Differential diagnosis of left ventricular hypertrophy: usefulness of multimodality imaging and tissue characterization with cardiac magnetic resonance

Differential diagnosis of asymmetrical left ventricular hypertrophy may be challenging, particularly in patients with history of hypertension. A middle‐aged man underwent an echocardiographic examination during workup for hypertension, which unexpectedly showed significant asymmetrical septal hypertrophy and raised suspicion for hypertrophic cardiomyopathy. Cardiovascular magnetic resonance confirmed the asymmetrical hypertrophy. No myocardial late gadolinium contrast enhancement was seen. However, precontrast T1 mapping revealed a low native myocardial T1 value. This was highly suggestive of Anderson‐Fabry disease, which was subsequently proved with very low alpha galactosidase enzyme levels and mutation analysis. The case illustrates clinical usefulness of multimodality imaging and the novel tissue characterization techniques for assessment of left ventricular hypertrophy.     

Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study

This study reviews the clinical and echocardiographic findings in a cohort of Fabry patients (n=12) and compares echocardiographic findings to normal controls. Almost all patients had extracardiac manifestations. Five out of 12 patients had cardiovascular symptoms. Nine out of 12 patients had left ventricular hypertrophy (LVH) on the electrocardiogram (ECG) and one patient had short PR interval. Three patients had epicardial coronary disease. Four patients had 'rat-tail' appearance on left ventriculogram. Six patients who had myocardial biopsy showed extensive vacuolation of the myocytes on light microscopy and concentric, myelinoid lamellar cytoplasmic inclusion bodies on electron microscopy. On echocardiography, LV mass was significantly increased in the Fabry group compared to normal controls. Traditional parameters of diastolic function including peak E velocity, peak A velocity and deceleration time were no different to normal controls. The IVRT was significantly prolonged in the Fabry subjects. The PV atrial reversal duration exceeded that of mitral A wave duration in the Fabry group. The septal E' velocity with Doppler tissue imaging (DTI) was significantly lower in the Fabry group than the normal controls. Fabry disease should be considered in the differential diagnosis in patients with unexplained LVH and late onset hypertrophic cardiomyopathy. Extracardiac manifestations are common.     

Apical Left Ventricular Hypertrophy and Mid‐Ventricular Obstruction in Fabry Disease

We report the case of a rare cardiac presentation of Fabry disease. Although concentric left ventricular hypertrophy is a major cardiac finding in Fabry disease, there is no case report of dynamic obstruction at mid‐left ventricular level. We describe a 59‐year‐old‐woman suffering from a severe form of Fabry disease, mimicking an apical hypertrophic cardiomyopathy with mid‐ventricular obstruction. Differentiation of Fabry disease from hypertrophic cardiomyopathy is crucial given the therapeutic and prognostic differences. Fabry disease should always be suspected in an adult, independently of the pattern of left ventricular hypertrophy.     

Histopathological evidence of Fabry disease in a female patient with left ventricular noncompaction

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase gene. The most frequent cardiac presentation of Fabry disease is cardiomyopathy characterized by left ventricular (LV) hypertrophy, usually concentric.Heart disease in affected females tends to be clinically recognized later than in males and cardiac complications are the most frequently reported cause of death in females with Fabry disease. There are few data regarding the association between Fabry disease and LV noncompaction. We report a case of a 30-year-old asymptomatic woman, heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X), who presented LV noncompaction on cardiac magnetic resonance imaging, without LV wall hypertrophy. Histopathological examination of myocardial fragments showed marked deposition of glycosphingolipids in cardiomyocytes, confirming the diagnosis of Fabry cardiomyopathy. Based on this finding, the patient was proposed for enzyme replacement therapy. This case illustrates the role of endomyocardial biopsy in the clarification of doubtful or atypical findings related to cardiac Fabry disease, even in heterozygous women, and corroborates the contention that Fabry disease should be included in the differential diagnosis of LV hypertrabeculation/noncompaction.     

