenerative disease or chordal rupture, infective endocarditis, embolic cerebrovascular accident, arrhythmias, and SCD ,116. In Athletes with MVP without significant regurgitation generally may not experience any symptoms. Instead, the condition is often an incidental finding on cardiac auscultation of a mid-to-late systolic click at the apex or detected on screening echocardiography . HoweverA high degree of valve regurgitation in MVP is widely acknowledged as a significant factor contributing to the incidence of SCD; nevertheless, the detection of MVP in victims of SCD or those who have survived life-threatening VAs indicates that there may be a connection between MVP without hemodynamic complications and arrhythmic SCD .The histopathological investigation in 43 young patients (<40 years) with MVP and SCDs  revealedIn MVP, LV fibrosis is closely linked to the MV apparatus’s excessive mobility and the myocardium’s systolic stretch, which are both associated with MAD and systolic curling of the posterior MV leaflet  . In addiSpecifically, MAD is an abnormal insertion of the hinge point of the posterior mitral leaflet on the atrial wall valve away from the ventricular myocardium, characterized by a clear separation of the basal portion of the posterolateral LV myocardium and the MA-left atrial wall . MAD is p < 0.001) [As a result, VAs in MVP are due to myocardial fibrosis, marked leaflet redundancy, and MAD ,127. In < 0.001) .MR is another category that should be considered in the athlete population. Indeed, MR is a common valvular disease and ranks as the third most prevalent form of VHD worldwide and second in Europe ,118.From a pathophysiological point of view, MR can be caused either by a primary abnormality of the mitral valvular apparatus  or secondary to non-valvular myocardial pathology  ,62.The etiology of primary MR includes rheumatic heart disease, infective endocarditis, DCM, connective tissue disease (such as Marfan syndrome), and ischemic heart disease; however, the leading cause of MR among athletes is MVP ,62Although uncommon, acute severe MR can manifest among CAs . The priGenerally, two main types of secondary MR are VFMR and atrial functional MR (AFMR). The VFMR occurs in dilated ventricles as a consequence of the increased distance between the displaced PM and MA, which leads to tethering (with a “seagull sign” of anterior MV leaflet), limited systolic leaflets motion, and a reduced coaptation height ,130. ConChronic MR prompts eccentric remodeling and hypertrophy of the LV in response to the increased volume resulting from rapid early diastolic filling; however, over time, this initial compensatory response may progress into maladaptive pathology, culminating in progressive LV dilatation . Remarka2/m2, p-value < 0.05) [Fábián et al. conducted a retrospective cohort study on 423 healthy athletes, including 42 (9.9%) with mild MR [On the other hand, LV’s physiologic hypertrophy can decrease the prevalence and severity of MR . Indeed When the regurgitant jet grows, progressively becoming severe, MR is accompanied by a raised atrial pressure and higher LV preload with an escalating dilation of the LV cavity . TherefoThere is a different contribution in the MR between CAs engaged in various sports. Small sizes and hypertrophy due to strength training preserve the mitral leaflet coaptation; at the same time, competitive endurance athletes have more frequent annular dilatation and enlarged LV, contributing to the PM’s outward and downward displacement of the MV edge. In the absence of cordae elongation, this feature leads to poorer coaptation and a greater prevalence of MR ,134,135.2 and 40 mm/m2  was shown to help identify athletes with primary MR with a clinically significant LV cavity increase [2; therefore, a customized strategy that considers these characteristics is advised before placing exercise limitations [2).A LVEDD with a cut-off of 35 mm/mincrease . Howeverincrease . In addiitations . LV dysfAthletes with MR should be evaluated yearly by a physical exam, Doppler echocardiogram, and exercise stress test that matches the physical demands of their respective sports .Primarily causes of MS are rheumatic or degenerative factors. Nevertheless, rheumatic valve disease remains a significant contributor to valve disease worldwide, with a prevalence of approximately 0.02–0.2% in developed countries ,62.Although rheumatic valve disease is rare in high-income countries, with the increasing globalization of elite sport and emigration patterns, cardiologists in the Western world may encounter rheumatic MS among individuals who aspire to exercise or athletes from the developing world . In addiThe characteristic mid-diastolic rumbling murmur detected during auscultation can indicate the presence of MS . PatientThe risk stratification of exercising individuals with MS is mainly based on symptoms and a detailed echocardiogram with a specific interest in the severity of the lesion and accompanying sPAP. In addition, the assessment should include a maximal exercise stress test to identify concealed symptoms and functional capacity. At the same time, most people with severe MS are usually sufficiently symptomatic during exercise and incapable of engaging in competitive sports involving moderate or high CV demand . However2, translating to a mean transmitral gradient of 5 to 10 mm Hg at normal resting HRs [The continuity equation method for echocardiographic defining of MS severity is recommended in patients with degenerative valvular or annular calcification as other parameters (such as the PHT-related method) will not be valid in case of noncompliant LA or LV. However, the benchmark method for evaluating MS is mitral valve area (MVA) measurement using planimetry, considering the difficulties in performing it. On the other hand, mean transvalvular gradient and sPAP reflect its effects and have a better predictive value . An MVA ting HRs . Howeverting HRs .2 per year. Therefore, the risk of adverse events increases when patients develop limiting symptoms or substantial PH in the presence of severe MS [The narrowing of the valve area occurs gradually, at a rate of 0.1–0.3 cmevere MS .TR may be due to acquired pathologies such as rheumatic fever, infective endocarditis, carcinoid syndrome, or congenital disease such as Ebstein’s anomaly. The rheumatic disease affects the TV in 20 to 30% of cases, often associated with mitral and aortic involvement. In general, it is a mild involvement that is difficult to appreciate in 2DE if particular attention is not paid to the search for valve leaflets and commissural fusion. In addition, rheumatic disease causes more frequent regurgitation than stenosis .However, in most instances, TR occurs in conjunction or is functional secondary to the RV, RA, or TA dilation from other pathologies, including left-sided heart or valve diseases, AF remodeling, PH, or right ventricular dysfunction. Therefore, exercise limitations relate to the underlying pathology in most patients with secondary TR .Primary VHDs show a similar prevalence in athletes as in the general population. However, athletes report TR more frequently than sedentary subjects, suggesting predominantly secondary functional origin . For exaAlthough the pathophysiological mechanism underlying this increased prevalence of TR in athletes is not yet fully understood, it is essential to underline that TR in athletes represents an adaptive mechanism secondary to the dilation of the RA and RV. During exercise, the RV is subject to a lower pressure overload than LV because the pulmonary resistance is lower than the systemic resistance . HoweverIn addition, during exercise, the increased LV CO determines an augmented venous return to the right chambers, with consequent progressive enlargement. This feature is associated with increased wall thickness and altered diastolic function for the increased atrial component of the flow pattern across the TV . In addiIn front of a bilateral chambers dilation, the TA has more lipidic and less fibrotic characteristics than the MA, making it more likely to dilate . As demoAs proof of EICR, a recent study proposed mid-diastolic tricuspid regurgitation (MDTR) as a possible novel echocardiographic marker of the athlete’s heart. MDTR is a physiological finding in a highly trained endurance athlete due to distinct sports adaptations. MDTR is observed between the passive early diastolic and active late diastolic ventricular filling, and the extent of regurgitation is dependent on intrathoracic pressure . The authors postulated two possible mechanisms typical features of the athlete’s heart: sinus bradycardia, which determines an increased diastole time, and a dilated and compliant RV, which determines a direct transfer of intrathoracic pressure variations related to respiration .2 in the apical four-chamber view) is the main contributor to mal-coaptation and regurgitation, which, together with RA enlargement, precedes RV dilation [Conditions that result in an increase in RV volume or pressure overload cause local remodeling of RV geometry, PM displacement , deformation of the spatial arrangement among chords, PMs, leaflets, TA enlargement, and its dynamics alteration, bringing to leaflet tethering and mal-coaptation with a VFTR . Unlike dilation . SimilarIndeed, Gjerdalen et al.  found thDue to their prognostic significance, TA enlargement, RV and RA measurements, and the performance of RV should all be assessed in secondary TR . HoweverIsolated TS is rare in adults. Instead, in almost all cases, it is caused by rheumatic disease with concomitant MV involvement. In addition, carcinoid tumors can affect the right heart sections leading to TR or TS .The 2D echocardiography is used to evaluate the TV’s anatomy utilizing a variety of windows, including the parasternal right ventricular inflow, the parasternal short axis, the apical four-chamber, and the subcostal four-chamber . In 2DE,2 [Nevertheless, there are no generally accepted and standardized parameters for TS severity grading, even though some variables are indicative of hemodynamically significant TS, such as mean pressure gradient ≥ 5 mmHg at normal HR, inflow VTI > 60 mm, pressure half-time (T1/2) ≥ 190 ms and valve area by continuity equation ≤ 1 cm2 ,148.Principal recommendations according to valvular disease severity are resumed in Given that the spectrum of disease for MVP can range from benign imaging finding to fatal VAs, there has been a recent interest in characterizing risk factors for arrhythmic MVP, including imaging features .In particular, ventricular function and severity of MR by echocardiography, exclusion of fibrosis by CMR, in addition to electrocardiographic alterations, presence of arrhythmias, syncope, and patient history, make part of the most significant societies of cardiology’s criteria for competitive sports eligibility . GeneralGeneral recommendations regarding exercise and sports in athletes with MR should consider different aspects that can aid in determining the appropriate level of physical activity and help in decision-making. These include symptomatic status, MR severity, LV dimensions and function, estimation of sPAP at rest and during exercise, functional capacity, myocardial reserve, and the presence or absence of arrhythmias ,6,62.Athletes with mild MR are encouraged to participate in all competitive sports  , and an 2 in men and <40 mm/m2 in women, LVEF is ≥60%, resting sPAP is <50 mmHg, in sinus rhythm, and exercise test is normal without complex arrhythmias [Athletes with moderate MR should be considered  for all competitive sports if they are asymptomatic with a suitable functional capacity, provided LVEDD is <60 mm or <35.3 mm/mhythmias ,6. Athlehythmias .2 in men and <40 mm/m2 in women, LVEF is ≥60%, resting sPAP is <50 mmHg and exercise test is normal without complex arrhythmias [Athletes with severe MR may be deemed suitable  for low-intensity sports if they are asymptomatic with a suitable functional capacity, LVEDD is <60 mm or <35.3 mm/mhythmias ,6. Athlehythmias ,6.Therefore, individuals with LVEF < 60%, symptomatic MR, and reduced exercise capacity or individuals with MR with exercise-induced complex arrhythmias should not participate in competitive or leisure sports. Finally, individuals on long-term anticoagulation therapy for AF should not engage in contact/collision sports ,6.The indications for surgical intervention in athletes are similar to those in the general population, and surgical MV repair performed by an experienced surgeon is preferred over MV replacement . After MFor patients with MS who want to participate in competitive sports with minimal or no symptoms, it is recommended to undergo exercise stress testing to evaluate their ability to handle the activity required for their sport . In addi2) can engage in all competitive sports  if they are asymptomatic, in sinus rhythm, have a resting sPAP < 40 mmHg, and have a normal exercise test [Guidelines suggest that individuals with a mild MS (MVA 1.5–2.0 cmise test .2) may participate in low-intensity competitive sports  if they are asymptomatic, in sinus rhythm, have a resting sPAP < 40 mmHg, and have a normal exercise test [Athletes with moderate MS (MVA 1.5–1.0 cmise test .2) should avoid participating in any competitive sports  [Instead, individuals with severe MS (MVA < 1.0 cmdence C) . Indeed,2), regular exercise and competitive sport may be considered in asymptomatic individuals with suitable functional capacity.Furthermore, those with MS of any severity who develop AF should be long-term anticoagulated and avoid any competitive sports involving physical contact ,62. FinaIn CAs, echocardiographic evaluation of sPAP is vital among the criteria for sports eligibility. However, it is crucial to remember that with greater severity of TR, higher resting RA pressures, and diminished RV function, rapid equilibration of the RV and RA pressures ensues, making it impossible to estimate correctly sPAP .In most patients with secondary TR, exercise limitations relate to the underlying pathology. Individuals with any degree of TR, with a resting sPAP > 50 mmHg at rest, and RV dysfunction may participate in low-intensity sports only. Also, individuals with right atrial pressure > 20 mmHg and any degree of TR should avoid competitive sports ,6.Nevertheless, individuals with mild TR, without the above-mentioned limitations, can participate in all sports. Certainly, mild TR is common in athletes and accompanied by physiological dilatation of the inferior vena cava, which is easily collapsible with inspiration .Individuals with mild TR, without the above-mentioned limitations, are eligible for all levels of exercise .Individuals with moderate TR, without the above-mentioned limitations, are eligible for all sports disciplines of any intensity if also they have a normal biventricular systolic function, normal exercise testing, and sPAP is <40 mmHg at rest .Finally, individuals with severe TR, without the above-mentioned limitations, are eligible for only low-intensity exercises .Athletes with mild TS are eligible for all sports if they are asymptomatic and have a normal ventricular function; however, individuals with moderate or severe stenosis should avoid sports . FinallyAtrioventricular valve diseases are more frequently experienced by athletes than non-athletes, suggesting predominantly functional origin. Indeed, adaptation to exercise determines several changes, including atrioventricular remodeling. Therefore, assessing and interpreting athletes with valve pathology requires special attention since the pathologic mechanisms may differ from inactive individuals. In addition, the differential diagnosis of some cases of cardiac chambers dilation can be problematic in the presence of regurgitation.In this complex scenario, the possible imaging modalities in athletes are several, including quantifying direct and indirect signs of atrioventricular valve disease at rest or during exercise. Nevertheless, these techniques provide an accurate, objective, non-invasive, and reproducible method for MV and TV assessment. Furthermore, they help clarify the etiologic mechanism, the EICR contribution to regurgitation, the identification of athletes at higher risk of arrhythmias and SCD, and eventually indicate whether athletes are eligible for participation in competitive sport.


