Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC nPPXf94kznSSLSFNZVhwGLp S0066-782X2019001100979 10.36660/abc.20180370 Review Article Deposit Diseases as Differential Diagnosis of Left Ventricular Hypertrophy in Patients with Heart Failure and Preserved Systolic Function 0000-0002-9323-8805 Fernandes Fábio 1 Antunes Murillo Oliveira 1 0000-0002-9236-3815 Hotta Viviane Tiemi 1 2 Rochitte Carlos Eduardo 1 Mady Charles 1 Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas São Paulo SP Brazil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil Fleury Medicina e Saúde São Paulo SP Brazil Fleury Medicina e Saúde, São Paulo, SP - Brazil Mailing Address: Fábio Fernandes, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Av. Dr. Eneas C. Aguiar, 44. Postal Code 05403-000, São Paulo, SP - Brazil. E-mail: fabio.fernandes@incor.usp.br

Author contributions

Conception and design of the research and Acquisition of data: Fernandes F, Antunes MO; Analysis and interpretation of the data and Writing of the manuscript: Fernandes F, Antunes MO, Hotta VT, Rochitte CE; Critical revision of the manuscript for intellectual content: Fernandes F, Antunes MO, Hotta VT, Rochitte CE, Mady C.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 02 12 2019 11 2019 113 5 979 987 22 11 2018 10 04 2019 15 05 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Keywords Heart Failure Hipertrophy, Ventricular Cardiomyopaty, Restrictive Amyloidosis Fabry Disease

Heart failure with preserved systolic function is the main clinical manifestations of patients with ventricular hypertrophy. Conventional treatment is based on the improvement of diastolic dysfunction and congestion. However, no drug has been shown to be effective in the survival of these patients. Thus, it is important to look for the etiology of ventricular hypertrophy with the aim of a treatment directed to the underlying disease.

Among patients with heart failure with preserved systolic function and increased ventricular wall thickness, the clinician should consider as possible differential diagnoses: hypertensive heart disease, deposit disease and hypertrophic cardiomyopathy (Figure 1).1

Diagnostic flow chart heart failure patients with and without left ventricular hypertrophy.<xref ref-type="bibr" rid="B1">1</xref>

Restrictive cardiomyopathies are the least common forms of heart muscle disease. They can be characterized as infiltrative and non-infiltrative, deposit disease or endomyocardial disorders. Possible restrictive cardiomyopathies that may mimic and even be diagnosed as hypertrophic cardiomyopathy are: Amyloidosis, Fabry disease (FD) and Glycogen deposit disease.1

We have observed in our group that many patients with deposit disease have been followed for years with a diagnosis of left ventricular hypertrophy (LVH) or hypertrophic cardiomyopathy.

A non-systematic literature review was performed to address the principal papers that suggest deposit diseases such as ventricular hypertrophy etiology and the “red flags” for a possible diagnosis. The database consulted was PubMed (www.ncbi.nlm.nih.gov/pubmed). Original articles and review performed in humans, written in Portuguese and English, were selected and the keywords MeSH hypertrophic cardiomyopathy, amyloidosis, Fabry's disease and glycogen deposit disease were used as keywords. In the present literature review, we will first address amyloidosis and later FD and finally glycogen deposit disease.

Amyloidosis is a disease caused by the deposition of amyloid fibrils in various organs,2 including the heart, where amyloid proteins infiltrate the ventricular wall, with consequent thickening causing systolic and diastolic dysfunction, heart failure (HF) and conduction disorders, with high mortality.2-4

More than 30 proteins can form amyloidosis, and among these, five can affect the heart. However, the most common types of amyloidosis that infiltrate the heart are: 1) light chain immunoglobulin, also called primary amyloidosis or AL amyloidosis;5 2) Transthyretin called amyloidosis-ATTR, which may be of genetic origin also called familial form ATTRm and form ATTRwt, also called wild type.

Detection and differentiation between these two forms are fundamental because they have different treatment and clinical evolution. Some patients with ATTRm and ATTRwt may have increased serum immunoglobulins, which may confuse the clinician regarding the correct type of amyloidosis.

The importance of the proper diagnosis of amyloidosis is based on that the treatment is different from other forms of heart failure and hypertrophic cardiomyopathy. In patients with amyloidosis, digitalis, calcium blockers and high doses of beta-blockers should be avoided, in addition, there are currently new therapeutic possibilities related to the underlying disease.6

The goal of amyloidosis treatment is to stop protein production by reducing the burden of circulating amyloid proteins.6-8

In AL amyloidosis there is a direct toxic effect of circulating immunoglobulin that may contribute to myocardial dysfunction and lead to early diastolic dysfunction. This may explain the discrepant findings between the severity of symptoms and changes in diastolic function in patients with little or no thickening evaluated by echocardiography. Patients have seen five clinicians with an average of two years before the correct diagnosis of AL amyloidosis and when this is often made the prognosis is reserved. Therefore, it is important for clinicians to consider AL amyloidosis as a differential diagnosis of hypertrophy or heart failure with preserved systolic function.1,8

More than 150 mutations are described in genetic form related to the ATTR protein gene. The most common allele in the US is Val122Ile, found in 4% of African American individuals. In our country, the change of valine by methionine to position 30 is the most common mutation (Val30Met). In countries like Japan, there is a bimodal pattern of presentation in this mutation (Val30Met): an early form that occurs around 20 to 40 years, characterized by loss of thermal and sensory sensitivity, family history, high penetrance, autonomic dysfunction and conduction disorders. In the late form, which begins around 50 years of age, patients have sensory-motor symptoms in the lower distal extremities, low penetrance, mild dysautonomia and greater myocardial impairment. The presence of neurological or systemic symptoms should suggest to clinicians as red flags to the possibility of ATTRm amyloidosis.3,4,7

The wild form, formerly called senile, as it can also affect individuals under the age of 50, predominantly affects the heart. It usually affects males with aged 77 years and usually there are neurological symptoms, such as carpal tunnel and spinal canal stenosis, five years before cardiac symptoms. Wild amyloidosis is more prevalent than we previously thought and can be detected at necropsy in up to 20% of individuals with preserved systolic heart failure (HFPEF) and in 13% of HFPEF patients hospitalized with ventricular wall thickening over 12 mm.9,10

Patients with TTR amyloidosis have ventricular wall thickening, diastolic dysfunction, and conduction system disorders.6,11 Although, these patients have better survival when compared to patients with AL amyloidosis. ATTR-amyloidosis progresses when not treated properly with heart failure (HF), reduced functional capacity, and severe arrhythmias.12

We have observed in our group that patients with ATTRwt have been treated as hypertensive heart disease or HFPEF. The presence of left ventricular hypertrophy disproportionate to the degree of hypertension, previous motor sensory symptoms and the presence of dysautonomia may be the red flags for a possible diagnosis of deposit disease.

Degenerative aortic calcification occurs in elderly individuals over 75 years and may evolve with signs and symptoms of HF. However, in a necropsy study, the presence of cardiac amyloidosis and aortic stenosis has been observed in this population.13

Amyloidosis causes diastolic dysfunction and ventricular thickening that shares some features with aortic stenosis. The concomitance of ATTRwt and aortic stenosis may lead to significant ventricular hypertrophy and functional impairment that may be confused with low flow, low gradient aortic stenosis. Amyloid deposition may lead to the use of pacemaker after percutaneous procedures (TAVI) and high prevalence of late enhancement evaluated by cardiac magnetic resonance imaging.14

Treibel et al.14 studying patients with severe aortic stenosis found a prevalence of amyloidosis in 6% of cases, all with ATTRwt. In these patients, there was a higher mortality, about 50%, and the authors suggest that nuclear scintigraphy could be a complementary method in the diagnosis of amyloidosis and could influence the need for interventional treatment and the use of specific therapies for amyloidosis. We have observed in our group that some patients despite interventional aortic valve treatment remain symptomatic and that the real aetiology for the symptoms was ATTRwt.

Deposits of amyloid may also be found in a histopathological study of patients with hypertrophic cardiomyopathy undergoing myectomy surgery.15,16

TTR mutation may be common in individuals > 55 years diagnosed as HCM, particularly African Americans. Danny et al evaluated 298 patients from 9 French centers the presence of amyloidosis in patients with ventricular hypertrophy over 15 mm. Mutation genotype of ATTRm was found in 17 patients. The prevalence of ATTRm was 5% and 8.3% in patients > 55 years, respectively. The mutations found were: V142I (8), V50M (2) and I127V (2). Patients with ATTRm mutation were older, had a higher frequency of neuropathy (53%), carpal tunnel syndrome (46%), low ECG voltage (36%), symmetrical hypertrophy (92%), abnormal left ventricular function, increased filling pressures and late gadolinium enhancement when compared to patients without the mutation. Thus, amyloidosis should be considered as a differential diagnosis in patients with hypertrophic heart disease.17 In our group, four patients initially diagnosed with HCM had the diagnose of ATTRm form with V142I mutation.

