Myocardial deformation imaging and rare cardiomy-opathies with hypertrophic phenotype : a review focused on Fabry disease , Friedreich ataxia and amyloidosis

Tissue Doppler and deformation imaging, including Doppler-derived strain and speckle tracking, have significantly improved our understanding of cardiac mechanics in both physiological and pathological states. The various modes of left ventricular deformation (longitudinal, circumferential, radial and twist) leading to systolic contraction can nowadays be quantified. One of the best applications of deformation imaging is in the area of hypertrophic cardiomyopathies. Deformation imaging allows the evaluation of global and regional myocardial performance and the noninvasive characterization of abnormal intramural myocardial mechanics. In this review, we discuss the role of myocardial deformation imaging derived by echocardiography in the assessment of rare hypertrophic phenotype including Fabry disease, Friedreich ataxia and amyloidosis. Deformation imaging allows for early identification of myocardial dysfunction in many hypertrophic disorders, at an earlier stage than that provided by standard imaging or echocardiographic techniques. This allows for the implementation of appropriate therapy before significant disease progression has occurred and prior to the development of advanced myocardial fibrosis. Thus therapy would likely be more effective and may potentially lead to improvement in patient outcome. Additionally strain imaging allows to better monitoring the efficacy of therapy by assessing the progression and regression of myocardial involvement. Finally, findings on strain imaging carry important prognostic information in many hypertrophic disorders.


Introduction
5][6] Deformation imaging allows the evaluation of global and regional myocardial performance and the noninvasive characterization of abnormal intramural myocardial mechanics.5][6] In this review, we discuss the role of myocardial deformation imaging derived by echocardiography in the assessment of rare hypertrophic phenotype including Fabry disease, Friedreich ataxia and amyloidosis.

Strain and strain rate imaging
][3] Briefly, the difference between myocardial motion assessed by tissue velocities and myocardial deformation assessed by strain and strain rate may be explained by this example: a moving object will change its position (motion) over time but will not deform if all of its parts move at the same velocity.2][3] Strain, i.e., the amount of deformation, is a time independent parameter and is expressed in percent (%).Strain rate (SR) is the rate at which the deformation occurs and is expressed in 1/s.2][3] In fact, two objects may have the same total defor-mation (i.e., identical strain) attained at different times, and thus have different SR at a constant strain.A positive strain describes thickening or lengthening whereas a negative strain describes thinning or shortening of a myocardial segment compared to its original length.Initially, strain and SR were derived from tissue Doppler imaging (TDI).This approach has several drawbacks: 1-3 i) ability to measure only one-dimensional strain and SR; ii) time-consuming data acquisition and postprocessing; iii) necessity for expert readers; iv) low signal to noise ratio; v) inability to interrogate the tip of the LV apex; vi) requirement for good alignment between the ultrasound beam and myocardial motion (angle of interrogation <15°).][3] However in experienced and trained hands this method can be a very sensitive tool to assess early and focal myocardial contractile abnormalities. 2 Moreover, this technique is the only one able to fully resolve SR because of its high frame rate. 2 A more recent echocardiographic approach to myocardial deformation analysis is speckle tracking.2][3] The motion pattern of myocardial tissue is reflected by the motion pattern of acoustic markers or speckles.These are statistically equally distributed throughout the myocardium.2][3] Strain and SR are then derived from the velocity.2][3] It is also important to realize that various tracking algorithms manufactured by different vendors may produce different results. 7Still strain derived from speckle tracking has a better reproducibility than TDI-derived strain and its automated measurement is less time consuming, allowing for easier use in clinical practice. 3