Fabry disease: percutaneous transluminal septal myocardial ablation markedly improved symptomatic left ventricular hypertrophy and outflow tract obstruction in a classically affected male

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disease in which left ventricular hypertrophy (LVH) is common, and if severe, may mimic hypertrophic obstructive cardiomyopathy. Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) has been used as a safe and effective method to alleviate LVH obstruction in patients with hypertrophic obstructive cardiomyopathy (HCM). We describe a case of a classically affected Fabry 53-year-old male with symptomatic HCM (NYHA class III with exertional angina) who was treated with PTSMA. The procedure safely and effectively alleviated symptomatic left ventricular outflow tract obstruction at long-term follow-up, and the patient's NYHA classification was reduced to NYHA class I to II.     

Enfermedad relacionada con IgG4 con posible afectación miocárdica

IgG4-related disease is characterized by mass lesions, a dense lymphoplasmacytic infiltrate with immunohistochemical positivity for IgG4, storiform fibrosis and, frequently, elevated serum IgG4 levels. It can be multisystemic; however, myocardial involvement, which is objectively determined by imaging tests, has not been described in the medical literature. We report the case of a man with IgG4-related disease with possible myocardial involvement, detected by cardiac magnetic resonance. This raises the question of a differential diagnosis with other diseases such as sarcoidosis and Fabry disease, the differential diagnosis of which is of great importance due to its therapeutic impact.     

Tissue Doppler imaging in Fabry disease

PURPOSE OF REVIEW: The development of effective enzyme replacement/enhancement therapy makes of clinical relevance considering Fabry disease in the differential diagnosis of patients with hypertrophic cardiomyopathy. In particular the opportunity to significantly modify the clinical progression of the disease has reinforced the need for early diagnosis of Fabry cardiomyopathy. RECENT FINDINGS: The study with tissue Doppler of Fabry patients with endomyocardial biopsy-proven cardiac involvement showed a reduction of both diastolic and systolic myocardial velocities recorded at septal and lateral corners of mitral annulus. Tissue Doppler abnormalities were present not only in patients with left ventricular hypertrophy but also in younger patients with normal cardiac wall thickness and represent the first sign of myocardial damage. Furthermore tissue Doppler studies have been shown useful in detecting cardiac involvement in female carriers with no systemic manifestations of Fabry disease. In patients already submitted to enzyme-replacement therapy tissue Doppler and strain rate imaging represent useful noninvasive tools in assessing treatment efficacy. SUMMARY: Tissue Doppler imaging can provide early detection of cardiac involvement in Fabry disease and represents the most accurate and sensitive noninvasive tool for the diagnosis of myocardial dysfunction and for the assessment of cardiac improvement during enzyme replacement therapy. The detection of tissue Doppler abnormalities in female carriers may represent a hint for an invasive assessment of cardiac involvement.     

Determination of left ventricular volume, ejection fraction, and myocardial mass by real-time three-dimensional echocardiography

Reconstructed three-dimensional (3-D) echocardiography is an accurate and reproducible method of assessing left ventricular (LV) functions. However, it has limitations for clinical study due to the requirement of complex computer and echocardiographic analysis systems, electrocardiographic/respiratory gating, and prolonged imaging times. Real-time 3-D echocardiography has a major advantage of conveniently visualizing the entire cardiac anatomy in three dimensions and of potentially accurately quantifying LV volumes, ejection fractions, and myocardial mass in patients even in the presence of an LV aneurysm. Although the image quality of the current real-time 3-D echocardiographic methods is not optimal, its widespread clinical application is possible because of the convenient and fast image acquisition. We review real-time 3-D echocardiographic image acquisition and quantitative analysis for the evaluation of LV function and LV mass.     

Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy

Background

Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.

Electrophysiological study in a patient with Fabry disease and a short PQ interval.

A short PQ interval is a common finding in patients with Fabry disease. However, there have been few electrophysiological studies in Fabry disease, and it is not clear whether the short PQ interval that is present in this disease results from preexcitation or enhanced atrioventricular nodal conduction. We present a case of a 43-year-old man with syncope, sick sinus syndrome, a PQ interval of 80 ms, and palpitations. Electrophysiological study showed PA, AH, and HV intervals of 24, 32, and 34 ms, respectively, and features of enhanced atrioventricular nodal conduction. The presence of an atrioventricular accessory pathway was excluded. We conclude that the short PQ interval in Fabry disease can result from accelerated conduction in the atrioventricular node.     