Amyloidosis should be suspected in patients with bilateral carpal tunnel syndrome, unexplained neuropathic pain, orthostatic hypotension, and hypertrophic cardiomyopathy diagnosed after the 6th decade of life.6

Complementary methods (ECHO and CMR) contribute to the recognition of cardiac amyloid infiltration, degree of ventricular hypertrophy and systolic and diastolic dysfunction.18,19However, these morphological and functional changes represent an advanced picture of disease and correlate it with the amount of amyloid in the whole body.20 This stage of the disease is also related to worsening clinical signs and symptoms.21

Typical echocardiographic findings are: Left ventricular thickness with right ventricular (RV) involvement, decreased biventricular longitudinal axis function with normal or near normal ejection fraction (EF) and increased valve thickness.22and blood flow assessment by Doppler allows also the identification of cardiac hemodynamics present in the restrictive form.23,24

Patients with ATTRwt had a higher left ventricular thickness and lower ejection fraction and the longitudinal strain is lower in ATTRwt and AL forms when compared to ATTRm.2(Figure 3, 4 and 5)

Evaluation of patients with suspected cardiac amyloidosis.<xref ref-type="bibr" rid="B1">1</xref>

Image obtained from transthoracic echocardiography. Longitudinal parasternal section showing the increased myocardial thickness of the anterior and inferior lateral septal walls of a patient with AL form amyloidosis. Bright aspect of the myocardial walls suggestive of infiltrative disease is observed.

Image obtained from transthoracic echocardiography. 4-chamber apical section showing a diffuse increase in the thickness of the left ventricular myocardial walls. Below, on the right, there is a parametric image of the longitudinal myocardial deformation evaluation by the speckle tracking technique.

Image obtained from transthoracic echocardiography. Mitral Doppler spectral curve of a patient with amyloidosis showing a restrictive diastolic pattern (E/A ratio > 2)

More advanced ECO techniques such as strain and strain rate derived from speckle tracking may assist in the assessment of cardiac torsion movements and facilitate the differentiation between cardiac amyloidosis and hypertrophic cardiomyopathy. In patients with amyloidosis there is a regional variation from the base to the apex to the longitudinal strain, where the apical portion is preserved, and this accurate and reproductive pattern in the differentiation between cardiac amyloidosis and other forms of left ventricular hypertrophy.18 LV strain analysis at rest is an independent predictor of mortality from both cardiac and other causes.25

Cardiac magnetic resonance imaging (CMR) provides information on cardiac function and morphology in patients with amyloidosis.19 However, CMR is better for assessing and quantifying abnormalities in ventricular diastolic function. The images from CMR allow 3-dimensional evaluation of cardiac volumes, cardiac wall thickening and mass. In addition, new techniques used by CMRI such as gadolinium late enhancement are fundamental in identifying cardiac amyloid infiltrates and enable the differentiation between a patient with amyloidosis and patients with ventricular hypertrophy, such as patients with hypertension and hypertrophic cardiomyopathy. However, the clinician should consider the high degree of clinical suspicion combined with complementary imaging methods, as often the anatomical features of hypertrophy can simulate both diseases.26

The asymmetric pattern of myocardial hypertrophy in patients with ATTR amyloidosis differs from AL patients, usually symmetrical. In a study of 263 patients with TTR amyloidosis confirmed by grade 2 myocardial scintigraphy and compared with 50 patients with AL form, it was observed: in the TTR form there was asymmetric hypertrophy in 79% of cases, symmetrical in 18% and 3% without LVH. The late enhancement pattern was 29% subendocardial and 71% transmural.26

We can identify three stages of disease by resonance with different prognosis: phase 1 - no evidence of late enhancement, but with increased extracellular volume and T1 map with 92% survival at 24 months; phase 2 - increased extracellular volume and T1 map and appearance of late subendocardial enhancement with 81% survival; and phase 3 - increased extracellular volume and T1 map and progression to late transmural enhancement with 61% survival. In multivariate analysis, the presence of transmural late enhancement increased mortality 4-fold and extravascular space correlated with amyloid loading and was an independent prognostic marker of survival.19

Technetium bone scintigraphy may be useful for differentiating the AL form from TTR. TTR amyloidosis often has a higher number of microcalcifications, which would justify its higher uptake of these radiopharmaceuticals. Using a visual score (0: absence of uptake, 1: uptake less than bone, 2: uptake equal to bone and 3: uptake upwards - more intense than bone uptake) to assess cardiac technetium uptake, it is possible to differentiate the shape TTR of other types of cardiac amyloidosis in conjunction with absence of light chain immunoglobulins in blood and urine. Thus, the diagnosis of TTR amyloidosis can be performed without the need for biopsy.6

Figure 2 flowchart for evaluation of patients with suspected cardiac amyloidosis.

Amyloidosis is a heart disease with heterogeneous phenotype and in many cases there are symptoms preceding in years the onset of cardiac manifestations. Thus, clinicians should have a high degree of suspicion to be able to direct the exams and do a correct diagnosis

Fabry Disease

Fabry's disease FD is a genetic, lysosomal storage disorder caused by total or partial alpha-galactosidase (α-Gal A) deficiency of the enzyme that degrades glycolipid globotriaosylceramide (Gb3) in lysosomes.27 Therefore Gb3 deposits accumulate in the endothelial cells and heart, resulting in organic dysfunction.28 The gene that causes FD is located in the long arm of the X chromosome (locus Xq22) and currently hundreds of pathogenic mutations have been described.29 Thus, male homozygous patients develop the classic disease, while female heterozygous patients present variable clinical manifestations from conditions without apparent clinical disease to the complete expression of the disease.29-31

In clinical practice, early diagnosis is important because actually there are specific treatment with enzyme replacement therapy (ERT) that may change the natural history, reducing and/or stabilizing the progression of the disease.32,33

The FD cardiac phenotype is left ventricular hypertrophy (LVH) and FD should be considered as a differential diagnosis of hypertrophic cardiomyopathy Some studies have shown that up to 5% of these patients would have the diagnosis of FD.34-36 We have observed in our outpatient clinic patients with FD and onset of hypertrophy in adulthood, a progressive character, with electrocardiographic alterations and echocardiographic findings similar to those of HCM, including LV outflow tract obstruction. Just like amyloidosis, there are also systemic manifestations that may infer the diagnosis of FD.34-36

Gb3 deposits are present in all cellular components of the myocardium, such as cardiomyocytes, conduction system, valvular fibroblasts, endothelial cells and vascular smooth muscle cells, but their totality represents only 1% to 2% of all cardiac mass, suggesting activation of other signaling pathways leading to hypertrophy, apoptosis, necrosis and fibrosis.37

Concentric ventricular hypertrophy is the most typically found in FD, but approximately 5% of cases present as asymmetric septal hypertrophy with dynamic LV outflow tract obstruction. Although LVH has been detected in some children, cardiovascular signs and symptoms are usually present in the third or fourth decade of life in men and one decade later in women.38,39 The presence of LVH leads to a reduction in life expectancy by approximately 20 years in men and 15 years in women when untreated compared to the general population.40,41

The magnitude of hypertrophy increases with age and is inversely related to renal function and α-Gal A activity. Right ventricular involvement is common with no functional or clinical consequences.42 Cardiac manifestations may occur as the only manifestation of the disease called “cardiac variant”.43

The diagnosis of myocardial hypertrophy is performed by echocardiography with the presence of bright endocardium or binary appearance of the border of the endocardium. This fact represents the compartmentalization of Gb3 and was proposed as a marker of Fabry's disease.44 However, subsequent studies demonstrated limited sensitivity (15%-35%) and specificity (73%-80%).45,46 Diastolic dysfunction occurs early more frequently than systolic dysfunction, and before the development of hypertrophy.47,48

Delayed gadolinium enhancement is common in patients with FD.49-51 The enhancement presenting with a non-ischemic pattern, located in the mesocardium and not affecting subendocardium, in basal and middle segments of the anterolateral and inferolateral walls.52 Among men, myocardial fibrosis occurs only in those with ventricular hypertrophy, differently myocardial fibrosis emerge without LVH in women.38,53

Other findings are commonly identified in FD patients: mild thickening and mitral and/or aortic valves regurgitation but usually without the need for valve repair.37,38,54 Coronary artery disease manifested as angina often occurs in men and women.55,56 Atrial arrhythmias, including atrial fibrillation, are common and appear to be age-related. Non-sustained ventricular tachycardia usually associated to LV wall thickness. Conduction abnormalities may be caused by glycolipid deposition in the atrioventricular (AV) node, His bundle, and branches.57,58 The short PR interval, particularly in younger patients,59,60 and EKG changes compatible with LVH (QRS complex voltages and repolarization change, opposite to other depository diseases with low QRS complex voltages on electrocardiogram. Sinus node dysfunction and atrioventricular blocks result in bradyarrhythmia requiring pacemaker implantation in older patients.58,60,61

The definitive diagnosis of FD in male patients is generally confirmed by measuring alpha-Gal A activity of leukocytes.62 However, this assay will identify less than 50% female heterozygotes. In female with suspected Fabry disease (and men with marginal levels of alpha-Gal A activity), genetic testing is recommended.63,64

The specific treatment for FD is through ERT which, if started as early as possible, as soon as cardiac manifestations are detected and although there is no evidence yet establishing an effect on cardiovascular outcomes, may prevent the disease from developing in young people, and at least slow the progression of multiple organ dysfunction in older patients.65-69(Table 1)

When Fabry's disease suspect
1. Unexplained left ventricular hypertrophy (LVH)
• Male gender
• Atypical: diffuse concentric, med-ventricular or free wall
2. Electrocardiogram
• PR shortening (< 120 ms)
3. Clinical manifestations
• Angiokeratoma
• Orthostatic hypotension, chronotropic incompetence, syncope and/or recurrent dizziness
• Anidrosis or hyperhidrosis
4. Others
• Renal insufficiency
• Stroke
• Verticilata cornea
Glycogen depot disease

Glycogen deposit diseases are inherited metabolic diseases of glycogen metabolism that can affect its synthesis or degradation in muscle, liver and heart tissues.70

Danon's disease has an autosomal dominant X-linked character due to LAMP2 enzyme deficiency and the triad of heart failure with hypertrophic cardiomyopathy, skeletal myopathy and mental deficit in male patients and only cardiomyopathy in women.71 The phenotype of cardiomyopathy is usually hypertrophic but dilated has also been described. Myopathy is usually mild with proximal weakness of the limb and cervical muscles, and nerve conduction studies show sensory and motor polyneuropathy. In male patients, the mental deficit may be observed in half of the cases and 10% in females with mild symptoms.