Hypertensive heart disease (HHD) develops in response to the chronic exposure of the left ventricle and left atrium to elevated systemic blood pressure. Left ventricular structural changes include hypertrophy and interstitial fibrosis that in turn lead to functional changes including diastolic dysfunction and impaired left atrial and LV mechanical function. Ultimately, these changes can lead to heart failure with a preserved (HFpEF) or reduced (HFrEF) ejection fraction. This review will outline the clinical evaluation of a patient with hypertension and/or suspected HHD, with a particular emphasis on the role and recent advances of multimodality imaging in both diagnosis and differential diagnosis. Worldwide, the age-standardised prevalence of hypertension continues to rise and has reached 30% in the general population and up to two-thirds in those over the age of 60 ,2. HyperLeft ventricular hypertrophy (LVH)—defined as an increase in the LV wall thickness or mass—is widely regarded as a cardinal feature and phase in the evolution of HHD . TraditiLV structural changes include hypertrophy and interstitial fibrosis that in turn lead to functional changes including diastolic dysfunction and impaired LA and LV mechanical function. Ultimately, these changes can lead to heart failure with a preserved (HFpEF) or reduced (HFrEF) ejection fraction . It shouMost patients with hypertension are asymptomatic and, as such, the condition has often been described as a silent killer . HistoryAll patients should have a baseline 12-lead Electrocardiogram to screen for LVH/end-organ damage although it has a low sensitivity for detecting LVH . All patGiven its availability and low cost, transthoracic echocardiography (TTE) is the first-line diagnostic imaging test to detect structural and functional changes in HHD. Left ventricular mass index (LVMI), left ventricular diastolic dysfunction (LVDD), and impaired global longitudinal strain (GLS) have prognostic implications in patients with arterial hypertension ,10,11. HEchocardiographic assessment of LVH and thus left ventricular mass (LVM) relies on linear measurements of LV dimensions on 2-dimensional images. Calculation of myocardial mass then uses geometric assumptions with respect to LV shape , which, LV systolic function is maintained at normal or near-normal values until the late stages of HHD. The most commonly used surrogate marker of LV systolic function is left ventricular ejection fraction (LVEF), which depends not only on LV contractility but also on pre- and afterload and left atrial function. In clinical practice, LVEF is measured on 2D echocardiography using Simpson’s biplane method or on 3D echocardiography using manually assisted semi-automated endocardial border tracking . Of noteWhile LVEF may remain normal along the natural history of HHD, echocardiographic techniques such as speckle tracking strain have been shown to be able to detect subtler impairments in myocardial mechanics such as reduced global longitudinal strain (GLS) . In hypeInherent to the LV structural changes including hypertrophy and interstitial fibrosis, LV elasticity, compliance, and stiffness are compromised in hypertensive patients and lead to LVDD. While a complete description of an echocardiographic assessment of diastolic function is beyond the scope of the present review, measurements include Doppler and tissue Doppler measurements of mitral inflow and mitral annular velocities . These mThe LA dilates as a consequence of LVDD in HHD, and the LA volume index (LAVI) has been shown to independently predict cardiovascular events . RecentlFurthermore, arterial hypertension is a risk factor for developing an abdominal aortic aneurysm. Screening for abdominal aortic aneurysms can easily be integrated into a routine echocardiography assessment and is indicated in patients with long-standing hypertension and individuals over 65 years of age  .Serial echocardiography can be used in principle to monitor longitudinal changes in LV mass in response to treatment, which may have prognostic implications; however, the higher accuracy and precision of CMR make this more suited for this application.Hypertensive patients with LV hypertrophy disproportionate to the degree of hypertension may be referred for CMR for further examination and differential diagnosis. CMR is regarded as the non-invasive gold standard for the evaluation of LV volumes, systolic function, LV mass, and myocardial tissue characterisation . Image aSimilar to echocardiography, LV geometry can be assessed using relative wall thickness (RWT) and CMR-specific normal values for LV myocardial mass . LA dimeFeature-tracking strain imaging can also be performed in CMR with the advantage of better image quality, lack of angle dependency or impediment from difficult acoustic windows, and less observer dependency . MyocardHypertension is a well-established atherosclerotic risk factor for the evolution of coronary artery disease (CAD). Both macrovascular CAD of the epicardial coronary arteries and microvascular CAD  are detectable by CMR stress perfusion . There iCMR stress perfusion essentially visualizes myocardial first-pass perfusion during pharmacological stress. Images are interpreted in conjunction with rest perfusion images and late gadolinium enhancement (LGE) images. In the presence of a significant epicardial coronary stenosis, the myocardial contrast uptake is reduced in a specific coronary territory (coronary pattern). Conversely, microvascular dysfunction displays a more diffuse and delayed but synchronous myocardial contrast uptake during stress. Stress CMR offers excellent sensitivity and specificity for the detection of anatomically and functionally significant CAD  and alloTo avoid the low but important risks of endomyocardial biopsy, which can have an overall complication rate of up to 6% , myocardLGE has become the reference standard for non-invasive imaging of myocardial scar and focal fibrosis . GadolinT1 before and after the administration of contrast agents, as well as the patient’s haematocrit. ECV can then be calculated using the formula:LGE allows the detection of focal alterations in the myocardium, but diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods such as T1 and ECV mapping has the potential to detect and quantify both focal and diffuse alterations in the myocardial structure. Furthermore, changes in the myocardium over time may be assessed longitudinally . EstimatECV values vary between 25.3 and 3.5% . C,6. CECV  methods . FurtherT1 and ECV has been shown to have incremental diagnostic benefits even in very early disease stages , there is an overlap between different cardiomyopathies and some overlap with normal T1 values. The difference in ECV between normal subjects and patients with HHD is small (0.29 ± 0.03 vs. 0.27 ± 0.02) , a, a68], aSarcoid can occasionally cause LV thickening when there is focal or extensive granulomatous infiltration of the myocardium . If therThe extent/severity of hypertrophy can be of value in a differential diagnosis. It is unusual for hypertensive heart disease to produce very severe hypertrophy (>20 mm) and never extreme hypertrophy (>30 mm). Similarly, it is often suggested that high levels of athletic activity can be associated with LVH. However, most patients who experience athletic remodelling develop mild symmetrical cavity dilatation and modest increases in LV mass. Increases in LV wall thickness are uncommon and, if present, tend to be very mild (13–15 mm). Such changes are more commonly seen in athletes with black African ancestry. Increases in LV wall thickness can often be seen in recreational bodybuilders who take androgens or an exogenous growth hormone . InteresAs LVH increases, there is a reduction in ECV in athletes (cellular hypertrophy) but an increase in ECV in patients with HCM (cellular disarray and extracellular matrix expansion). Based on this divergent finding, ECV may be helpful to distinguish HCM and athletic remodelling, particularly in subjects with indeterminate maximal wall thickness (13–15 mm) .p < 0.05) [The relationship between hypertension grade and coronary atherosclerosis was evaluated in 8238 patients who underwent calcium scoring and computed tomography coronary angiography (CTCA) for screening purposes. The prevalence of calcified and non-calcified plaques increased with the grade of hypertension and was 17%, 28%, 34%, and 40% in normotensive, pre-hypertension, stage 1 hypertension, and stage 2 hypertension, respectively ( < 0.05) .CTCA has the highest negative predictive value of all imaging techniques regarding the exclusion of macrovascular CAD. Often coronary artery tortuosity can be documented M. ArteriThe correlation between blood pressure and myocardial metabolism has been evaluated in 86 individuals undergoing fluorodeoxyglucose positron emission tomography (18-F-FDG-PET) PET . This isApart from diagnosing macrovascular disease/ischaemia in patients with HHD, myocardial perfusion reserve (MPR) assessed by Rubidium (Rb)-82 PET can be used to risk stratify patients with hypertension. In a study of 517 hypertensive patients undergoing Rb-PET imaging, the 26% of patients who had resistant hypertension had more frequent LVH, lower myocardial blood flow rates, and lower MPR than subjects without resistant hypertension. Age, resistant hypertension, and impaired MPR were independent predictors of adverse events over a median follow-up of 38 months .Secondary hypertension affects approximately 5–10% of the general hypertensive population . ImagingThe most common cause of primary hyperaldosteronism is an aldosterone-producing adrenal adenoma. Adrenal adenomas usually present as round or oval masses. Using a threshold value of ≤10 Hounsfield units (HU) at non-contrast CT leads to high sensitivity and specificity in their detection . Given tPhaeochromocytomas are a rare cause of secondary hypertension and account for only <5% of patients with secondary hypertension. These tumours usually present as large, heterogeneous masses with both necrosis and cystic changes and avid contrast enhancement .Common non-endocrine causes are aortic coarctation N and renAortic coarctation is defined as luminal narrowing near the origin of the left subclavian artery and ligamentum arteriosum and is a very rare cause of secondary hypertension with only 0.2% of patients with hypertension affected . IncreasRegarding renovascular hypertension, FMD or renal artery stenosis are the most common causes O. Both cPatients with long-standing hypertension often also develop increased arterial stiffness with accelerated aortic pulse wave velocity as measured by CMR velocity-encoded imaging. A stiff aorta may further increase LV afterload .All markers of cardiac damage in HHD are influenced by age, gender, and ethnicity. Normalisation to body surface area may be misleading in obese individuals; normalisation for body height, a good surrogate of fat-free mass, appears to be more acceptable but used less frequently in clinical practice . All imaDue to the high prevalence of hypertension, HHD is one of the most common heart diseases and a frequent cause of diastolic heart failure and LV impairment. In clinical practice, comprehensive echocardiography may be sufficient to recognize most features of HHD. In patients with LV hypertrophy disproportionate to the degree of hypertension and patients where dual pathology is assumed, tissue characterization with CMR can be very helpful in the differential diagnosis, risk stratification, and also to detect extracardiac pathology associated with HHD.