Detection of preclinical left ventricular dysfunction in Fabry disease: the contribution of tissue Doppler.

INTRODUCTION: Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase, which results in progressive intracellular accumulation of glycosphingolipids in various tissues. Cardiac involvement is frequent, with left ventricular (LV) hypertrophy (concentric, apical or asymmetric septal) as the most common finding. Evaluating LV systolic dysfunction with conventional echocardiography is not sufficiently sensitive to detect impaired myocardial function early in the course of the disease. Doppler myocardial imaging can quantify changes in global and regional longitudinal myocardial function with great precision. AIM: To identify parameters of cardiac dysfunction in patients with Fabry disease with no cardiac symptoms using conventional or Doppler echocardiography and tissue Doppler (including tissue tracking, strain and strain rate). METHODS: Four patients with Fabry disease (3 female; mean age 47 +/- 17 years) and 29 healthy controls (19 female and 10 male; mean age 38 +/- 14 years) were studied with conventional echocardiography and tissue Doppler imaging using a Vivid 7 scanner. The following parameters were measured: LV dimensions, ejection fraction (using Simpson's rule), systolic and diastolic velocities and tissue tracking of the mitral annulus at six sites (apical views). LV peak systolic strain and strain rate were obtained in 12 segments from apical views. RESULTS: Two patients had LV hypertrophy (one concentric and one apical). Diastolic impairment was detected in three patients by reduced flow propagation velocity of early transmitral flow (Vp) and E/Vp ratio. Mitral annulus systolic velocities were lower in Fabry disease than in the controls. Peak systolic strain and strain rate were diminished in all segments in three patients, showing impaired myocardial systolic function. The results are presented for each of the four patients. CONCLUSIONS: In patients with Fabry disease, with no cardiac symptoms and normal LV systolic function on conventional echocardiography, diastolic dysfunction was detected by Vp and E/Vp ratio regardless of LV hypertrophy. However, tissue Doppler imaging was able to detect impaired myocardial systolic function, particularly in patients with LV hypertrophy.     

Simple criteria for differentiation of Fabry disease from amyloid heart disease and other causes of left ventricular hypertrophy

AIMS: Fabry disease may be difficult to differentiate from other causes of left ventricular hypertrophy such as other myocardial storage diseases (including amyloidosis), hypertrophic cardiomyopathy (HCM), or hypertensive heart disease (HHD). We sought to determine simple criteria to best differentiate the above mentioned cardiac diseases. METHODS AND RESULTS: All patients in a six-year time period with left ventricular hypertrophy due to Fabry disease (13 patients), biopsy proven cardiac amyloidosis (16 patients), non-obstructive HCM (17 patients), and 22 randomly selected patients with advanced HHD were compared. Retrospective analysis of clinical characteristics, findings of electrocardiogram (ECG) and echocardiography by blind review was performed. RESULTS: No single clinical characteristic or findings of ECG or echocardiography could reliably differentiate between the various diseases. Increased echogenicity/granular sparkling, valvular abnormalities, abnormal renal function, and diastolic function were not helpful discriminators. In a univariate analysis, four criteria (acroparesthesia, anhydrosis, absence of hypertension and presence of Sokolow criteria for left ventricular hypertrophy in the ECG) were significant for Fabry disease. By logistic regression analysis, the following most suitable discriminative parameters were identified: hypertension in HHD (specificity 82%), orthostasis and/or pericardial effusion for amyloidosis (specificity 93%), papillary muscle anomaly in non-obstructive HCM (specificity 92%), and Fabry disease if neither hypertension orthostatis, pericardial effusion nor a papillary muscle anomaly was present (specificity 87%). CONCLUSION: A combination of symptoms, echocardiographic findings and ECG in unexplained left ventricular hypertrophy may help to differentiate amyloidosis, non-obstructive HCM and hypertensive heart disease from Fabry disease. The results of this preliminary study will have to be confirmed in a prospective study.     

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.     

Morbus Fabry of the heart. Why should cardiologists care?