Laboratory tests show a rise in serum creatine kinase (CPK) levels from 5 to 10 x normal limits. Electrocardiogram is abnormal in all patients, showing Wolff-Parkinson-White syndrome (WPW), the high voltage on precordial leads, giant negative T waves, atrioventricular block, atrial flutter, atrial fibrillation, bradycardia, abnormal Q waves, and complete left bundle branch block. Echocardiograms show that most patients present a phenotype of concentric hypertrophic cardiomyopathy with impaired left ventricular function.71

PRKAG2 syndrome is a rare autosomal dominant inherited disease characterized by cardiac hypertrophy, ventricular pre-excitation, and conduction system abnormalities and increased risk of sudden death.72 It is characterized by increased glycogen storage and glucose uptake as opposite to what occurs due to a defect in glycogen degradation. The clinical presentation is ventricular hypertrophy and tachyarrhythmias that can lead to sudden death, conduction tissue disease, severe myocardial hypertrophy, skeletal myopathy and arrhythmias, often related to Wolff-Parkinson-White syndrome. Occasionally, LV systolic dysfunction and high-grade AV block may require pacemaker implantation. The electrocardiographic appearance is a short PR interval in 70% of cases, right bundle branch block, atrioventricular or sinoatrial blocks.

Cardiac hypertrophy can mainly affect the left ventricle, with progressive character accompanied by systolic and diastolic dysfunction with mean ventricular hypertrophy of 24 mm. High voltage in QRS complexes with ventricular repolarization abnormalities is observed even in the absence of left ventricular hypertrophy on echocardiography.

 Conclusions

There are currently over 6,000 rare diseases in the world. Among those that affect the heart, many may be underdiagnosed, or even mistakenly mistaken for heart diseases most commonly seen in clinical practice, such as hypertensive heart disease and hypertrophic cardiomyopathy. The clinician should always ask for if the diagnosis is correct and should review his concepts. The clinician should try to complete all the puzzle pieces. For these purpose, they can visualize or even suggest the correct diagnosis and towards to a specific treatment. We emphasize the saying of Mark Krane: “A doctor is not required to know everything. It's impossible. But you need to know where to go when you don't have the answer”.

Sources of Funding

There were no external funding sources for this study.