Fabry disease (FD) is an X-linked genetic lysosomal disease, in which a deficit in the alpha-galactosidase A enzyme results in lysosomal build-up of globotriaosylceramide in several organs, causing cardiac, renal and cerebrovascular complications. The aim of this study was to assess the prevalence of papillary muscle hypertrophy (PMH) in patients with FD.A group of 63 patients with FD and a positive genetic diagnosis were studied and were divided into two groups: one included 24 patients with FD and LVH and another group included 39 patients with FD and without LVH. Papillary muscles were measured from the left parasternal short axis view, defining PMH as a diastolic thickness greater than 11 mm in any diameter.Patients with FD and LVH had a high prevalence of anterolateral PMH (66.6%), and such prevalence was lower for the posteromedial PMH (33.3%). However, patients who had not yet developed LVH had a high prevalence of anterolateral PMH (33.3%).Patients with FD in the pre-clinical stage (without LVH) have a high prevalence of PMH, especially involving the anterolateral papillary muscle. This finding could be an early marker for the development of LVH, allowing to suspect the disease during its early stages, and begin enzyme replacement therapy in the appropriate patients. Fabry disease (FD) is caused by a recessive, X-linked genetic defect, which leads to a deficit in the activity of a lysosomal enzyme, α-galactosidase A . As a reRegarding its prevalence, FD is the 2nd most frequent storage disorder , after Gaucher’s disease. Cardiac involvement occurs frequently in FD, and occasionally the heart is the only affected organ. The characteristic phenotype is symmetric left ventricular hypertrophy (LVH), that may mimic hypertrophic symmetric non-obstructive cardiomyopathy (HCM) , 6.The pAccording to the European Registry of Cardiomyopathies  and the Since the clinical presentation is variable, it is difficult to make an early diagnosis and the mean diagnostic delay is 15 to 20 years after the beginning of symptoms.In patients with FD, a targeted history taking, physical exam, laboratory workup to assess enzyme levels, and genetic testing are the main pillars for the differential diagnosis of the disease.Symptoms of FD reflect the various organs affected . However, in spite of early multisystemic manifestations, the diagnosis is currently made late and many cases are still diagnosed as non-obstructive HCM.Hence, a high level of suspicion is required for the diagnosis of FD, especially in patients with a normal 2-D echocardiogram.The goal of this study was to demonstrate that FD can be suspected in patients with papillary muscle hypertrophy and an otherwise normal 2-D echocardiogram.That would allow to detect early cardiac involvement in patients with FD without LVH, and decide whether they require enzyme replacement therapy to prevent irreversible damage to the heart, kidney and brain.To assess the prevalence of papillary muscle hypertrophy in FD.This was a single-center, cross-sectional study, which assessed the presence of papillary muscle hypertrophy (PMH) in patients with FD, with and without LVH.Thirty-nine patients with a diagnosis of FD without LVH and 24 patients with FD and LVH were included.Patients included had an enzymatic and genetic diagnosis of FD, and were aged 18 years or older, with or without LVH. Their α-galactosidase A levels had to be reduced or absent, and a chromosome X-linked mutation was present (locus Xq 22.1).The normal value of α-galactosidase A enzymatic activity is greater than 5 µmol/l/hour. An α-galactosidase A level below 1 µmol /l/hour was required for the diagnosis of FD.The normal value of α-galactosidase A in peripheral blood leukocytes, measured with the fluorometric method, is 395 to 780 nmol/mg/hour. A value below 80 nmol/mg/h was required for the diagnosis of FD.Exclusion criteria were a history of coronary, valvular or pericardial disease, congenital heart disease, hypertension, diabetes mellitus, anemia, asthma, chronic obstructive pulmonary disease, thyroid dysfunction, renal failure, pregnancy, alcoholism, patients younger than 18 years old, and patients with a poor ultrasound window.The study was approved by the Research and Ethics Committee of the Hospital “Dr. Cosme Argerich”. Written consent for submission and publication of this study, including images and associated text, has been obtained from the patient in line with COPE guidance.The 2-D echocardiogram was performed with a Vivid 7 machine  and a 1.5 to 4 MHz transducer.Left parasternal (long and short axes) as well as apical 2-, 3- and 4-chamber views were obtained. Two-D and M-mode images were obtained from the left parasternal short axis view at the papillary muscle level, and the following measurements were made according to the American and European Societies of Echocardiography: end-diastolic LV diameter (LVEDD), end-systolic LV diameter (LVESD), diastolic thicknesses of the ventricular septum and LV posterior wall, right ventricular and left atrial (LA) diameters , 11.Both diameters of each papillary muscle were measured at the end diastole in the left parasternal short axis view. Hypertrophy of the papillary muscles was diagnosed when the horizontal or vertical diameters measured more than 11 mm Figs.  12]..12].To assess interobserver variability, two independent investigators performed a 2-D echocardiogram with the appropriate measurements in 10 patients included in the study, in a period < 24 h to avoid differences attributable to variations in hemodynamic status.Subsequently, after a 24-hour interval, one of the investigators re-analyzed the echocardiographic parameters in the images obtained, to assess the intraobserver variability.t test for paired data was used to compare quantitative variables with a normal distribution, and for variables with a non-normal distribution we used the Wilcoxon Signed Rank Test. Statistical analyses were performed with Statistix 7.0. software and a p value < 0.05 was considered significant.Quantitative data with a normal distribution were expressed as means ± standard deviation and data with non-gaussian distribution were expressed as medians and inter-quartile intervals. The Student We included 66 patients with an enzymatic and genetic diagnosis of FD. Among them, 3 patients were excluded due to a poor ultrasound window.The final study population comprised a total of 63 patients, 24 patients with FD and LVH, and 39 patients with FD without LVH. As shown in Table Regarding conventional echocardiographic measurements, the group with LVH had greater wall thickness, LV mass and LA size (p < 0.05). Although LVDD was normal in both groups, patients with LVH had a larger diameter (p < 0.05). No significant difference was seen in RV dimension, SF, or LVEF.Patients with FD and LVH had a higher prevalence of anterolateral PMH  and to a lesser extent posteromedial PMH . However, the group of patients who had not yet developed LVH exhibited a high prevalence of anterolateral PMH (33.3%). Table In FD the catabolism of glycosphingolipids (Gb3) is altered, due to a deficit of the alpha-galactosidase A enzyme, resulting in systemic buildup of