Fabry disease
9] It results in progressive intracellular accumulation of glycosphingolipid globotriaosylceramide in various tissues including the heart, vascular endothelium, skin, kidneys and peripheral nervous system.Substrate accumulation in cardiomyocytes leads to progressive left ventricular hypertrophy (LVH), usually symmetrical and concentric [8][9] The increase in wall thick-ness may mimic the non-obstructive form of hypertrophic cardiomyopathy (HCM).In one study 3% of male subjects with LVH were found to have α-galactosidase A deficiency. 10 In another study, 4% of patients referred to a tertiary center for evaluation of suspected HCM were found to have FD. 11Histologically myeloid figures are noted on electron microscopy in the majority of cardiomyocytes, a characteristic finding of Fabry cardiomyopathy (FC). 8,9ardiac symptoms are the presenting manifestations of the disease in approximately 50% of affected individuals.Isolated cardiac involvement can also develop without clinical evidence of other organ involvement.Furthermore cardiac involvement is the most common cause of death in Fabry patients. 8,9tandard echocardiography does not allow distinguishing FC from other causes of LVH.The binary appearance of the LV endocardial border is not a sensitive or specific marker of the disease. 12-14Among patients with severe asymmetrical basal septal hypertrophy and outflow obstruction suggestive of obstructive HCM, FD is unlikely. 15Similar to other forms of LVH, diastolic dysfunction is often present at an early stage of the disease with impairment of left ventricular relaxation properties. 8,14Left ventricular ejection fraction (LVEF) is often normal and does not decline until the late stages of the disease due to progressive myocardial fibrosis. 8,14ewer echocardiographic modalities allow detection of abnormalities in myocardial function in the pre-clinical stage and prior to the development of morphological abnormalities on standard echocardiography (Table 1). 14ssue Doppler and deformation imaging demonstrate impairment in longitudinal systolic function (reduced S', E' and strain rate) in the presence of normal LVEF 16,17 and prior to the development of hypertrophy. 18Hypertrophy is as well associated with reduction in radial contractile parameters with an inverse correlation between wall thickness and radial strain rate values (lower strain rate in segments showing the worst hypertrophy). 19ven though myocardial involvement is often global with a concentric pattern to the hypertrophy, there is regional preponderance to the development of myocardial fibrosis.1][22][23] These segments ultimately demonstrate late enhancement indicative of fibrosis on follow-up CMR.3 The availability of enzyme replacement therapy (ERT) has allowed for temporal assessment of the morphological and function-  Following ERT, regression of LVH is typically noted with improvement of LV systolic parameters including strain and strain rate values. 23,24However segments showing even mild degree of myocardial fibrosis on late enhancement CMR show no functional improvement following ERT as evidenced by lack of improvement in strain rate. 23,24This emphasizes the need for early detection of FC and the initiation of ERT prior to the development of any myocardial fibrosis.When combined with standard echocardiographic techniques, newer imaging modalities including tissue Doppler, strain imaging and CMR provide incremental diagnostic value, allow for earlier detection of myocardial involvement and monitoring of the response to ERT.It is essential that FD patients are not misdiagnosed as HCM.Not only effective replacement therapy that results in LVH regression is not instituted, such patients could be needlessly subjected to invasive management strategies such as catheter-based septal ablation or surgical myomectomy.

Friedreich ataxia
6][27] Its deficiency leads to mitochondrial iron accumulation causing oxidative stress and secondary deficiency in respiratory chain enzymes. 27At the cellular level, myocytes hypertrophy, interstitial fibrosis, and focal myocardial necrosis ensue. 276][27][28] The degree and nature of LV hypertrophy (concentric, asymmetrical, or both) are highly variable.
The most common echocardiographic abnormality is an asymmetric LV hypertrophy with thickening of the papillary muscles, although the range of morphological abnormalities appears to be wide. 26,28,29Volumebased global systolic parameters such as ejec-

Review
Figure 2. A and B) A case of Friedreich ataxia: of interest strain rate imaging is able to detect linear improvements in longitudinal myocardial deformation when higher dosage of idebenone were used.tion fraction are either normal or supranormal. 26,28,29Nevertheless, the most common cause of death in FA patients is heart failure. 25,26This suggests that our traditional parameters to assess LV systolic function are not sensitive enough to follow FA patients.
The use of the new deformation indices is of great clinical value in FA.Tissue Doppler imaging demonstrates reduction in systolic and diastolic myocardial velocities in the absence of cardiac symptoms. 30Interestingly, an inverse correlation is found between the number of GAA triple repeats and myocardial velocities suggesting a relationship between myocardial and the severity of the genetic defect. 30Strain imaging demonstrates a uniform reduction in regional systolic and diastolic deformation properties even in the absence of LVH. 30 This reduction is also noted equally in hypertrophied and non-hypertrophied myocardial segments despite a preserved ejection fraction.The reduction in regional deformation properties in the left ventricle correlated with end-diastolic wall thickness. 30The basal anterior and lateral segments show the lowest deformation values again implying a degree of regionality to the cardiac involvement in systemic illnesses.As described with Fabry disease, regional alterations in myocardial function appear to precede the development of morphological changes in LV geometry.The absence of right ventricular involvement is probably related to a weaker pressure development and lower myocardial oxygen consumption in the right than the left ventricle, thus preventing the phenotypic expression of the genotypic disorder. 302][33] Its anti-oxidant action might be related to preservation or improvement of mitochondrial func-tion. 312][33] Using Doppler-derived strain and strain rate imaging, treatment with idebenone resulted in an early (4 months) and linear improvement in regional myocardial function (Figure 2) that preceded a non-linear regression of LVH that was detected after 1 year of therapy. 34Interestingly, regional myocardial velocities did not improve during idebenone administration suggesting that they have no role in the monitoring of therapy. 34