Invited editor for this paper: Dra. Gláucia Maria Moraes de Oliveira

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

 References 1 Pereira NL, Grogan M, Dec GW. Spectrum of restrictive and infiltrative cardiomyopathies: Part 1 of a 2-Part Series. J Am Coll Cardiol. 2018;71(10):1130-48. Pereira NL Grogan M Dec GW Spectrum of restrictive and infiltrative cardiomyopathies: Part 1 of a 2-Part Series J Am Coll Cardiol 2018 71 10 1130 1148 2 Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-9. Quarta CC Solomon SD Uraizee I Kruger J Longhi S Ferlito M Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis Circulation 2014 129 18 1840 1849 3 Kristen AV, Maurer MS, Rapezzi C, Mundayat R, Suhr OB, Damy T, et al. Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS). PLoS One. 2017;12(4):e0173086. Kristen AV Maurer MS Rapezzi C Mundayat R Suhr OB Damy T Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS) PLoS One 2017 12 4 e0173086 4 Gutierrez PS, Fernandes F, Mady C, Higuchi Mde L.Clinical, electrocardiographic and echocardiographic findings in significant cardiac amyloidosis detected only at necropsy: comparison with cases diagnosed in life. Arq Bras Cardiol. 2008;90(3):191-6. Gutierrez PS Fernandes F Mady C Higuchi Mde L Clinical, electrocardiographic and echocardiographic findings in significant cardiac amyloidosis detected only at necropsy: comparison with cases diagnosed in life Arq Bras Cardiol 2008 90 3 191 196 5 Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989-95. Kumar S Dispenzieri A Lacy MQ Hayman SR Buadi FK Colby C Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements J Clin Oncol 2012 30 9 989 995 6 Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-77. Maurer MS Elliott P Comenzo R Semigran M Rapezzi C Addressing Common questions encountered in the diagnosis and management of cardiac amyloidosis Circulation 2017 135 14 1357 1377 7 Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis. 2018;13(1):6. Sekijima Y Ueda M Koike H Misawa S Ishii T Ando Y Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment algorithm Orphanet J Rare Dis 2018 13 1 6 6 8 Gertz MA. Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018. Blood Cancer J. 2018;8(5):44. Gertz MA Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018 Blood Cancer J 2018 8 5 44 44 9 González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-94. González-López E Gallego-Delgado M Guzzo-Merello G de Haro-Del Moral FJ Cobo-Marcos M Robles C Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction Eur Heart J 2015 36 38 2585 2594 10 Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-22. Mohammed SF Mirzoyev SA Edwards WD Dogan A Grogan DR Dunlay SM Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction JACC Heart Fail 2014 2 2 113 122 11 Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey); THAOS Investigators. J Am Coll Cardiol. 2016;68(2):161-72. Maurer MS Hanna M Grogan M Dispenzieri A Witteles R Drachman B Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey); THAOS Investigators J Am Coll Cardiol 2016 68 2 161 172 12 Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-12. Rapezzi C Merlini G Quarta CC Riva L Longhi S Leone O Systemic cardiac amyloidosis: disease profiles and clinical courses of the 3 main types Circulation 2009 120 13 1203 1212 13 Nietlispach F, Webb JG, Ye J, Cheung A, Lichtenstein SV, Carere RG, et al. Pathology of transcatheter valve therapy. JACC Cardiovasc Interv. 2012;5(5):582-90. Nietlispach F Webb JG Ye J Cheung A Lichtenstein SV Carere RG Pathology of transcatheter valve therapy JACC Cardiovasc Interv 2012 5 5 582 590 14 Treibel TA, Fontana M, Gilbertson JA, Castelletti S, White SK, Scully PR, et al. Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement. Circ Cardiovasc Imaging. 2016;9(8). pii: e005066. Treibel TA Fontana M Gilbertson JA Castelletti S White SK Scully PR Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement Circ Cardiovasc Imaging 2016 9 8 e005066 15 Lamke GT, Allen RD, Edwards WD, Tazelaar HD, Danielson GK. Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy. A study of 204 cases (1996-2000). Cardiovasc Pathol. 2003;12(3):149-58. Lamke GT Allen RD Edwards WD Tazelaar HD Danielson GK Surgical pathology of subaortic septal myectomy associated with hypertrophic cardiomyopathy: A study of 204 cases (1996-2000) Cardiovasc Pathol 2003 12 3 149 158 16 Helder MR, Schaff HV, Nishimura RA, Gersh BJ, Dearani JA, Ommen SR, et al. Impact of incidental amyloidosis on the prognosis of patients with hypertrophic cardiomyopathy undergoing septal myectomy for left ventricular outflow tract obstruction. Am J Cardiol. 2014;114(9):1396-9. Helder MR Schaff HV Nishimura RA Gersh BJ Dearani JA Ommen SR Impact of incidental amyloidosis on the prognosis of patients with hypertrophic cardiomyopathy undergoing septal myectomy for left ventricular outflow tract obstruction Am J Cardiol 2014 114 9 1396 1399 17 Damy T, Costes B, Hagège AA, Donal E, Eicher JC, Slama M, et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016;37(23):1826-34. Damy T Costes B Hagège AA Donal E Eicher JC Slama M Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness Eur Heart J 2016 37 23 1826 1834 18 Phelan D, Collier P, Thavendiranathan P, Popovic ZB, Hanna M, Plana JC, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-8. Phelan D Collier P Thavendiranathan P Popovic ZB Hanna M Plana JC Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis Heart 2012 98 19 1442 1448 19 Fontana M, Pica S, Reant P, Abdel-Gadir A, Treibel TA, Banypersad SM. Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis. Circulation. 2015;132(16):1570-9. Fontana M Pica S Reant P Abdel-Gadir A Treibel TA Banypersad SM Prognostic value of late gadolinium enhancement cardiovascular magnetic resonance in cardiac amyloidosis Circulation 2015 132 16 1570 1579 20 Clesham GJ, Vigushin DM, Hawkins PN, Pepys MB, Oakley CM, Nihoyannopoulos P. Echocardiographic assessment of cardiac involvement in systemic AL amyloidosis in relation to whole body amyloid load measured by serum amyloid P component (SAP) clearance. Am J Cardiol. 1997;80(8):1104-8. Clesham GJ Vigushin DM Hawkins PN Pepys MB Oakley CM Nihoyannopoulos P Echocardiographic assessment of cardiac involvement in systemic AL amyloidosis in relation to whole body amyloid load measured by serum amyloid P component (SAP) clearance Am J Cardiol 1997 80 8 1104 1108 21 Hongo M, Ikeda S. Echocardiographic assessment of the evolution of amyloid heart disease: a study with familial amyloid polyneuropathy. Circulation. 1986;73(2):249-56. Hongo M Ikeda S Echocardiographic assessment of the evolution of amyloid heart disease: a study with familial amyloid polyneuropathy Circulation 1986 73 2 249 256 22 Mesquita ET, Jorge AJL, Souza CV Junior, Andrade TR. Cardiac amyloidosis and its new clinical phenotype: heart failure with preserved ejection fraction. Arq Bras Cardiol. 2017;109(1):71-8. Mesquita ET Jorge AJL Souza CV Junior Andrade TR Cardiac amyloidosis and its new clinical phenotype: heart failure with preserved ejection fraction Arq Bras Cardiol 2017 109 1 71 78 23 Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol. 1988;12(2):426-40. Appleton CP Hatle LK Popp RL Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study J Am Coll Cardiol 1988 12 2 426 440 24 Appleton CP, Hatle LK, Popp RL. Demonstration of restrictive ventricular physiology by Doppler echocardiography. J Am Coll Cardiol. 1988;11(4):757-68. Appleton CP Hatle LK Popp RL Demonstration of restrictive ventricular physiology by Doppler echocardiography J Am Coll Cardiol 1988 11 4 757 768 25 Sun JP, Stewart WJ, Yang XS, Donnell RO, Leon AR, Felner JM, et al. Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography. Am J Cardiol. 2009;103(3):411-5. Sun JP Stewart WJ Yang XS Donnell RO Leon AR Felner JM Differentiation of hypertrophic cardiomyopathy and cardiac amyloidosis from other causes of ventricular wall thickening by two-dimensional strain imaging echocardiography Am J Cardiol 2009 103 3 411 415 26 Martinez-Naharro A, Treibel TA, Abdel-Gadir A, Bulluck H, Zumbo G, Knight DS, et al. Magnetic resonance in transthyretin cardiac amyloidosis. J Am Coll Cardiol. 2017;70(4):466-77. Martinez-Naharro A Treibel TA Abdel-Gadir A Bulluck H Zumbo G Knight DS Magnetic resonance in transthyretin cardiac amyloidosis J Am Coll Cardiol 2017 70 4 466 477 27 Desnick RJ, Joannou YA, Eng CM. Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D(eds). The metabolic bases of inherited disease. 8(th) ed. New York:Mac Graw-Hill;2001.p.3733-74. Desnick RJ Joannou YA Eng CM Galactosidase A deficiency: Fabry disease Scriver CR Beaudet AL Sly WS Valle D The metabolic bases of inherited disease. 8(th) ed 2001 New York Mac Graw-Hill 3733 3774 28 Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002;81(2):122-38. Branton MH Schiffmann R Sabnis SG Murray GJ Quirk JM Altarescu G Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course Medicine (Baltimore) 2002 81 2 122 138 29 Bishop DF, Kornreich R, Desnick RJ. Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3' untranslated region. Proc Natl Acad Sci USA. 1988;85(11):3903-7. Bishop DF Kornreich R Desnick RJ Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3' untranslated region Proc Natl Acad Sci USA 1988 85 11 3903 3907 30 Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236-42. Mehta A Ricci R Widmer U Dehout F Garcia de Lorenzo A.Kampmann C Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey Eur J Clin Invest 2004 34 3 236 242 31 Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338-46. Desnick RJ Brady R Barranger J Collins AJ Germain DP Goldman M Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy Ann Intern Med 2003 138 4 338 346 32 Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker W, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation. 2003;108(11):1299-301. Weidemann F Breunig F Beer M Sandstede J Turschner O Voelker W Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study Circulation 2003 108 11 1299 1301 33 Spinelli L, Pisani A, M Sabbatini, Petretta M, Andreucci MV, Procaccini D, et al. Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry's disease. Clin Genet. 2004;66(2):158-65. Spinelli L Pisani A Sabbatini M Petretta M Andreucci MV Procaccini D Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry's disease Clin Genet 2004 66 2 158 165 34 Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM. Prevalence of Anderson-Fabry disease in male patients with late-onset hypertrophic cardiomyopathy. Circulation. 2002;105(12):1407-11. Sachdev B Takenaka T Teraguchi H Tei C Lee P McKenna WJ Elliott PM Prevalence of Anderson-Fabry disease in male patients with late-onset hypertrophic cardiomyopathy Circulation 2002 105 12 1407 1411 35 Morita H, Larson MG, Barr SC, Vasan RS, O'Donnell CJ, Hirschhorn JN, et al. Monogenic mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study. Circulation. 2006;113(23):2697-705. Morita H Larson MG Barr SC Vasan RS O'Donnell CJ Hirschhorn JN Monogenic mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study Circulation 2006 113 23 2697 2705 36 Ommen SR, Nishimura RA, Edwards WD. Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy? Heart. 2003;89(8):929-30. Ommen SR Nishimura RA Edwards WD Fabry disease: a mimic for obstructive hypertrophic cardiomyopathy? Heart 2003 89 8 929 930 37 Linhart A, Palecek T, Bultas J, Ferguson JJ, Hrudová J, Karetová D, et al. New insights in cardiac structural changes in patients with Fabry's disease. Am Heart J. 2000;139(6):1101-8. Linhart A Palecek T Bultas J Ferguson JJ Hrudová J Karetová D New insights in cardiac structural changes in patients with Fabry's disease Am Heart J 2000 139 6 1101 1108 38 O'Mahony C, Elliott P. Anderson-Fabry disease and the heart. Prog Cardiovasc Dis. 2010;52(4):326-35. O'Mahony C Elliott P Anderson-Fabry disease and the heart Prog Cardiovasc Dis 2010 52 4 326 335 39 Kampmann C, Linhart A, Baehner F, Palecek T, Wiethoff CM, Miebach E, et al. Start and progression of Anderson-Fabry disease-related cardiomyopathy. Int J Cardiol. 