lysosomal Gb3 .Phenotypes of FD vary, from the “classic” form which begins early during childhood and affects multiple organs, to the late form, where the heart is predominantly affected .Accumulation of Gb3 in cardiomyocytes, the conduction system, vascular endothelium and fibroblasts leads to cellular and vascular dysfunction, causing cardiac manifestations. These include ventricular hypertrophy, progressive diastolic and systolic LV dysfunction, bradyarrhythmias and tachyarrhythmias, microvascular ischemia and mild valve dysfunction , 15.Skeletal muscle abnormality is frequently documented among individuals diagnosed with FD. Muscular symptoms stand out as a primary manifestation of FD, emerging before the onset of both cardiomyopathy and chronic kidney dysfunction. It remains uncertain whether this stems from the same cardiac dysfunction or from direct muscular involvement. In younger patients, muscle myocytes are usually unaffected, while blood vessels show the presence of mild glycosphingolipid accumulation in endothelial and smooth muscle cells. On the other hand, in older patients, signs of myopathy are detected in electromyography, along with an increase in left ventricular mass .Recently, a high glycolytic rate and underutilization of lipids as an energy fuel have been observed in FD patients. In the pursuit of a potential mechanism, an upregulation of HIF-1 (hypoxia-inducible factor-1) has been identified in both mice and FD patients, leading to a reversal of cellular metabolic remodeling, revealing a Warburg effect. Blood lactate has surfaced as a potent biosensor of this metabolic disruption, introducing a novel prospect as a diagnostic and monitoring tool .Left ventricular hypertrophy is a maladaptive and non-specific cardiac response to a great variety of stimuli in many cardiac and systemic disorders  It is a The mild to moderate impairment in diastolic filling is a relatively common finding, and probably represents the most important cause of dyspnea in patients with FD. Valve structural abnormalities are frequent due to valve infiltration .The LVH is usually concentric, without LV outflow tract obstruction. However, in severe cases an asymmetric variant may be found, with septal thickening and fibrotic thinning of the posterior wall, characteristics that are unique to FD  Right veSeveral review papers and case reports on FD have shown that patients with Fabry cardiomyopathy have a high prevalence of PMH , 21, 22.Other cardiac diseases that cause LVH also result in PMH. For example, in hypertensive cardiac disease, stress leads to an increase in wall thickness, which may be accompanied by an increased size of the PM during the last stage of the disease, albeit not as marked as in FD. Friedreich’s ataxia is a mitochondrial disorder that causes LVH. However, wall thickness rarely exceeds 14 mm and therefore, PM size does not increase as much. In cardiac amyloidosis LVH is also relatively frequent, although the PM do no exhibit similar degrees of hypertrophy .Only in FD cardiomyopathy LVH and PMH are seen associated with a relatively small LV cavity, resulting in an absolute and relative increase in PM size. Two-D strain allows detection of early abnormalities in FD without myocardial hypertrophy, when the longitudinal strain of the LV is ≥-15% in at least one segment. Possibly in FD, beyond the lysosomal storage of glycosphingolipids or the abnormal synthesis of sarcomeric proteins, there is interference in sarcomeric contraction and relaxation, resulting in a decrease in longitudinal myocardial strain , 23. LefCurrently, cardiac magnetic resonance (CMR) with tissue characterization and T1 and T2 mapping techniques, contributes to the diagnosis and suspicion of FD . Also, tThe accumulation of sphingolipids at the myocardial level can be detected using native T1 mapping. Typically, the low native T1 value precedes the development of the classic sign of LVH, making it a considered early marker of the disease. Myocardial native T1 captures signals from both myocytes (with sphingolipids) and intramyocardial blood. Blood has a longer and more variable T1 value, and the contaminating signal acts as noise, diminishing the precision and accuracy of myocardial T1 measurement for sphingolipid accumulation in myocytes. However, blood’s T1 can be independently measured in the cardiac blood pool, allowing for a correction strategy. This blood-based correction of native myocardial T1 has been observed to increase the proportion of subjects with FD who exhibit a low myocardial T1 value .However, echocardiography is a simple and widely available method for the assessment of ventricular geometry and specific myocardial structures, used as diagnostic markers for several cardiac diseases .Nowadays, echocardiography and CMR are complementary examinations that aid in the diagnosis and monitoring of Fabry disease treatment. This includes identifying the specific cardiac phenotype of FD, distinguishing it from other types of left ventricular hypertrophy (LVH), and selecting suitable patients for therapeutic interventions. Advances in cardiac imaging hold the promise of identifying Fabry disease-related abnormalities in their early stages, thereby facilitating early prognostic characterization .The presence of PMH in patients without LVH could allow to suspect the disease in its early stages, and early treatment could allow for partial remission of the disease and prevention of its long-term complications.Although 2-D echocardiography is the standard diagnostic tool in daily cardiology practice, papillary muscles are three-dimensional structures that may not be completely evaluated with a two-dimensional method, and that is a limitation of the method.Since the study was conducted at a single center, the results might not be representative of the genetic and ethnic diversity of other populations.We acknowledge that the number of patients in our study is small, which might limit the generalizability of the results to a larger population. FD is an infrequent disorder, with an incidence of 1/40.000 men. Thus, our study population represents 11.6% of the estimated number of patients with FD in our country. A larger sample size could provide a more comprehensive picture of the prevalence of PMH in FD patients.The study design is cross-sectional, preventing the establishment of causal relationships between the presence of PMH and the disease’s progression over time. A longitudinal study could offer deeper insights into this association.Included patients had a positive genetic diagnosis of FD. This might introduce selection bias, as patients with more severe forms of the disease could be more likely to undergo genetic testing and thus be overrepresented in the sample.Patients with FD in the preclinical stage (without LVH) have a high prevalence of PMH, especially the anterolateral PM, and that could be a predictor for the development of LVH.These findings could provide useful information regarding the pathophysiology of cardiac involvement in FD and help understand whether early enzyme replacement therapy might be useful in modifying the clinical course and prognosis of patients with this disease.