Summary Fabry Disease is an X-linked lysosomal storage disorder leading to the accumulation of glycosphingolipids, mainly globotriaosylceramides in all tissues and solid organs of the body. The disease was described by Johannes Fabry and William Anderson coevally in 1898. Beside the involvement of the central nervous system, peripheral nerves, kidneys, skin and endovascular endothelium, the heart plays a major role in the disease. Left ventricular hypertrophy is one hallmark initially presenting with preserved ventricular function. However, with progression of the disease patients die due to heart failure. Though angina is often reported, the incidence of epicardial coronary stenosis is not a dominant feature, if at all small vessel disease can occur. In respect of arrhythmias a broad spectrum can be seen including shortened or prolonged PR-intervals, AV blocks of different degrees and sometimes malignant ventricular arrhythmias. In the past, women were considered to be carriers of the disease but hardly to develop clinical symptoms. In recent years there is evidence that female carriers may more often be affected with severe symptoms. In addition, a group of Fabry patients displaying mainly cardiac involvement were described as having a cardiac variant of the disease. This implied the hypothesis that some of those patients with unexplained myocardial hypertrophy do suffer from Fabry disease. Since 2002 enzyme replacement therapy is available and there is first evidence for its efficacy to reduce hypertrophy and increase myocardial function. If this is associated with a prognostic improvement has to be determined in future studies.     

Fabry disease in patients with hypertrophic cardiomyopathy (HCM)

Fabry disease is an X-linked recessive lysosomal storage disorder with variable phenotype characterized by the accumulation of glycosphingolipid in various tissues. Unlike patients with the classical systemic Fabry disease entity, who present with multiple organ involvement, patients with a cardiac variant of Fabry disease are characterized mainly by myocardial hypertrophy. Therefore, the cardiac variant of Fabry disease may be defined as a cardiomyocytic storage disorder, thus, mimicking the clinical features of hypertrophic obstructive and especially non-obstructive cardiomyopathy. In patients with unexplained left ventricular hypertrophy the diagnosis of a cardiac variant of Fabry disease is performed by light- and electron microscopic evaluation of endomyocardial catheter biopsy specimens and/or serologic investigations (decreased activity of alpha-galactosidase A in plasma or leucocytes). Several studies show that between 4% and 8% of unselected patients with the clinical features of hypertrophic non-obstructive cardiomyopathy have a cardiac variant of Fabry disease. In each patient with unexplained myocardial hypertrophy concealed myocardial storage disease, especially cardiac Fabry disease has to be considered and should be ruled out or confirmed by endomyocardial catheter biopsy. This is important because of the recently reported alpha-galactosidase A enzyme replacement therapy in Fabry disease. Randomized, multicenter studies are mandatory to test the hypothesis that enzyme replacement therapy leads to a beneficial clinical effect in the cardiac variant form of Fabry disease and may prevent the progression of the disease in asymptomatic patients.     

A new echocardiographic approach for the detection of non-ischaemic fibrosis in hypertrophic myocardium.

AIMS: Regional myocardial fibrosis detected by magnetic resonance imaging (MRI) using late enhancement (LE) indicates an unfavorable prognosis. We investigated in a prospective study whether regional non-ischaemic fibrosis in hypertrophic myocardium can also be detected by ultrasonic strain-rate imaging based on specific visual features of the myocardial deformation traces. METHODS AND RESULTS: This diagnostic study aimed to define left ventricular fibrotic segments in 30 patients with hypertrophic cardiomyopathy (n = 10), severe aortic valve stenosis (n = 10), Fabry disease cardiomyopathy (n = 10), and 10 healthy controls. MRI and strain-rate imaging (=deformation imaging) was performed in all patients and controls to detect LE. In total, 42 segments showed LE according to MRI criteria. Using strain-rate imaging, all LE positive segments displayed a characteristic pattern consisting of a first peak in early systole followed by a rapid fall in strain rate close to zero and a second peak during isovolumetric relaxation. This 'double peak sign' was never seen in segments of healthy controls. However, it was detected in 10 segments without LE. These 'false-positive' segments belonged to Fabry patients who often develop a fast progressing fibrosis. In a follow-up MRI study after 2 years (available for 6/10 segments), all these segments had developed LE. CONCLUSION: The 'double peak sign' in strain-rate imaging tracings seems to be a reliable tool to diagnose regional fibrosis.     