2008;130(3):367-73. Kampmann C Linhart A Baehner F Palecek T Wiethoff CM Miebach E Start and progression of Anderson-Fabry disease-related cardiomyopathy Int J Cardiol 2008 130 3 367 373 40 MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and disease impact in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750-60. MacDermot KD Holmes A Miners AH Anderson-Fabry disease: clinical manifestations and disease impact in a cohort of 98 hemizygous males J Med Genet 2001 38 11 750 760 41 MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and disease impact in a cohort of 60 obligated female patients. J Med Genet. 2001;38(11):769-75. MacDermot KD Holmes A Miners AH Anderson-Fabry disease: clinical manifestations and disease impact in a cohort of 60 obligated female patients J Med Genet 2001 38 11 769 775 42 Niemann M, Breunig F, Beer M, Herrmann S, Strotmann J, Hu K, Emmert A, et al. The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy. Heart. 2010;96(23):1915-9. Niemann M Breunig F Beer M Herrmann S Strotmann J Hu K Emmert A The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy Heart 2010 96 23 1915 1919 43 Wu JC, Ho CY, Skali H, Abichandani R, Wilcox WR, Banikazemi M, et al. Cardiovascular manifestations of Fabry's disease: relationships between left ventricular hypertrophy, disease severity and alpha-galactosidase A activity. Eur Heart J. 2010;31(9):1088-97. Wu JC Ho CY Skali H Abichandani R Wilcox WR Banikazemi M Cardiovascular manifestations of Fabry's disease: relationships between left ventricular hypertrophy, disease severity and alpha-galactosidase A activity Eur Heart J 2010 31 9 1088 1097 44 Pieroni M, C Chimenti, De Cobelli F, Morgante E, Del Maschio A, Gaudio C, et al. Fabry disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol. 2006;47(8):1663-71. Pieroni M Chimenti C De Cobelli F Morgante E Del Maschio A Gaudio C Fabry disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization J Am Coll Cardiol 2006 47 8 1663 1671 45 Koskenvuo JW, Engblom E, Kantola IM, Hartiala JJ, Saraste A, Kiviniemi TO, et al. Echocardiography in Fabry disease: diagnostic value of endocardial border binary appearance. Clin Physiol Funct Imaging. 2009;29(3):177-80. Koskenvuo JW Engblom E Kantola IM Hartiala JJ Saraste A Kiviniemi TO Echocardiography in Fabry disease: diagnostic value of endocardial border binary appearance Clin Physiol Funct Imaging 2009 29 3 177 180 46 Zamorano J, Serra V, Pérez de Isla L, Feltes G, Calli A, Barbado FJ, et al. Usefulness of tissue Doppler in the early detection of heart disease in patients with Fabry and possible role of enzyme replacement therapy (ERT) to prevent the progression of the disease. Eur J Echocardiogr. 2011;12(9):671-7. Zamorano J Serra V Pérez de Isla L Feltes G Calli A Barbado FJ Usefulness of tissue Doppler in the early detection of heart disease in patients with Fabry and possible role of enzyme replacement therapy (ERT) to prevent the progression of the disease Eur J Echocardiogr 2011 12 9 671 677 47 Pieroni M, Chimenti C, Ricci R, Sale P, Russo MA, Frustaci A. Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation. 2003;107(15):1978-84. Pieroni M Chimenti C Ricci R Sale P Russo MA Frustaci A Early detection of Fabry cardiomyopathy by tissue Doppler imaging Circulation 2003 107 15 1978 1984 48 Kounas S, Demetrescu C, Pantazis AA, Keren A, Lee PJ, Hughes D, et al. The binary endocardial appearance is a poor discriminator of Anderson-Fabry disease from familial hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;51(21):2058-61. Kounas S Demetrescu C Pantazis AA Keren A Lee PJ Hughes D The binary endocardial appearance is a poor discriminator of Anderson-Fabry disease from familial hypertrophic cardiomyopathy J Am Coll Cardiol 2008 51 21 2058 2061 49 Krämer J, Niemann M, Liu D, Hu K, Machann W, Beer M, et al. Two-dimensional speckle tracking as a non-invasive tool of identification of myocardial fibrosis in Fabry disease. Eur Heart J. 2013;34(21):1587-96. Krämer J Niemann M Liu D Hu K Machann W Beer M Two-dimensional speckle tracking as a non-invasive tool of identification of myocardial fibrosis in Fabry disease Eur Heart J 2013 34 21 1587 1596 50 Moon JC, Sheppard M, Reed E, Lee P, Elliot PM, Pennell DJ. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson. 2006;8(3):479-82. Moon JC Sheppard M Reed E Lee P Elliot PM Pennell DJ The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease J Cardiovasc Magn Reson 2006 8 3 479 482 51 De Cobelli F, Esposito A, Belloni E, Pieroni M, Perseghin G, Chimenti C, et al. Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy. AJR Am J Roentgenol. 2009;192(3):W97-102. De Cobelli F Esposito A Belloni E Pieroni M Perseghin G Chimenti C Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy AJR Am J Roentgenol 2009 192 3 W97 102 52 Moon JC, Sachdev B, Elkington AG, McKenna WJ, Mehta A, Pennell DJ, et al. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J. 2003;24(23):2151-5. Moon JC Sachdev B Elkington AG McKenna WJ Mehta A Pennell DJ Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease: Evidence for a disease specific abnormality of the myocardial interstitium Eur Heart J 2003 24 23 2151 2155 53 Niemann M, Hermann S, Hu K, Breunig F, Strotmann J, Beer M, et al. Differences in Fabry cardiomyopathy between female and male patients: consequences for the diagnostic assessment. JACC Cardiovasc Imaging. 2011;4(6):592-601. Niemann M Hermann S Hu K Breunig F Strotmann J Beer M Differences in Fabry cardiomyopathy between female and male patients: consequences for the diagnostic assessment JACC Cardiovasc Imaging 2011 4 6 592 601 54 Weidemann F, Strotmann JM, Niemann M, Herrmann S, Wilke M, Beer M, et al. Heart valve involvement in Fabry cardiomyopathy. Ultrasound Med Biol. 2009;35(5):730-5. Weidemann F Strotmann JM Niemann M Herrmann S Wilke M Beer M Heart valve involvement in Fabry cardiomyopathy Ultrasound Med Biol 2009 35 5 730 735 55 Chimenti C, Morgante E, Tanzilli G, Mangieri E, Critelli G, Gaudio C, et al. Angina in Fabry disease reflects coronary small vessel disease. Circ Heart Fail. 2008;1(3):161-9. Chimenti C Morgante E Tanzilli G Mangieri E Critelli G Gaudio C Angina in Fabry disease reflects coronary small vessel disease Circ Heart Fail 2008 1 3 161 169 56 Shah JS, Hughes DA, Sachdev B, Tome M, Ward D, Lee P, et al. Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease. Am J Cardiol. 2005;96(6):842-6. Shah JS Hughes DA Sachdev B Tome M Ward D Lee P Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease Am J Cardiol 2005 96 6 842 846 57 Ikari Y, Kuwako K, Yamaguchi T. Fabry's disease with complete atrioventricular block: histological evidence of involvement of the conduction system. Br Heart J. 1992;68(3):323-5. Ikari Y Kuwako K Yamaguchi T Fabry's disease with complete atrioventricular block: histological evidence of involvement of the conduction system Br Heart J 1992 68 3 323 325 58 Mehta J, Tuna N, Moller JH, Desnick RJ. Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease. Am Heart J. 1977;93(6):699-705. Mehta J Tuna N Moller JH Desnick RJ Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease Am Heart J 1977 93 6 699 705 59 Pochis WT, Litzow JT, King BG, Kenny D. Electrophysiological findings in Fabry's disease with a short PR interval. Am J Cardiol. 1994;74(2):203-4. Pochis WT Litzow JT King BG Kenny D Electrophysiological findings in Fabry's disease with a short PR interval Am J Cardiol 1994 74 2 203 204 60 Blum A, Ashkenazi H, Haromankov I, Khazim K, Sheiman J. First-degree atrioventricular block and restrictive physiology as cardiac manifestations of Fabry's disease. South Med J. 2003;96(2):212-3. Blum A Ashkenazi H Haromankov I Khazim K Sheiman J First-degree atrioventricular block and restrictive physiology as cardiac manifestations of Fabry's disease South Med J 2003 96 2 212 213 61 Chamoles NA, Blanco M, Gaggioli D. Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta. 2001;308(1-2):195-6. Chamoles NA Blanco M Gaggioli D Fabry disease: enzymatic diagnosis in dried blood spots on filter paper Clin Chim Acta 2001 308 1-2 195 196 62 Pastores GM, Lien YH. Biochemical and molecular genetic basis of Fabry disease. J Am Soc Nephrol. 2002;13(2):S130-3. Pastores GM Lien YH Biochemical and molecular genetic basis of Fabry disease J Am Soc Nephrol 2002 13 2 S130 S133 63 Germain DP. Fabry disease. Clinical and genetic aspects. Therapeutic perspectives. Rev Med Interne. 2000;21(12):1086-103. Germain DP Fabry disease: Clinical and genetic aspects. Therapeutic perspectives Rev Med Interne 2000 21 12 1086 1103 64 Linhart A, Kampmann C, Zamorano JL, Sunder-Plassmann G, Beck M, Mehta A, et al.; European FOS Investigators. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007;28(10):1228-35. Linhart A Kampmann C Zamorano JL Sunder-Plassmann G Beck M Mehta A European FOS Investigators Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey Eur Heart J 2007 28 10 1228 1235 65 Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized study. Ann Intern Med. 2007;146(2):77-86. Banikazemi M Bultas J Waldek S Wilcox WR Whitley CB McDonald M Agalsidase-beta therapy for advanced Fabry disease: a randomized study Ann Intern Med 2007 146 2 77 86 66 El Dib RP, Birth P, GM Shepherds. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev. 2013;(2):CD006663. El Dib RP Birth P Shepherds GM Enzyme replacement therapy for Anderson-Fabry disease Cochrane Database Syst Rev 2013 2 CD006663 CD006663 67 Imbriaco M, Pisani A, Spinelli L, Cuocolo A, Messalli G, Capuano E, et al. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance study. Heart. 2009;95(13):1103-7. Imbriaco M Pisani A Spinelli L Cuocolo A Messalli G Capuano E Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance study Heart 2009 95 13 1103 1107 68 Weidemann F, Niemann M, Störk S, Breunig F, Beer M, Sommer C, et al. Long-term results of enzyme-replacement therapy in advanced Fabry disease: evidence of disease progression towards severe complications. J Intern Med. 2013;274(4):331-41. Weidemann F Niemann M Störk S Breunig F Beer M Sommer C Long-term results of enzyme-replacement therapy in advanced Fabry disease: evidence of disease progression towards severe complications J Intern Med 2013 274 4 331 341 69 Frustaci A, Chimenti C, Ricci R, Natale L, Russo MA, Pieroni M, et al. Improvement of cardiac function in the heart variant of Fabry's disease with galactose infusion therapy. N Engl J Med. 2001;345(1):25-32. Frustaci A Chimenti C Ricci R Natale L Russo MA Pieroni M Improvement of cardiac function in the heart variant of Fabry's disease with galactose infusion therapy N Engl J Med 2001 345 1 25 32 70 Vertilus SM, Austin SL, Foster KS, Boyette KE, Bali DS, Li JS, et al. Echocardiographic manifestations of Glycogen Storage Disease III: increase in wall thickness and left ventricular mass over time. Genet Med. 2010;12(7):413-23. Vertilus SM Austin SL Foster KS Boyette KE Bali DS Li JS Echocardiographic manifestations of Glycogen Storage Disease III: increase in wall thickness and left ventricular mass over time Genet Med 2010 12 7 413 423 71 Sugie K, Komaki H, Eura N, Shiota T, Onoue K, TsukaguchiH, et al. A Nationwide Survey on Danon Disease in Japan. Int J Mol Sci. 2018;19(11):3507. Sugie K Komaki H Eura N Shiota T Onoue K Tsukaguchi H A Nationwide Survey on Danon Disease in Japan Int J Mol Sci 2018 19 11 3507 3507 72 van der Steld LP, Campuzano O, Pérez-Serra A, Moura de Barros Zamorano M, Sousa Matos S, Brugada R. Wolff-Parkinson-White syndrome with ventricular hypertrophy in a Brazilian Family. Am J Case Rep. 2017 Jul;18:766-76. van der Steld LP Campuzano O Pérez-Serra A Moura de Barros Zamorano M Sousa Matos S Brugada R Wolff-Parkinson-White syndrome with ventricular hypertrophy in a Brazilian Family Am J Case Rep 2017 07 18 766 776 Artigo de Revisão Doenças de Depósito como Diagnóstico Diferencial de Hipertrofia Ventricular Esquerda em Pacientes com Insuficiência Cardíaca e Função Sistólica Preservada 0000-0002-9323-8805 Fernandes Fábio 1 Antunes Murillo Oliveira 1 0000-0002-9236-3815 Hotta Viviane Tiemi 1 2 Rochitte Carlos Eduardo 1 Mady Charles 1 Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brasil Fleury Medicina e Saúde, São Paulo, SP - Brasil Correspondência: Fábio Fernandes, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo - Av. Dr. Eneas C. Aguiar, 44. CEP 05403-000, São Paulo, SP - Brasil. E-mail: fabio.fernandes@incor.usp.br