This study aims to determine the association between clinical patterns of early respiratory disease and diastolic dysfunction in preterm infants.R) to help differentiate between cardiac or pulmonary pathophysiology.Preterm infants <29 weeks’ gestation underwent cardiac ultrasounds around day 7 and 14–21. Respiratory dysfunction patterns were classified as stable (ST), respiratory deterioration (RD) or early persistent respiratory dysfunction (EPRD) according to oxygen need. Diastolic dysfunction was diagnosed using a multi-parameter approach including left atrial strain (LASR was lower in the EPDR group.98 infants (mean 27 weeks) were included. The prevalence of ST, RD and EPRD was 53%, 21% and 26% respectively. Diastolic dysfunction was more prevalent in the RD and EPRD groups with patent ductus arteriosus and significant growth restriction as risk factors. Not all infants with a PDA developed diastolic dysfunction. LASRespiratory dysfunction patterns are associated with diastolic dysfunction in preterm infants. Others have higher FiO2 at birth and remain oxygen dependent for several weeks, referred to as early and persistent respiratory dysfunction (EPRD). A third group recover from their initial respiratory disease, only to deteriorate in the second week of life, described as a group with respiratory deterioration (RD). The RD or persistent dysfunction has mostly been attributed to pulmonary parenchymal disease with abnormal lung development due to preterm birth. However, some preterm infants have been shown to have early respiratory morbidity due to diastolic dysfunction from immature myocardial development [Most very preterm infants require respiratory support early after birth and in the first few postnatal weeks . Three delopment , 4.Clinical trials have targeted very preterm infants with EPRD and RD in the second or third week of life with systemic steroids targeting lung inflammation to prevent further lung disease –7. The rHeart failure is defined as an inability of the heart to pump blood to the body at a rate matching its needs, or to do so only at the cost of high ventricular filling pressures . When heUp to 1 in 5 very preterm infants develop diastolic dysfunction on cardiac ultrasound in the first weeks after birth . About 1This single centre prospective observational study approached all preterm infants <29 weeks’ gestation. Exclusion criteria were significant cardiac or other congenital abnormalities and death before 21 days of life. Infants with a small muscular VSD or small ASD could be included. During the study period local guidelines suggested early surfactant and nasal continuous positive airway pressure via a bubble system as main respiratory support strategy. Management of the PDA was directed by cardiac ultrasound, usually organized in the first week of life. Ethical approval for this study was obtained from the Hunter New England human research ethics committee. After informed consent, all infants received a cardiac ultrasound as close as possible to day 7 after birth, and again between day 14 and 21 after birth. Additional cardiac ultrasounds could be performed at clinicians’ discretion.2 < 0.23 between days 3 and 7 and FiO2 < 0.25 at day 14–21, as RD when FiO2 < 0.23 between days 3 and 7 and FiO2 ≥ 0.25 at day 14–21, and as early persistent respiratory dysfunction (EPRD) when FiO2 ≥ 0.23 between days 3 and 7, and FiO2 ≥ 0.25 at day 14–21. Respiratory support settings, and blood gas values closest to the cardiac ultrasounds were collected from the patient notes. Where available, chest X-rays were analyzed by two blinded radiologist using pattern recognition on an arbitrary 3 point Likert scale as more likely diffuse or focal neonatal pulmonary disorders, can’t differentiate, or more likely vascular congestion [Respiratory patterns were determined according to Laughon et al . Infantsngestion .Z-scores were determined using the Fenton growth charts [Z-score < 1.30. Late onset sepsis was defined as a clinical deterioration with a positive blood culture.Weight h charts . SignifiEchocardiography examinations were performed using a GE E90 system v202  with 12 MHz probe. Image acquisition was triggered to the R wave and followed the recommendations of the American Society of Echocardiography . AnalyseWe used a combination of pulse wave Doppler, Tissue Doppler, volumetric changes and speckle tracking imaging to assess diastolic function. Left atrial volume (LAvol) was determined by method of disks from the apical 4 chamber images by tracing the left atrium (LA) at maximum size, omitting the pulmonary vein confluence and the LA appendage . The EA Peak atrial longitudinal strain was used to help differentiate between diastolic dysfunction of cardiac origin and pulmonary venous hypertension as isolated feature. In isolated pulmonary venous hypertension, one would expect left atrial pressures and function to be normal. Progressive diastolic dysfunction of cardiac origin would increase pressure in all pulmonary vessels . Peak left atrial longitudinal strain was determined at QRS using speckle tracking analysis .Pulmonary hypertension can be the end-result of progressive diastolic dysfunction of cardiac origin, and was assessed by exploring tricuspid regurgitation, moderate to severe septal flattening in systole, or any bidirectional or right-to-left shunt, and recorded as present or not .Diastolic dysfunction was assessed using a multi-parametric approach which included 6 parameters and diagnosed as present when 3 or more parameters were outside the normal range for age. Based on previous work in preterm infants at comparable gestational and postnatal age we set the cut-points at LAvol > 1.50 ml/kg, EA ratio > 0.90, e’ velocity < 2.7, Ee’ ratio > 18, the presence of pulmonary hypertension, and peak left atrial strain <25% , 17.t-test and ANOVA. Categorical variables were expressed as counts (percent) and analyzed using the Chi squared or Fisher’s exact test.Parameters were expressed as mean and standard deviation or median and interquartile range where appropriate. Simple group analyses were conducted using an independent p values < 0.05 were considered statistically significant.This is an exploratory pilot study with primary outcomes respiratory disease patterns and diastolic dysfunction. An exact sample size could not be calculated due to limited published data on diastolic dysfunction in preterm infants. Assuming that the respiratory patterns are equally divided and 20% develops diastolic dysfunction, a sample of ~100 infants will be required. Known co-variates for respiratory dysfunction and/or diastolic dysfunction include a persistent PDA, mechanical ventilation, late onset sepsis and significant growth restriction , 20, 21.From June 2020 to June 2022, 124 preterm infants <29 weeks gestation were admitted in the John Hunter Children’s Hospital neonatal intensive care. Four infants died before 21 days of life, 1 infant was transferred out, 1 infant had significant cardiac abnormalities (large VSD), in 18 cases the investigators were not available and in 2 cases no consent was obtained, leaving 98 infants for analysis. The mean gestational age and birth weight of the cohort was 27.1 (1.4) weeks and 953 (230) grams respectively.Z-score at birth (p < 0.05) and were more likely to be male. Diastolic dysfunction was significantly more prevalent in both the RD and EPRD groups. The odds ratio of developing diastolic dysfunction (when compared to the ST group) was 2.2 (95%CI 0.5–9.2) and 3.0 (95%CI 0.8–10.9) on the first scan, and 25 (95%CI 3–225) and 34 (95%CI 4–287) on the second scan for infants with RD and EPRD respectively.The respiratory patterns and categories are presented in Table The first cardiac ultrasound scan was performed at a median of 7 (5–8) days after birth, and the second scan at 18 15–20) days. Figure 0 days. FTable 2 and base excess between the groups. Hemoglobin was significantly lower in the RD and EPRD groups at first scan (126(19) and 132(30) versus 147(22) gr/L, p < 0.01) and at the second scan (98(17) and 101(16) versus 115(18) gr/L, p < 0.01).There were no significant differences at the first or second cardiac scan in sodium, lactate, pH, pCOEight infants in the ST group (including the one infant with diastolic dysfunction) received a chest X-ray which were all scored as more likely to represent a pulmonary disorder. A total of 73 chest X-rays were taken in the RD and EPRD groups, with only 2 classified as more likely vascular congestion.The