Echocardiographic evaluation of systolic and diastolic function in patients with cardiac amyloidosis

The typical appearance of cardiac amyloidosis using standard echocardiographic techniques is usually a late finding only in patients with relatively advanced stages of the disease. Early noninvasive identification of cardiac amyloidosis is of growing clinical importance. Newer echocardiographic techniques, including tissue Doppler imaging and deformation imaging (strain rate imaging and 2-dimensional speckle tracking), are powerful tools for quantifying regional myocardial motion and deformation. Using these advanced techniques, early functional impairment in cardiac amyloidosis may be detectable when the results of standard echocardiography are still normal or inconclusive. This review provides a comprehensive overview of the different echocardiographic approaches for the assessment of systolic and diastolic function in patients with cardiac amyloidosis. Special attention is paid to regional myocardial function assessed by tissue Doppler imaging, strain rate imaging, and 2-dimensional speckle-tracking imaging.     

Early Diagnosis of Right Ventricular Systolic Dysfunction by Tissue Doppler-Derived Isovolumic Myocardial Acceleration in Patients with Chronic Obstructive Pulmonary Disease

Objectives: The aim of the study was to assess validity of tissue Doppler imaging (TDI)-derived right ventricular (RV) myocardial systolic velocities in early detection of RV systolic dysfunction in chronic obstructive pulmonary disease (COPD). Methods: Ninety COPD patients (50 pure COPD and 40 with right heart failure [RHF]) and 40 controls were enrolled. Respiratory function tests, conventional echocardiographic parameters, and TDI-derived isovolumic myocardial acceleration (IVA), peak myocardial velocity during isovolumic contraction (IVV), peak velocity during systolic ejection (Sa) were measured. Results: All the TDI-derived RV systolic velocities were impaired in COPD (P = 0.0001) compared to controls. IVA was the only parameter that could distinguish the patients with pure COPD and COPD with RHF (P = 0.0001). IVA was found to be significantly correlated with FEV1 (r = 0.41, P = 0.0001), FEV1/FVC (r = 0.43, P = 0.0001), pulmonary artery pressure (r =−0.34, P = 0.001), pulmonary flow acceleration time (r = 0.48, P = 0.0001), and tricuspid annular systolic excursion (r =−0.41, P = 0.0001). In addition, IVA ≤ 2.7 m/sec² was able to predict COPD patients from controls with 81% sensitivity, 98% specificity and IVA ≤ 1.9 m/sec² predicted COPD patients accompanied by RHF with 82% sensitivity, 77% specificity from patients without RHF. Conclusions: TDI-derived RV IVA is a novel, noninvasive echocardiographic index which may be used in the assessment of subclinical RV dysfunction in patients with COPD.     

Transient global left ventricular dysfunction in a localized myocardial infarction related to occlusion of the distal left anterior descending artery

In some patients with acute myocardial infarction (MI), wall motion in the noninfarcted area declines globally despite localized myocardial damage. In most, an infarct-related lesion is the proximal part of the left anterior descending artery (LAD). Previous studies have reported that hypokinesis of remote myocardium may be related to multivessel disease, impaired coronary flow, or coronary flow reserve in nonculprit arteries. This report describes the case of a 53-year-old man who presented with severe global left ventricular (LV) dysfunction after an acute MI associated with distal LAD occlusion. Follow-up echocardiographic examination revealed nearly normalized LV function 5 days after the episode. We discuss a plausible mechanism of dysfunction of noninfarcted myocardium.     

New application of myocardial antimyosin scintigraphy: diagnosis of myocardial disease in polymyositis.

Heart disease is a rare but important complication of polymyositis. Diagnosis of myocardial disease is usually based on non-specific clinical, electrocardiographic, and echocardiographic data. This paper reports a case of polymyositis with myocardial disease diagnosed by myocardial imaging with radiolabelled antibody to myosin, a specific marker of the necrotic myocardial fibre.