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The Vessels: Focusing on the Aorta
Clinical Therapeutics/Volume 34, Number 4S, 2012
FURTHER READING Flett AS, Hayward MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010;122:138 –144. Iles L, Pfluger H, Phrommintikul A, et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008;52:1574 –1580. Wansapura JP, Hor KN, Mazur W, et al. Left ventricular T2 distribution in Duchenne muscular dystrophy. J Cardiovasc Magn Reson. 2010;12:14. Beer M, Weidemann F, Breunig F, et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. Am J Cardiol. 2006;97:1515–1518. Weidemann F, Niemann M, Sommer C, et al. Females with Fabry’s disease—an interdisciplinary diagnostic and therapeutic challenge [in German]. Med Klin (Munich). 2010;105:627– 634. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119:524 –529. Weidemann F, Niemann M, Herrmann S, et al. A new echocardiographic approach for the detection of non-ischaemic fibrosis in hypertrophic myocardium. Eur Heart J. 2007;28:3020 –3026. Weidemann F, Strotmann JM. Use of tissue Doppler imaging to identify and manage systemic diseases. Clin Res Cardiol. 2008;97:65–73. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J. 2005;26:1221–1227. Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation. 2003;108:1299 –1301. Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010;363:552–563.
The Vessels: Focusing on the Aorta Elie Mousseaux, MD, PhD Department of Cardiovascular Imaging, Institut National de la Santé et de la Recherche Médicale, Paris, France Since accumulation of globotriaosylceramide (GL-3) in lysosomes of parenchymal and interstitial cells in multiple organs of the body is further associated with major storage in endothelial cells and smooth cell proliferation in the arterial media, Fabry disease (FD) has to be considered as a specific vasculopathy.1 Several studies indicate that these vascular lesions occur as a result of vascular dysfunction with major endothelial alteration, modification of perfusion at the basal state and/or in response to stimuli, and prothrombic state due to capillary damage. Although enzyme-replacement therapy has shown significant improvement in clearing the endothelium of stored GL-3, the more complex alterations in vascular function may not be influenced by therapeutic intervention. Using echo Doppler, increased intima-medial thickness has been found within carotid arteries in several studies, but without significant atherosclerotic plaque composed of a combination of fibrous tissue and cholesterol-rich lipids. Concerning endothelial function, authors have suggested that the abnormal vascular response is not nitric oxide dependent, but that the nitric oxide pathway should be downregulated. Since no significant endothelial storage was found in females and atypical cardiac variants are histopathologic findings, smooth muscle cell involvement with stored GL-3 has to be considered as the most prominent and probably as the earliest feature in Fabry arteries. After Barbey et al2 found that Fabry plasma was capable of inducing proliferation of vascular smooth cells and cardiomyocyte hypertrophy, 2 circulating compounds (sphingosine-1 phosphate and lyso-globotriaosylceramide [lyso-Gb-3]) have now been described to induce such proliferation. Despite a marked peripheral artery hypertrophy in patients with FD, only limited data are available on the structural properties of the thoracic aorta. In the recent study by Barbey et al2 in 106 patients with FD from 3 European centers, the diameter of the thoracic aorta was assessed using echocardiography and cardiovascular magnetic resonance imaging (MRI). Aortic dilatation at the sinus of Valsalva was found in 32.7% of males and
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Clinical Therapeutics/Volume 34, Number 4S, 2012 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. In our personal study (submitted), 44 consecutive adult males with FD (mean [SD] age, 38.1 [11.3] years) have been matched for age with 44 healthy male controls; the diameters of the ascending and descending aortas were measured by MRI at the level of the sinuses of Valsalva, sinotubular junction, tubular portion, aortic arch, and descending aorta. Cardiac geometry and properties were also assessed by MRI. We found that dilatation of the ascending aorta was observed in 40.9% of the patients with FD and was predominantly located at the sinuses of Valsalva (mean diameter, 38.2 [4.6] vs 32.4 [3.1] mm; P ⬍ 0.0001). The dilatation was associated with increased left ventricular mass (LVM), independently of age and presence of hypertension. On multivariate analysis, LVM was the main determinant of the sinus diameter (R2 ⫽ 13.6%; P ⬍ 0.05). When assessing the regional remodeling of the ascending aorta by a mean diameter estimated at 3 different levels, both LVM (R2 ⫽ 30.4%; P ⫽ 0.0001) and renal failure (R2 ⫽ 7.3%; P ⫽ 0.0297) were independently associated with aortic dilatation. Thus, dilatation of the ascending aorta has to be further considered as a common finding in male patients with FD, which correlates with left ventricular hypertrophy. This further expands the phenotype expression of FD. REFERENCES 1. Rombach SM, Twickler TB, Aerts JM, et al. Vasculopathy in patients with Fabry disease: current controversies and research directions. Mol Genet Metab. 2010;99:99 –108. 2. Barbey F, Qanadli SD, Juli C, et al. Aortic remodelling in Fabry disease. Eur Heart J. 2010;31:347–353.