association between patterns of respiratory disease, diastolic dysfunction and the prevalence of other pathology is presented in supplementary table p < 0.001). Not all infants with a large PDA diameter developed diastolic dysfunction.Figure This exploration study found a strong association between clinical patterns of respiratory dysfunction and the prevalence of diastolic dysfunction on cardiac ultrasound. We hypothesize that cardiac pathophysiology plays an important role in the development of clinical signs and symptoms in a subgroup of preterm infants. Our data showed a strong association between clinical patterns of respiratory dysfunction and the prevalence of diastolic dysfunction on cardiac ultrasound.Diastolic function of the heart describes the filling of the ventricles. When the mitral valve opens, blood enters the LV through suction caused by elastic recoil of myocardial fibers re-lengthening toward their resting length (restoring forces) and thereby lowering LV cavity pressure. With further filling and increase in LV cavity size, and the myocardial fibers expanding beyond their resting length, stiffness of the myocardial tissues will slow the rate of filling and increase LV cavity pressure. The final phase of diastolic function is created by atrial contraction, increasing the LA pressure above the LV pressure and establishing the final LV end diastolic volume and pressure before the mitral valve closes and contraction begins. Diastolic dysfunction is characterized by an increased pressure at the end of diastole or abnormal patterns or LV myocardial relaxation.The preterm heart undergoes significant changes with the transition from fetus to newborn, and is exposed to higher preload and afterload than the fetus . The intOur current study supports the above-described mechanistic pathways in the development of diastolic dysfunction and associated clinical respiratory signs and symptoms in preterm infants. Blood pressure was lower in the infants with respiratory signs and/or diastolic dysfunction. Atrial volume and the Ee’ ratio was increased in infants with respiratory signs, both parameters associated with raised atrial pressure, and atrial dysfunction was found in the EPRD group where persistent high atrium volume was common. Increased LA pressure can lead to pulmonary venous congestion and a subsequent increase in right ventricle afterload. To compensate the right ventricular driving pressure has to increase, which can explain the higher rate of pulmonary hypertension found in the RD and EPRD groups , 25. PulThe prevalence of diastolic dysfunction was high in infants with respiratory signs and a persistent PDA for more than 10 days, mechanical ventilation for more than 10 days, significant growth restriction and late onset sepsis. The PDA is a hemodynamic condition where high volumes of blood pass through an open shunt into the left side of the heart, leading to progressive morphological and functional changes in the LA and the LV . BesidesMechanical ventilation and respiratory signs and symptoms are inherently associated with each other, but the relationship between mechanical ventilation and diastolic dysfunction is less well understood. Cyclic changes in intrathoracic pressure can theoretically enhance early diastolic recoil forces . Some stLate onset sepsis was more common in infants who developed respiratory dysfunction, but we were unable to establish a significant association with concomitant diastolic dysfunction. Late onset sepsis in preterm infants is usually linked with high blood flows, and one would expect similar pathophysiology in diastolic function as with a PDA , 35.Z-score contributed to persistent respiratory problems and diastolic dysfunction. Intrauterine growth restriction is known for abnormalities in cardiac structure and function that can persist into adulthood [We found that a lower birth weight dulthood . SGA headulthood –40. Diasdulthood . In someThere are several limitations to the findings of our pilot exploration study. Based on the actual prevalence of some co-variates in this cohort, we acknowledge that our sample is not large enough to provide strong associations between all subgroups. Disparity between patient populations, postnatal age, used ultrasound hardware and analysis software can lead to variation in reference values used to establish diastolic dysfunction. We recommend establishing local reference values to validate a multi-parameter approach to diastolic dysfunction. There remains a significant lack of normative data of ultrasound parameters of diastolic function in preterm infants at various gestation and postnatal age. Our data should not be used to infer judgment on the relationship of diastolic function, treatments for it, and closure effects in the setting of a PDA. This would require a prospective study with selection of patients with truly pathologic shunts.Our data showed a strong association between clinical patterns of respiratory dysfunction and the prevalence of diastolic dysfunction on cardiac ultrasound. A multi-parameter approach was able to assess diastolic function and estimate LA pressure. Estimates of high LA pressure could be used to differentiate between cardiac or pulmonary pathophysiology of clinical respiratory signs. The findings in this study can be used to establish the clinical diagnosis of DHF and help select very preterm infants for future studies that target possible treatments to the principal pathophysiology.Supplementary Table 1


P = 0.015 and P = 0.013, respectively). RT-induced myocardial damage is a significant predictor of cardiac events. LV V45 is associated with RT-induced myocardial damage and subsequent cardiac events.This prospective study aimed to evaluate whether radiation (RT)-induced myocardial damage by cardiac magnetic resonance (CMR) imaging could be a predictor of cardiac events after chemoradiotherapy (CRT) for esophageal cancer and determine the dose-volume histogram (DVH) parameters of the left ventricle (LV) in predicting cardiac events. CMR imaging was performed before and 6 months after CRT in patients receiving definitive CRT. RT-induced myocardial damage was defined as abnormal CMR findings indicating myocardial fibrosis corresponding to an isodose line of ≥30 Gy. The cutoff values of the LV DVH parameters were calculated using the receiver operating characteristic curve based on the presence of RT-induced myocardial damage. The prognostic factors related to cardiac events of Grade 3 or higher were examined. Twenty-three patients were enrolled in the study. RT-induced myocardial damage by late gadolinium enhancement and/or an increase of 100 ms or higher in native T1 post-CRT was detected in 10 of the 23 patients. LV V45 was the best predictive factor for RT-induced myocardial damage with a cutoff value of 2.1% and an area under the curve of 0.75. The median follow-up period was 82.1 months. The 5- and 7-year cumulative incidences of cardiac events of Grade 3 or higher were 14.7 and 22.4%, respectively. RT-induced myocardial damage and LV V45 were significant risk factors ( Chemoradiotherapy (CRT) is one of the main treatments for esophageal cancer. Some studies have demonstrated comparable treatment outcomes between CRT and surgery for esophageal cancer, and lonVarious RIHDs including pericarditis, coronary disease, cardiomyopathy, heart failure, valvular disease and conduction failure after definitive RT for esophageal cancer have been reported , 10. Althttps://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037126), the design and results of which have been previously reported [This study was a subanalysis of a prospective observational study  7th], I, II, III or IV with supraclavicular or paraaortic lymph node metastasis; Eastern Cooperative Oncology Group performance status, 0–1; estimated glomerular filtration rate ≥ 30 ml/min/1.73 m2 on Day 1 and continuous infusion of 5-fluorouracil at 700 mg/m2 for 24 h on Days 1–4) with a 4-week interval were administered during RT.The CRT and RT regimens were described in our previous report . GeneralThree-dimensional conformal RT was administered to all patients. The initial clinical target volume (CTV) was defined as the region from the supraclavicular to celiac lymph nodes. Boost CTV was defined as the primary tumor with a 20- to 30-mm craniocaudal margin and an ~5-mm radial margin, and nodal metastasis. The planning target volume was defined as the CTV plus a 5- to 15-mm margin. Generally, the initial CTV dose was ~40 Gy, using