Amyloidosis
Cardiac involvement may occur with all forms of systemic amyloidosis due to the extracellular deposition of abnormal insoluble fibrillar proteins. 35,36These include: i) primary (AL) amyloidosis, the most common cause of cardiac amyloidosis (CA), is associated with a light chain monoclonal gammopathy due to a blood cell dyscrasia with deposition of light chain immunoglobulin in various organs including the heart.Clinical evidence of cardiac involvement occurs in up to 50% of patients; ii) secondary amyloidosis associated with chronic infection and inflammation is becoming increasingly uncommon; iii) hereditary or familial amyloidosis, an autosomal dominant disease, results from deposition of a mutant transthyretin protein; iv) senile systemic amyloidosis results from deposition of wild-type transthyretin.][37] Amyloid deposition occurs uniformly throughout the heart involving the myocardium, endocardium, pericardium, interatrial septum, conduction system, valves and coronary arteries.Oxidative stress with cellular necrosis and interstitial fibrosis is probably due to a combination of chronic interstitial infiltration and acute toxic effect of circulating light chains. 14,37Morphologically, progressive increase in biventricular wall thickness (rather than true hypertrophy) ensues with small or normal LV chamber size, dilated atria, often thickened interatrial septum and a pericardial effusion. 14The previously described speckled or granular appearance of the myocardium is not specific for CA. 14,37he availability of some therapies for CA particularly for the early stages of the disease coupled with the very poor prognosis, particularly with AL amyloidosis, emphasizes the need for an early diagnosis of cardiac involvement. 38nfortunately, standard echocardiographic and Doppler techniques, including tissue Doppler analysis, do not allow the detection of CA at an early stage when therapy can be most effective. 398][39] Therefore it is desirable to use more sensitive measures to detect LV early dysfunction.
Diastolic dysfunction occurs relatively early in the disease process with an impaired relaxation pattern on spectral and TDI with progression towards a restrictive pattern on spectral Doppler with further disease progression.][39] The subendocardial layer where longitudinally oriented fibers are predominantly located is primarily involved with the amyloid process leading to early and marked impairment of longitudinal function.This can be detected by Mmode, pulsed TDI and strain imaging demonstrating significant reduction in displacement, velocity and deformation values along the longitudinal plane. 40Of these strain imaging is the most sensitive measure, providing the earliest clues to the presence of myocardial involvement even prior to reduction in tissue velocity parameters. 41Reduction in longitudinal strain and strain rate in all 16 LV segments can be detected in patients with AL amyloidosis without any other echocardiographic 2D or Doppler evidence of cardiac involvement and without any reduction in radial or circumferential strain. 40This finding indicates that assessment of longitudinal function by strain imaging provides the earliest clues to the presence of myocardial dysfunction in patients with systemic amyloidosis (Figure 3).Despite the impairment in longitudinal function, left ventricular ejection fraction remains normal due to preservation or even compensatory increase in radial and circumferential function in order to maintain cardiac output. 40,42Not until late in the disease process that EF declines, being inversely proportional to the severity of wall thickness. 40,42However, the role Findings on strain imaging may also allow discriminate some forms of CA, distinguish CA from other causes of LVH and carry important prognostic implications. 43For example, standard echocardiographic parameters and myocardial velocities cannot distinguish familial amyloid polyneuropathy (FAP) from AL amyloidosis. 43Telling apart these forms of amyloidosis is relevant since patients with FAP have less heart failure symptoms and better prognosis with much lower cardiac mortality.Despite similar degrees of LV wall thickness, longitudinal strain is significantly lower in the basal and mid segments in patients with AL amyloidosis in spite of a preserved global systolic function. 43Additionally despite similarities on 2D echocardiographic findings between CA and HCM, strain imaging allows to distinguish these 2 forms of hypertrophic phenotypes.As described above, each shows a characteristic pattern for longitudinal deformation.Whereas radial strain may be reduced in both groups of myopathies, patients with CA show a gradual increase in strain values from base to apex.In contrast, HCM patients demonstrate preservation of the physiological base to apex decrease in gradient. 44,45ifferent patterns of LV torsion are noted in AL patients with and without evidence of cardiac involvement.Twisting and untwisting of the LV are reduced in the first group patients and are increased in the second group.This finding suggests that impairment in LV longitudinal function induces a compensatory mechanism in the early phase of the disease that fails as myocardial involvement worsens. 46,47ince the atria are equally involved in CA, abnormal deformation properties are noted early in the disease process. 47Left atrial (LA) dysfunction appears to be independent of global LV systolic and diastolic function and degree of atrial dilatation.Similar to the findings in the LV, peak systolic atrial SR was reduced in AL patients and no apparent cardiac involvement as compared to healthy subjects. 47This further suggests the higher sensitivity of deformation imaging for the detection of myocardial involvement in the pre-clinical stage and in the setting of otherwise normal echocardiogram.Furthermore, strain imaging shows worse LA deformation properties in AL patients demonstrating heart failure than in those without suggestive of a more advanced degree of amyloid myocardial infiltration. 47train imaging provides incremental prognostic information beyond those provided by clinical and standard echocardiographic assessment in patients with CA.In patients with AL amyloidosis, the mean basal strain, a measure of longitudinal LV function, is a powerful predictor of clinical outcome and superior to standard 2D, spectral Doppler and tissue velocity parameters. 41The combination of parameters including peak longitudinal systolic strain in the basal anteroseptum (≤7.5%), an elevated titer of brain natriuretic peptide (>493 pg/mL) and a shortened LV ejection time (<273 ms) demonstrated the independent predictor value of clinical outcome, in 249 patients with AL amyloidosis. 41