Review of Brain-Assessment Techniques Dr. Juan Politei Department of Neurology, Hospital General de Agudos Juan A. Fernandez, Buenos Aires, Argentina Fabry disease is a hereditary deficiency of lysosomal ␣-galactosidase A resulting in the accumulation of globotriaosylceramide in the vascular endothelium and smooth muscle cells. Neurologic manifestations include severe attacks of neuropathic pain and acroparesthesias at the early age and small vessel occlusive disease in adults. Through the findings collected by the Fabry Registry, we now know that cerebrovascular involvement may be present before renal and cardiac manifestations have developed. In many cases, stroke occurs even before the diagnosis Fabry disease is made. Currently, many different brain-assessment techniques are available, such as positron emission tomography, single-photon emission computed tomography, computed tomography, transcranial Doppler, and magnetic resonance imaging (MRI). Transcranial Doppler studies have shown controversial results. We have evaluated all of the brain arteries and the cerebrovascular autoregulation (CVA) in both territories, and our observations were identical to the findings reported by Dr. Hilz’s group: flow velocities in the posterior territory were reduced, and CVA was impaired in both territories. Today, MRI is the most useful assessment method, as part of the initial multidisciplinary examination or performed in patients with symptoms signaling neurologic involvement. The most important features that can be demonstrated by MRI are ischemic and hemorrhagic involvement, pulvinar sign, Arnold-Chiari type I malformation, and vascular disturbances. MRI should be used as an important diagnostic tool and, when the images are interpreted correctly, it can provide clues to the mechanism of damage and allows us to perform further studies and initiate specific treatment.
White Matter Lesions and Brain Vessels Prof. Dr. Andreas Fellgiebel Department of Psychiatry, University of Mainz, Mainz, Germany This presentation demonstrates the association of brain structural imaging findings in Fabry disease with: (1) the underlying pathophysiologic processes; and (2) the neuropsychiatric symptoms of the patients. Structural imaging in Fabry disease reveals a distinctive lesion pattern deriving from different—albeit overlapping—pathomechanisms.
2012
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FURTHER READING Flett AS, Hayward MP, Ashworth MT, et al. Equilibrium contrast cardiovascular magnetic resonance for the measurement of diffuse myocardial fibrosis: preliminary validation in humans. Circulation. 2010;122:138 –144. Iles L, Pfluger H, Phrommintikul A, et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008;52:1574 –1580. Wansapura JP, Hor KN, Mazur W, et al. Left ventricular T2 distribution in Duchenne muscular dystrophy. J Cardiovasc Magn Reson. 2010;12:14. Beer M, Weidemann F, Breunig F, et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. Am J Cardiol. 2006;97:1515–1518. Weidemann F, Niemann M, Sommer C, et al. Females with Fabry’s disease—an interdisciplinary diagnostic and therapeutic challenge [in German]. Med Klin (Munich). 2010;105:627– 634. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation. 2009;119:524 –529. Weidemann F, Niemann M, Herrmann S, et al. A new echocardiographic approach for the detection of non-ischaemic fibrosis in hypertrophic myocardium. Eur Heart J. 2007;28:3020 –3026. Weidemann F, Strotmann JM. Use of tissue Doppler imaging to identify and manage systemic diseases. Clin Res Cardiol. 2008;97:65–73. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease. Eur Heart J. 2005;26:1221–1227. Weidemann F, Breunig F, Beer M, et al. Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation. 2003;108:1299 –1301. Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010;363:552–563.