parallel opposed anterior and posterior fields with or without the field-in-field technique, and the boost CTV received 20 Gy using parallel oblique fields to avoid the spinal cord. The dose distribution was determined using an ECLIPSE Varian Medical Systems  with an analytical anisotropic algorithm.et al. [The LV was contoured by a RT oncologist according to Feng et al. . The innCMR was performed before and 6 months after CRT using the protocol described in a previous study , 14. CMRSince there have been only a few studies on RT-induced myocardial damage, a clear definition of RT-induced myocardial damage has not been established. Therefore, based on the results of our previous studies , 14, abnAll patients underwent regular follow-up at our outpatient clinic and were referred to the Cardiology Department if any symptoms or laboratory abnormalities were suggestive of related cardiac events. Individual atherosclerotic risk factors at baseline were managed by clinicians.The primary endpoint was composite cardiac events of Grade 3 or higher, including acute coronary syndrome, arrhythmia, heart failure, pericarditis, valve disease and cardiomyopathy, which occurred >6 months after CRT. Individual adverse cardiac events were defined and confirmed based on the Common Terminology Criteria for Adverse Events version 4.0. with reference to a previous study . The secContinuous variables are presented as median values and interquartile ranges (IQRs). The average and SD values are also presented among the T1 mapping values.The cutoff values of the LV and WH DVH parameters for predicting cardiac events were determined. The receiver operating characteristic (ROC) curve was plotted to examine the correlations between RT-induced myocardial damage by CMR and the LV DVH parameters. We examined the correlations between pericardial effusion at post-CRT and the WH DVH parameters. The cutoff of LV and WH DVH parameters was calculated based on the frequency of RT-induced myocardial damage and pericardial effusion. The optimal cutoff value on the ROC curve, which corresponds to the maximum (sensitivity + specificity −1), was calculated using the Youden index . The areThe cumulative incidence of cardiac events and OS was calculated using the Kaplan–Meier method. The cumulative incidence of cardiac events was calculated from the start of CRT to the onset of cardiac events or was censored at the last follow-up. Log-rank tests were used to examine prognostic factors related to cardiac events of Grade 3 or higher. Patient demographic characteristics at pre-CRT, brain natriuretic peptide (BNP) and pericardial effusion at post-CRT, RT-induced myocardial damage at post-CRT, LV DVH parameters and WH DVH parameters were included as potential predictors in those analyses.P < 0.05. Statistical analyses were performed using JMP15 .All statistical tests were two-sided, and statistical significance was defined as Twenty-three patients were enrolled in the study. Patient characteristics are shown in Although pericardial effusion was detected in 13 patients 6 months after CRT, there were no symptoms at that time. On pre-CRT CMR, LGE was not found in any of the patients. The mean ± SD and median native T1 values in the interventricular septum at pre-CRT were 1184 ± 50.0 ms and 1169 ms , respectively. Based on these results, the 2 SD value of native T1 in the ventricular septum before CRT was 100 ms. Therefore, we defined an increased value of ≥100 ms in native T1 at post-CRT as positive for RT-induced myocardial damage. On post-CRT CMR, mean ± SD and median increased values of native T1 were 71.4 ± 43.0 ms and 69.0 ms , respectively. RT-induced myocardial damage was detected in 10 of 23 (43.5%) patients. The findings of both LGE and native T1 increase were positive in five patients. Only LGE was observed in four patients and only native T1 increase was observed in one patient. Although two patients did not undergo T1 mapping, we defined them as negative for RT-induced myocardial damage due to the absence of LGE. There were no significant differences in background characteristics between patients with and without RT-induced myocardial damage. The results of correlations between DVH parameters of LV and RT-induced myocardial damage and those between DVH parameters of WH and pericardial effusion post-CRT are shown in P = 0.015) for cardiac events. The 5- and 7-year cumulative incidences of Grade 3 cardiac events in patients with RT-induced myocardial damage were 30.0  and 53.3% , respectively (P = 0.032) (P = 0.013). The 5- and 7-year cumulative incidences of Grade 3 or higher cardiac events in patients with LV V45 of 2.1% or more were 28.4  and 64.2% , respectively (The median follow-up period from the completion of CRT was 82.1 months (IQR: 60.2–94.5 months). Non-cardiac death was observed in two patients. One patient died of recurrent esophageal cancer 14.5 months after CRT, and the other died of bacterial pneumonia after bypass surgery for esophageal stenosis at 48 months. Cardiac events of Grade 3 or higher were observed in 4 patients at a median of 40.6 months after CRT. The details of patients with Grade 3 or higher cardiac events are shown in ectively . When LG= 0.032) . Regardiectively . No signRIHD is an important concern in terms of quality of life and prognosis in long-term survivors of esophageal cancer. To our knowledge, this is the first study to demonstrate that noninvasive cardiac imaging testing predicts cardiac events after definitive CRT for esophageal cancer. We found (i) that RT-induced myocardial damage detected by CMR was significantly associated with higher cardiac risk in long-term follow-up and (ii) that LV DVH parameters were also associated with these adverse cardiac events. Multiple studies have demonstrated that RT-induced cardiac events are associated with lower OS , 19, indet al. [et al. [et al. [et al. [Although DVH parameters of the WH have often been used for predicting cardiac events, there is a possibility that the LV and coronary arteries could be similarly evaluated. Atkins et al.  reportedet al. . From thet al. . Capillaet al. . There h [et al.  reported [et al. , 30, the [et al. , 32. Bor [et al.  reported [et al.  reportedet al. [et al. [Based on the results of ours and previous studies, it is necessary to take measures to reduce the frequency of cardiac events during CRT for esophageal cancer. First, it may be necessary to consider the total prescribed dose for esophageal cancer. Previous clinical trials have not shown sufficient effectiveness of dose escalation , 34. Theet al.  reported [et al.  also rep [et al. , 40. ACEet al. [The present study has some limitations. First, the number of enrolled patients in the present study was small. Therefore, multivariable analysis was not performed in the present study. A further large study is warranted to assess whether these parameters are independently predictive of future cardiac events by multivariable analysis. Second, some patients took ACE inhibitors or angiotensin II receptor blockers, which may have affected the results of our study. Third, there was no histological validation of RT-induced myocardial damage in this study. However, invasive procedures with possible significant complications should be avoided in asymptomatic patients. Fourth, there was no comparison with the nonirradiated control group. Fifth, measures to compensate for respiratory movement were not performed because radiotherapy was delivered under the condition of free breathing in the present study. Therefore, the regions receiving a high-dose irradiation were susceptible to respiratory movement. Sixth, because the definition of RT-induced myocardial damage has not been established, it is doubtful whether the definition used in the present study is valid. Recently, Groot et al.  evaluateet al. . MoreoveIn conclusion, we demonstrated that RT-induced myocardial damage on MRI 6 months after CRT for esophageal cancer was a significant predictor of cardiac events. LV V45 is associated with RT-induced myocardial damage and subsequent cardiac events. It is important to avoid high-dose irradiation of the LV to reduce the frequency of RIHD as much as possible.Supplementary_Fig_1_rrad040Click here for additional data file.Supplementary_Fig_2_rrad040Click here for additional data file.Supplementary_Table_1_rrad040Click here for additional data file.Supplementary_Table_2_rrad040Click here for additional data file.Supplementary_Table_3_rrad040Click here for additional data file.