Contribuição dos autores

Concepção e desenho da pesquisa e Obtenção de dados: Fernandes F, Antunes MO; Análise e interpretação dos dados e Redação do manuscrito: Fernandes F, Antunes MO, Hotta VT, Rochitte CE; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Fernandes F, Antunes MO, Hotta VT, Rochitte CE, Mady C.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Palavras-chave Insuficiência Cardíaca Hipertrofia Ventricular Cardiomiopatia Restritiva Amiloidose Doença de Fabry

A insuficiência cardíaca (IC) com fração de ejeção preservada (ICFEP) é uma das principais manifestações clínicas de pacientes com hipertrofia ventricular. O tratamento convencional baseia-se na melhora da disfunção diastólica e congestão. Entretanto, até o momento nenhuma terapia medicamentosa mostrou-se eficaz na sobrevida desses pacientes. Dessa forma, é de fundamental importância a pesquisa da etiologia da hipertrofia ventricular com o objetivo de um tratamento específico direcionado para a doença de base.

Dentre os pacientes com ICFEP e aumento da espessura da parede ventricular, o clínico deve ter como diagnósticos diferenciais: doença cardíaca hipertensiva, doenças de depósito e cardiomiopatia hipertrófica (CMH) (Figura 1).1

Fluxograma diagnóstico pacientes com insuficiência cardíaca com e sem hipertrofia de ventrículo esquerdo.<xref ref-type="bibr" rid="B1">1</xref>

As cardiomiopatias restritivas são as formas menos comuns de doenças do músculo cardíaco. Podem ser caracterizadas como infiltrativas e não infiltrativas, doença de depósito ou desordens endomiocárdicas. As possíveis cardiomiopatias restritivas que podem simular e até ser diagnosticadas como CMH são: a amiloidose, doença de Fabry (DF) e doença de depósito de glicogênio.1

Temos observado em nosso grupo, que é especializado em miocardiopatias, que muitos desses pacientes com doenças de depósito são acompanhados por anos com diagnóstico de hipertrofia ventricular esquerda (HVE) ou CMH.

Diante do exposto, realizou-se uma revisão não sistemática da literatura a fim de abordar os principais trabalhos que sugerem doenças de depósito como etiologia de hipertrofia ventricular e os “red flags” para um possível diagnóstico. A base de dados consultada foi o PubMed (www.ncbi.nlm.nih.gov/pubmed). Foram selecionados artigos originais e revisão realizados em humanos, redigidos na língua portuguesa e inglesa e utilizou-se como palavras-chave os descritores MeSH: cardiomiopatia hipertrófica, amiloidose, DF e depósito de glicogênio. Na presente revisão da literatura, primeiro abordaremos amiloidose, posteriormente DF e, por fim, depósito de glicogênio.

Amiloidose é uma doença causada pela deposição de fibrilas amiloides em diversos órgãos,2 inclusive no coração, onde as proteínas amiloides infiltram a parede ventricular, com consequente espessamento ocasionando disfunção sistólica e diastólica, IC congestiva e distúrbios de condução, com elevada mortalidade.2-4

Mais de 30 proteínas podem causar amiloidose e, entre essas, cinco podem afetar o coração. No entanto, os tipos mais comuns de amiloidose que infiltram o coração são: 1) depósito de imunoglobulina cadeia leve, também chamada de amiloidose primária ou AL;5 2) depósito de transtiretina denominada amiloidose-ATTR, que pode ser de origem genética, também chamada de forma familiar ATTRm e a forma ATTRwt, também chamada de selvagem. A detecção e a diferenciação entre essas duas formas são de fundamental importância, pois apresentam tratamento e evolução clínica diferentes. Alguns pacientes com a forma ATTR e ATTRwt podem apresentar um aumento de imunoglobulinas séricas o que pode confundir o clínico quanto ao tipo de amiloidose.

A importância do correto diagnóstico da amiloidose reside no fato do tratamento ser diferente das outras formas de IC e da CMH. Nos pacientes com amiloidose não se deve usar digital, bloqueadores de cálcio e elevadas doses de beta-bloqueador, além do fato de atualmente existirem novas possibilidades terapêuticas relacionadas à doença de base.6

O objetivo do tratamento na amiloidose é interromper a produção de proteínas reduzindo a carga das proteínas amiloides circulantes.6-8

Na forma AL de amiloidose existe um efeito tóxico direto dos precursores das imunoglobulinas circulantes que podem contribuir para disfunção miocárdica e ocasionar disfunção diastólica inicial. Tal fato pode explicar os achados discrepantes entre a gravidade dos sintomas e das alterações de função diastólica em pacientes com pouco ou sem espessamento ao ecocardiograma (ECO). Os pacientes passam por cinco clínicos de diversas especialidades com uma média de dois anos antes do correto diagnóstico de amiloidose AL e quando esse é feito muitas vezes o prognóstico é reservado.1,8

Mais de 150 mutações são descritas na forma genética relacionadas ao gene da proteína ATTR. O alelo mais comum nos EUA é o Val122Ile, encontrado em 4% dos indivíduos afro-americanos. Em nosso meio, a mudança da valina por metionina na posição 30 é a mutação mais comum (Val30Met). Em países como Japão, existe um padrão bimodal de apresentação nessa mutação: uma forma precoce que ocorre por volta dos 20 a 40 anos, caracterizado por perda da sensibilidade térmica e sensorial, história familiar, elevada penetrância, disfunção autonômica e distúrbios de condução. Na forma tardia, que se inicia por volta dos 50 anos, os pacientes apresentam sintomas motores sensitivos em extremidades distais inferiores, baixa penetrância, discreta disautonomia e maior comprometimento miocárdico. A presença de sintomas neurológicos ou sistêmicos deve sugerir aos clínicos a possibilidade de amiloidose ATTRm.3,4,7

A forma selvagem, anteriormente chamada de senil, pois também pode afetar indivíduos com idade menor que 50 anos, acomete predominantemente o coração. Em geral afeta indivíduos do sexo masculino, com idade média de 77 anos, e em muitos casos há sintomas neurológicos 5 anos antes dos sintomas cardíacos, tais como: a síndrome de túnel do carpo e estenose do canal medular. A amiloidose selvagem é mais frequente do que se imaginava, podendo ser detectada à necropsia em até 20% dos indivíduos com ICFEP sem diagnóstico in vivo e em 13% de pacientes hospitalizados com ICFEP com espessamento da parede ventricular >12 mm.9,10

Pacientes com amiloidose na forma TTR apresentam espessamento da parede ventricular, disfunção diastólica e distúrbios no sistema de condução.6,11 Apesar de estes pacientes apresentarem melhor sobrevida, quando comparados com pacientes com amiloidose AL, a amiloidose-TTR, quando não tratada adequadamente, progride com IC, intolerância ao esforço e, em muitos casos, arritmias graves.12

Em nosso ambulatório, temos observado um grande número de pacientes com amiloidose ATTRwt e sendo tratados como cardiopatia hipertensiva ou ICFEP. A presença de HVE desproporcional ao grau de hipertensão, sintomas sensitivo-motores prévios e a presença de disautonomia podem ser pistas diagnósticas para uma possível doença de depósito.

A calcificação aórtica degenerativa ocorre em indivíduos idosos com idade >75 anos e pode evoluir com sinais e sintomas de IC. No entanto, tem-se observado em estudo de necropsia, a concomitância de amiloidose cardíaca e estenose aórtica nessa população.13

A apresentação da amiloidose com hipertrofia e disfunção diastólica tem algumas caraterísticas em comum com a estenose aórtica. A concomitância de ATTRwt e estenose aórtica pode ocasionar hipertrofia ventricular acentuada e comprometimento funcional que pode ser confundido com estenose aórtica de baixo fluxo e baixo gradiente. Sinais sugestivos de acometimento amiloide oculto pode levar ao uso mais frequente de marcapasso após procedimentos percutâneos (TAVI) e elevada prevalência de realce tardio avaliado pela ressonância magnética cardíaca (RMC).14

Treibel et al.,14 estudando pacientes com estenose aórtica importante, encontraram prevalência de amiloidose em 6% dos casos, todos com a forma selvagem. Nesses pacientes houve maior mortalidade, cerca de 50%, e os autores sugerem que a cintilografia óssea com tecnécio poderia ser um método complementar de utilidade no diagnóstico de amiloidose e que com um resultado positivo poderia influenciar a real necessidade do tratamento intervencionista e na utilização de terapias específicas para amiloidose. Em nosso grupo, temos observado que alguns pacientes permanecem sintomáticos, a despeito do tratamento intervencionista da valva aórtica, e que na verdade a real etiopatogenia dos sintomas era a concomitância de amiloidose forma ATTRwt.