The Vessels: Focusing on the Aorta Elie Mousseaux, MD, PhD Department of Cardiovascular Imaging, Institut National de la Santé et de la Recherche Médicale, Paris, France Since accumulation of globotriaosylceramide (GL-3) in lysosomes of parenchymal and interstitial cells in multiple organs of the body is further associated with major storage in endothelial cells and smooth cell proliferation in the arterial media, Fabry disease (FD) has to be considered as a specific vasculopathy.1 Several studies indicate that these vascular lesions occur as a result of vascular dysfunction with major endothelial alteration, modification of perfusion at the basal state and/or in response to stimuli, and prothrombic state due to capillary damage. Although enzyme-replacement therapy has shown significant improvement in clearing the endothelium of stored GL-3, the more complex alterations in vascular function may not be influenced by therapeutic intervention. Using echo Doppler, increased intima-medial thickness has been found within carotid arteries in several studies, but without significant atherosclerotic plaque composed of a combination of fibrous tissue and cholesterol-rich lipids. Concerning endothelial function, authors have suggested that the abnormal vascular response is not nitric oxide dependent, but that the nitric oxide pathway should be downregulated. Since no significant endothelial storage was found in females and atypical cardiac variants are histopathologic findings, smooth muscle cell involvement with stored GL-3 has to be considered as the most prominent and probably as the earliest feature in Fabry arteries. After Barbey et al2 found that Fabry plasma was capable of inducing proliferation of vascular smooth cells and cardiomyocyte hypertrophy, 2 circulating compounds (sphingosine-1 phosphate and lyso-globotriaosylceramide [lyso-Gb-3]) have now been described to induce such proliferation. Despite a marked peripheral artery hypertrophy in patients with FD, only limited data are available on the structural properties of the thoracic aorta. In the recent study by Barbey et al2 in 106 patients with FD from 3 European centers, the diameter of the thoracic aorta was assessed using echocardiography and cardiovascular magnetic resonance imaging (MRI). Aortic dilatation at the sinus of Valsalva was found in 32.7% of males and
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Volume 34 Number 4S
Clinical Therapeutics/Volume 34, Number 4S, 2012 5.6% of females; aneurysms were present in 9.6% of males and 1.9% of females. In our personal study (submitted), 44 consecutive adult males with FD (mean [SD] age, 38.1 [11.3] years) have been matched for age with 44 healthy male controls; the diameters of the ascending and descending aortas were measured by MRI at the level of the sinuses of Valsalva, sinotubular junction, tubular portion, aortic arch, and descending aorta. Cardiac geometry and properties were also assessed by MRI. We found that dilatation of the ascending aorta was observed in 40.9% of the patients with FD and was predominantly located at the sinuses of Valsalva (mean diameter, 38.2 [4.6] vs 32.4 [3.1] mm; P ⬍ 0.0001). The dilatation was associated with increased left ventricular mass (LVM), independently of age and presence of hypertension. On multivariate analysis, LVM was the main determinant of the sinus diameter (R2 ⫽ 13.6%; P ⬍ 0.05). When assessing the regional remodeling of the ascending aorta by a mean diameter estimated at 3 different levels, both LVM (R2 ⫽ 30.4%; P ⫽ 0.0001) and renal failure (R2 ⫽ 7.3%; P ⫽ 0.0297) were independently associated with aortic dilatation. Thus, dilatation of the ascending aorta has to be further considered as a common finding in male patients with FD, which correlates with left ventricular hypertrophy. This further expands the phenotype expression of FD. REFERENCES 1. Rombach SM, Twickler TB, Aerts JM, et al. Vasculopathy in patients with Fabry disease: current controversies and research directions. Mol Genet Metab. 2010;99:99 –108. 2. Barbey F, Qanadli SD, Juli C, et al. Aortic remodelling in Fabry disease. Eur Heart J. 2010;31:347–353.
Review of Brain-Assessment Techniques Dr. Juan Politei Department of Neurology, Hospital General de Agudos Juan A. Fernandez, Buenos Aires, Argentina Fabry disease is a hereditary deficiency of lysosomal ␣-galactosidase A resulting in the accumulation of globotriaosylceramide in the vascular endothelium and smooth muscle cells. Neurologic manifestations include severe attacks of neuropathic pain and acroparesthesias at the early age and small vessel occlusive disease in adults. Through the findings collected by the Fabry Registry, we now know that cerebrovascular involvement may be present before renal and cardiac manifestations have developed. In many cases, stroke occurs even before the diagnosis Fabry disease is made. Currently, many different brain-assessment techniques are available, such as positron emission tomography, single-photon emission computed tomography, computed tomography, transcranial Doppler, and magnetic resonance imaging (MRI). Transcranial Doppler studies have shown controversial results. We have evaluated all of the brain arteries and the cerebrovascular autoregulation (CVA) in both territories, and our observations were identical to the findings reported by Dr. Hilz’s group: flow velocities in the posterior territory were reduced, and CVA was impaired in both territories. Today, MRI is the most useful assessment method, as part of the initial multidisciplinary examination or performed in patients with symptoms signaling neurologic involvement. The most important features that can be demonstrated by MRI are ischemic and hemorrhagic involvement, pulvinar sign, Arnold-Chiari type I malformation, and vascular disturbances. MRI should be used as an important diagnostic tool and, when the images are interpreted correctly, it can provide clues to the mechanism of damage and allows us to perform further studies and initiate specific treatment.
White Matter Lesions and Brain Vessels Prof. Dr. Andreas Fellgiebel Department of Psychiatry, University of Mainz, Mainz, Germany This presentation demonstrates the association of brain structural imaging findings in Fabry disease with: (1) the underlying pathophysiologic processes; and (2) the neuropsychiatric symptoms of the patients. Structural imaging in Fabry disease reveals a distinctive lesion pattern deriving from different—albeit overlapping—pathomechanisms.
2012
e9