Conclusions
Hypertrophic phenotype represents a widely heterogeneous group of disorders with different etiologies, manifestations, clinical outcomes and therapies.2D echocardiography coupled with spectral Doppler and tissue velocity imaging is one of the first modalities of diagnosis.Unfortunately, traditional echocardiographic methods often fail to distinguish among these various forms of hypertrophy despite their dissimilarities, whether due to hypertension, HCM, athlete's heart, Fabry disease, Friedreich ataxia or amyloidosis.Needless to say, distinguishing apart these forms of hypertrophic phenotype has major diagnostic, therapeutic and prognostic implications.Strain imaging provides a unique tool for the assessment of such patients as it effectively helps differentiate these different types of hypertrophy.Thus it provides a non-invasive modality to physicians for better allocation of resources and minimizing invasive diagnostic strategies.As repeatedly demonstrated above, deformation imaging allows for early identification of myocardial dysfunction in many hypertrophic disorders, at an earlier stage than that provided by standard imaging or echocardiographic techniques.This allows for the implementation of appropriate therapy before significant disease progression has occurred and prior to the development of advanced myocardial fibrosis.Thus therapy would likely be more effective and may potentially lead to improvement in patient outcome.In addition strain imaging allows to better monitor the efficacy of therapy, especially for Fabry disease and Friedreich ataxia, by assessing the progression and regression of myocardial involvement.Finally, findings on strain imaging carry important prognostic information in many hypertrophic disorders.
One of the best clinical applications of cardiac strain imaging is in the field of hypertrophic phenotype.The data available from several studies are very encouraging as to the value of deformation imaging in this group of patients.In our opinion Strain imaging should be part of the echocardiographic study in patients with evidence of LVH.
It is noteworthy that, dealing with an unexplained left ventricular hypertrophy, standard and new echocardiographic findings must be carefully interpreted in the broader clinical context.Extracardiac manifestations and clinical red flags (for example conduction disorders, corneal opacity and proteinuria in Fabry disease, later onset of symptoms, alteration of creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase in neuromuscular diseases, low voltage and/or infarct pattern electrocardiogram in amyloidosis) could be of precious help in directing towards the correct differential diagnosis of hypertrophic phenotypes.
al changes in FC patients in response to treatment.

Figure 1 .
Figure 1.A case of Fabry disease showing uniformly reduced values of 2D longitudinal peak systolic strain; interestingly the segments of the lateral wall show the double peak sign.N o n -c o m m e r c i a l u s e o n l y

ReviewFigure 3 .
Figure 3.A case of amyloidosis showing reduced myocardial peak systolic strain rate in basal and mid segments, with a relatively preserved deformation at the apex.

Table 1 . Main features concerning standard and new echocardiographic findings in Fabry disease, Friedreich ataxia and amyloidosis. Fabry disease Freidreich ataxia Amyloidosis
parameters is correlated with end-diastolic values from base to apex wall thickness Early impairment of left Earlier improvement of strain rate atrial strain values values during treatment with idebenone Prognostic value of peak longitudinal systolic strain in basal anteroseptum ≤7.5% LV, left ventricular; TDI, tissue Doppler imaging.