Depósitos incidentais de amiloidose podem também ser encontrados em estudo histopatológico de pacientes com CMH submetidos a cirurgia de miectomia.15,16

A mutação da TTR pode ser frequente em indivíduos com idade >55 anos com diagnóstico de CMH, particularmente afro-americanos. Foram avaliados 298 pacientes em 9 centros franceses para avaliação sistemática da pesquisa de amiloidose TTR em pacientes com hipertrofia ventricular >15 mm. Foi encontrado genótipo de mutação da ATTRm em 17 pacientes. A prevalência de mTTR foi de 5% e 8,3% nos pacientes com idade >55 anos, respectivamente As mutações encontradas foram: V142I, V50M e I127V. Os pacientes com espessamento ventricular pela mutação da ATTRm eram mais idosos, tinham maior frequência de neuropatia (53%), síndrome do túnel do carpo (46%), baixa voltagem no eletrocardiograma (ECG) (36%), hipertrofia simétrica (92%), alteração da função ventricular esquerda, aumento das pressões de enchimento e realce tardio pelo gadolínio quando comparados aos pacientes sem mutação. Dessa forma, a amiloidose deve ser cogitada no diagnóstico diferencial de pacientes com hipertrofia ventricular e cardiopatia hipertrófica.17Em nosso ambulatório, quatro pacientes inicialmente diagnosticados como CMH na verdade tinham amiloidose ATTRm V142I.

A amiloidose deveria ser suspeitada com as seguintes pistas diagnósticas: história de síndrome de tunel do carpo bilateral em pacientes do sexo masculino, dores neuropáticas inexplicadas, hipotensão ortostática e diagnóstico de CMH após a 6ª década de vida.6

Os exames de imagem (ECO e RMC) contribuem para o reconhecimento da infiltração amiloide cardíaca, pois avaliam a presença e a gravidade da hipertrofia ventricular e da disfunção sistólica e diastólica.18,19 Figura 2 no entanto, estas alterações morfológicas e funcionais representam um quadro avançado da doença e correlacionam-se com a quantidade de amiloide no corpo inteiro.20 Este estágio da doença também está relacionado com piora nos sinais e sintomas clínicos.21

Amiloidose cardíaca - fluxograma diagnóstico.<sup>1</sup> ECO: ecocardiograma; ECG: eletrocardiograma.

Achados ecocardiográficos típicos desta doença são: aumento concêntrico da espessura ventricular com envolvimento do ventrículo direito (VD), função diminuída do eixo longitudinal biventricular com FE preservada e aumento do espessamento valvar22 e a avaliação do fluxo sanguíneo pelo Doppler permite também a identificação da hemodinâmica cardíaca presente na forma restritiva.23,24

Quando se compara as formas de amiloidose cardíaca, observa-se que pacientes com forma ATTRwt caracterizam-se por maior HVE e menor FE e o strain longitudinal é menor nas formas ATTRwt e AL do que nas formas ATTRm.2(Figura 3, 4 e 5)

Imagem obtida a partir da ecocardiografia transtorácica. Corte paraesternal longitudinal evidenciando aumento da espessura miocárdica das paredes septal anterior e lateral inferior de paciente com amiloidose forma AL. Observa-se aspecto brilhante das paredes miocárdicas sugestivas de doença infiltrativa.

Imagem obtida a partir da ecocardiografia transtorácica. Corte apical 4-câmaras evidenciando aumento difuso da espessura das paredes miocárdicas do ventrículo esquerdo. Abaixo, à direita, observa-se imagem paramétrica da avaliação da deformação miocárdica longitudinal pela técnica de speckle tracking. VD: ventrículo direito; VE: ventrículo esquerdo.

Imagem obtida a partir da ecocardiografia transtorácica. Curva espectral do Doppler mitral de paciente com amiloidose evidenciando padrão diastólico do tipo restritivo (relação E/A > 2).

Técnicas mais avançadas do ECO como strain e strain rate derivados do speckle tracking podem auxiliar na avaliação de movimentos cardíacos de torção e facilitar a diferenciação entre amiloidose cardíaca e miocardiopatia hipertrófica. Nos pacientes com amiloidose existe uma variação regional da base para o ápice ao strain longitudinal, onde a porção apical encontra-se preservada, sendo esse padrão acurado e reprodutivo na diferenciação entre amiloidose cardíaca e outras formas de hipertrofia de ventrículo esquerdo (VE).18 Além disso, a análise de strain do VE em repouso é um preditor independente de mortalidade tanto por causas cardíacas, quanto por outras causas.25

A RMC é outro meio de avaliação por imagem que fornece informações sobre função e morfologia cardíaca em pacientes com amiloidose, assim como o ECO.19 No entanto, as informações provenientes da RMC são melhores para avaliar e quantificar as anormalidades na função diastólica dos ventrículos. As imagens provenientes da RMC possibilitam avaliação em 3 dimensões dos volumes cardíacos, espessamento das paredes cardíacas e massa. Além disso, novas técnicas utilizadas pela RMC como o realce tardio com gadolínio são fundamentais na identificação das infiltrações amiloides cardíacas e possibilitam a diferenciação entre um paciente com amiloidose de pacientes com hipertrofia ventricular, como por exemplo, pacientes com hipertensão e CMH. No entanto, o clínico, deve considerar o alto grau de suspeita clínica aliado aos métodos de imagem complementares, pois muitas vezes as características anatômicas da hipertrofia podem simular ambas doenças.26

O padrão assimétrico de hipertrofia miocárdica nos pacientes com amiloidose ATTR difere dos pacientes com forma AL, geralmente simétrico. Em estudo de 263 pacientes com amiloidose ATTR confirmado pela cintilografia miocárdica grau 2 e comparados com 50 pacientes com a forma AL, observou-se: na forma TTR presença de hipertrofia assimétrica em 79% dos casos, simétrica em 18% e 3% sem HVE. O padrão de realce tardio foi 29% subendocárdico e 71% transmural.26

Podemos identificar três fases da evolução da doença pela ressonância com prognóstico variado: fase 1 - sem evidência de realce tardio, mas com aumento do volume extracelular e do mapa T1 com sobrevida de 92% em 24 meses; fase 2 - aumento do volume extracelular e do mapa T1 e aparecimento de realce tardio subendocárdico com sobrevida de 81% e fase 3 - aumento do volume extracelular e do mapa T1 e progressão para realce tardio transmural com sobrevida de 61%. Na análise multivariada a presença de realce tardio transmural aumentou a mortalidade em 4 vezes e o espaço extravascular correlacionou-se com a carga de amiloide e foi um marcador prognóstico independente de sobrevida.19

A cintilografia óssea com tecnécio pode ser útil para diferenciar a forma AL da ATTR. A amiloidose ATTR frequentemente apresenta maior número de microcalcificações, o que justificaria maior intensidade de captação desses radiofármacos. Utilizando um escore visual (0: ausência de captação, 1: captação menor que osso, 2: captação igual ao osso e 3: captação acentuada - mais intensa que a captação óssea) para avaliação da captação cardíaca de tecnécio, é possível diferenciar a forma ATTR dos demais tipos de amiloidose cardíaca em conjunto com a ausência sérica de imunoglobulinas de cadeia leve no sangue e urina. Dessa forma pode-se fechar o diagnóstico de amiloidose ATTR sem a necessidade de biopsia.6

Na Figura 2 observa-se fluxograma para avaliação de pacientes com suspeita de amiloidose cardíaca.

A amiloidose é uma doença de apresentação cardíaca fenotípica heterogênea e em muitos casos há sintomas sistêmicos antecedendo em anos o aparecimento das manifestações cardíacas. Dessa forma, os clínicos devem ter um alto grau de suspeição para poder direcionar os exames complementares e chegar a um correto diagnóstico.

Doença de Fabry

A DF é uma enfermidade genética, de armazenamento lisossômico, que ocasiona deficiência total ou parcial da enzima alfa-galactosidase (α-Gal A) que tem como função a degradação do glicolipídeo globotriaosilceramida (Gb3) nos lisossomos.27 Deste modo, de forma progressiva, ocorrem depósitos do Gb3 nas células endoteliais de vários órgãos e coração, resultando em disfunção orgânica e aparecimento da doença.28 O gene deficiente causador da DF localiza-se no braço longo do cromossomo X (locus Xq22) e, atualmente, centenas de mutações patogênicas já foram descritas.29 Assim, doentes do sexo masculino, homozigotos, desenvolvem a doença clássica, enquanto no sexo feminino, heterozigotos, apresentam manifestações clínicas variáveis, desde condições sem doença clínica aparente até a expressão completa da doença.29-31

Na prática clínica torna-se imprescindível o diagnóstico precoce de pacientes acometidos pela DF, sobretudo pela possibilidade de tratamento específico com a terapia de reposição enzimática (TRE) que alteram o curso natural, reduzindo e/ou estabilizando a progressão da doença.32,33

Do ponto de vista cardiológico, manifestação característica da DF é o achado de HVE e em pacientes que apresentam esta alteração sem uma etiologia definida a DF deve ser sempre considerada no diagnóstico diferencial. Em pacientes com CMH a exclusão da DF é um passo importante já que até 5% destes doentes teriam o diagnóstico de DF. Temos observado em nosso ambulatório, pacientes com DF e aparecimento de hipertrofia em fase adulta, de caráter progressivo, com alterações eletrocardiográficas e ecocardiográficas semelhante às da CMH, inclusive com presença de obstrução de via de saída de VE. À semelhança da amiloidose, existem também manifestações sistêmicas que podem inferir no diagnóstico de DF.34-36

Os depósitos de Gb3 estão presentes em todos os componentes celulares do coração, como cardiomiócitos, células do sistema de condução, fibroblastos valvulares, células endoteliais e células musculares lisas vasculares, porém sua totalidade representa apenas 1% a 2% de toda massa cardíaca, sugerindo que ocorra ativação de outras vias de sinalização que levariam à hipertrofia, apoptose, necrose e fibrose.37

A hipertrofia ventricular de forma concêntrica é a mais comum encontrada na cardiopatia de Fabry, mas aproximadamente 5% dos casos se apresentam como hipertrofia septal assimétrica e a presença de obstrução dinâmica da via de saída do VE é rara, mas pode ocorrer. Embora a HVE tenha sido detectada em algumas crianças, os sinais e sintomas cardiovasculares geralmente estão presentes na terceira ou quarta décadas de vida nos homens e uma década depois nas mulheres.38,39 A presença de HVE leva a uma redução da expectativa de vida em aproximadamente 20 anos em homens e 15 anos em mulheres, quando não tratados, em comparação com a população em geral.40,41

A magnitude da hipertrofia aumenta com a idade e é inversamente relacionada com a função renal e atividade da α-Gal A. O acometimento do VD é comum, mas não ocorrem consequências funcionais ou clínicas.42 As manifestações cardíacas, apesar de acompanharem outras manifestações da DF, podem também ocorrer como única manifestação da doença, conhecida como "variante cardíaca".43

O diagnóstico de hipertrofia miocárdica é feito normalmente pelo ECO, que não apresenta achados considerados patognomônico da DF. A presença do endocárdio hiperrefringente, ou aparência binária da borda do endocárdio, refletindo a compartimentalização dos Gb3 proposta como um marcador da cardiopatia de Fabry foi descrita por Pieroni et al.,44 porém estudos subsequentes demonstraram limitadas sensibilidade (15%-35%) e especificidade (73%-80%).45,46 A disfunção diastólica ocorre mais frequentemente que a sistólica, inclusive sendo identificada de forma precoce e antes do desenvolvimento da hipertrofia, que contribui na detecção de fases subclínicas em que o tratamento específico já poderia ser instituído.47,48 Apesar de ser uma doença de depósito, não é comum a observação do grau restritivo ao ecodoppler.

A fibrose miocárdica, identificada pelo realce tardio do gadolínio na ressonância magnética, é comum na DF,49-51 apresentando-se com padrão não isquêmico, localizada no mesocárdio e poupando o subendocárdio, acometendo os segmentos basal e médio das paredes ântero e ínfero-laterais.52 Entre os homens a fibrose miocárdica ocorre apenas naqueles com hipertrofia ventricular, diferente das mulheres, nas quais a fibrose miocárdica pode ser encontrada mesmo sem o aparecimento desta alteração.38,53

Outros achados são identificados comumente nos pacientes com DF: espessamento e regurgitação discretos das valvas mitral e/ou aórtica e geralmente sem necessidade de cirurgias valvares.37,38,54 Doença coronariana de pequenos vasos manifestada como angina ocorre com frequência em homens e mulheres.55,56 Arritmias atriais, incluindo fibrilação atrial, são comuns e a presença de taquicardia ventricular não sustentada está relacionada à espessura da parede do VE. Anormalidades de condução podem ser causadas pelo depósito glicolipídico no nó atrioventricular (AV), no feixe de His e nos ramos.57,58 Pode-se observar em indivíduos jovens intervalo PR curto.59,60 A disfunção do nó sinusal e os bloqueios AVs resultam em bradiarritmias, muitas vezes com necessidade de implante de marcapasso em pacientes com mais idade. Ao contrário de outras doenças de depósito que apresentam baixas voltagens do complexo QRS ao ECG, a DF determina traçado compatível com hipertrofia ventricular, com presença de aumento da voltagem do complexo QRS e alterações de repolarização ventricular.58,60,61

O diagnóstico definitivo de DF em pacientes do sexo masculino geralmente é confirmado pela medição da atividade de alfa-Gal A de leucócitos.62 No entanto, este ensaio identificará menos de 50% de heterozigotos femininos. Em mulheres com suspeita de DF (e homens com níveis marginais de atividade alfa-Gal A), o teste genético é recomendado.63,64

O tratamento específico para a DF é feito através da TRE que, se iniciado o mais precoce possível, logo que as manifestações cardíacas forem detectadas e embora ainda não tenham evidências estabelecendo efeito sobre os desfechos cardiovasculares, podem prevenir o desenvolvimento da doença nos jovens, e ao menos diminuir a progressão da disfunção dos múltiplos órgãos nos pacientes com maior idade.65-69 (Tabela 1)

Quando devemos suspeitar de doença de Fabry
1. Hipertofia ventricular esquerda inexplicada
• Sexo masculino
• Atípica: concêntrica, médio ventricular ou parede livre
2. Eletrocardiograma
• Intervalo PR curto (< 120 ms)
3. Manifestações clínicas
• Angioqueratoma
• Hipotensão postural, déficit cronotrópico, síncope e/ou vertigens
• Anidrose ou hiperhidrose
4. Demais associações
• Insuficiência renal
• Acidente vascular cerebral
• Córnea verticilata
Doença de depósito de glicogênio

As doenças de depósito de glicogênio são doenças metabólicas hereditárias do metabolismo do glicogênio que pode afetar sua síntese ou degradação nos tecidos musculares, hepáticos e cardíaco.70

A doença de Danon é de caráter autossômico dominante ligada ao comossomo X devido à deficiência da enzima LAMP2 e com a tríade de IC com fenótipo de CMH, miopatia esquelética e retardo mental em pacientes do sexo masculino e apenas miocardiopatia em mulheres.71 O fenótipo da miocardiopatia em geral é hipertrófico, mas há também descrito o dilatado. A miopatia em geral é leve, com fraqueza proximal dos músculos de membros e cervical e estudos de condução nervosa mostram polineuropatia sensorial e motora. Nos pacientes do sexo masculino o retardo mental pode ser observado em metade dos casos e nos do sexo feminino em 10%, com sintomas de leve intensidade.

Testes laboratoriais mostram elevação dos níveis séricos de creatinoquinase de 5 a 10x acima dos limites normais. Os achados eletrocardiográficos são anormais em todos os pacientes, com presença de síndrome de Wolff-Parkinson-White (WPW), voltagem alta nas derivações precordiais, ondas T negativas gigantes, bloqueio AV, flutter atrial, fibrilação atrial, bradicardia, ondas Q anormais e bloqueio completo de ramo esquerdo. O ECO evidencia que a maioria dos pacientes apresenta fenótipo de CMH concêntrica com comprometimento da função ventricular esquerda.71

A síndrome PRKAG2 é uma doença hereditária autossômica dominante rara, caracterizada por hipertrofia cardíaca, pré-excitação ventricular e anormalidades do sistema de condução e risco aumentado de morte súbita.72 É caraterizada pelo aumento do armazenamento de glicogênio e da captação celular de glicose, ao contrário do que ocorre devido a um defeito na degradação de glicogênio. A apresentação clínica é de hipertrofia ventricular e taquiarritmias que podem levar a morte súbita, doença do tecido de condução, hipertrofia miocárdica severa, miopatia esquelética e arritmias, frequentemente relacionadas com síndrome de WPW. Ocasionalmente, pode correr disfunção sistólica do VE e bloqueio AV de alto grau que necessita de implante de marcapasso. O aspecto eletrocardiográfico é de intervalo PR curto em 70% dos casos, bloqueio de ramo direito, bloqueios AVs ou sino-atriais.

A hipertrofia cardíaca pode acometer principalmente o VE, e tem caráter progressivo acompanhado de disfunção sistólica e diastólica com hipertrofia ventricular média de 24 mm. Alta voltagem nos complexos QRS com anormalidades de repolarização ventricular é observada mesmo na ausência de HVE ao ECO.

 Conclusões

Atualmente existem mais de 6.000 doenças raras no mundo. Dentre as que afetam o coração, muitas podem ser subdiagnosticadas, ou até erroneamente confundidas com doenças cardíacas mais comumente vistas na prática clínica, tais como: cardiopatia hipertensiva e CMH. O clínico deve sempre questionar seu diagnóstico e rever seus conceitos, além de uma boa avaliação cardiológica, não deixar de pesquisar presença de sintomas sistêmicos e tentar completar todas as peças do quebra cabeça. Dessa forma, pode-se visualizar, ou até mesmo sugerir o correto diagnóstico e direcionar tratamento específico. Enfatizamos o pensamento de Mark Krane: “A doctor isn’t required to know everything. It’s impossible. But you need to know where to go when you don’t have the answer” - “Um médico não precisa saber tudo. É impossível. Mas você precisa saber para onde ir quando não tem a resposta”.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Editora convidada para este artigo: Dra. Gláucia Maria Moraes de Oliveira

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.