European Heart Journal – Cardiovascular Imaging (2016) 17, 1248–1249 doi:10.1093/ehjci/jew169
EDITORIAL
Another piece in the puzzle of bicuspid aortic valve syndrome Stefano Nistri 1*, Betti Giusti 2, Guglielmina Pepe 2, and Filippo Cademartiri3,4 1 Cardiology Service, CMSR Veneto Medica, Via Vicenza 204, 36077 Altavilla Vicentina, Italy; 2Department of Experimental and Clinical Medicine, University of Florence—Regional (Tuscany) Referral Center for Marfan Syndrome and Related Disorders, Careggi Hospital, Firenze, Italy; 3Department of Radiology, Montreal Heart Institute, Universite` de Montreal, Montreal, Canada; and 4Department of Radiology, Erasmus Medical Center University, Rotterdam, The Netherlands
Online publish-ahead-of-print 7 August 2016
Bicuspid aortic valve (BAV) is a syndrome whose natural history is determined by valvular impairment (congenital or acquired) and/ or increased prevalence of aortic abnormalities ranging from reduced aortic elasticity to aortic dilatation/aneurysm [thoracic aortic aneurysm (TAA)] and dissection. Familial clustering has been documented in up to 20 –30% of patients with isolated BAV, supporting the notion of a relevant genetic background in BAV and highlighting the need for screening first-degree relatives of BAV patients.1 Schnell et al. 2 describe the 4D flow cardiovascular magnetic resonance (CMR) findings in 24 BAV relatives (mostly first-degree relatives) with trileaflet aortic valves and normal aortic size, in comparison with those obtained in 15 age-matched healthy individuals. A higher prevalence of cubic and gothic shaped aortas was found in BAV relatives, which were also associated with a significantly higher incidence of vortices in the ascending aortas of BAV relatives than in controls. This small study generates new intriguing perspectives. To date, there are two main pathogenetic hypotheses of BAV-related aortopathy, i.e. the haemodynamic and the genetic ones.3 Flow abnormalities have been attributed to the inherently dysfunctioning BAV shape, and the critical blood flow pattern in the ascending aorta of BAV patients is considered to be responsible for the development and progression of aneurysm. Schnell et al. show that abnormal flow in the ascending aorta may not be solely due to abnormal valvular shape or to aortic dilatation, suggesting a relationship between aortic shape and vortices in BAV relatives with trileaflet aortic valve and normally sized thoracic aorta. Functional and dimensional abnormalities of the ascending aorta have been previously reported in BAV relatives,4 and some data suggested that BAV and TAA may be independent manifestations of a single gene defect.5 Thus, individuals with normally functioning and normally shaped aortic valve, with normally sized but abnormally shaped thoracic aorta causing abnormal flow vortices, might be one end of a spectrum of an heritable condition having BAV in association with TAA at the other end, with patients with isolated BAV or TAA somewhere between these extremities. Unfortunately,
Schnell et al. could not derive data on aortic compliance due to limited spatial resolution of 4D flow data. Since abnormal stiffness is a recognized and independent feature of BAV aortopathy in patients6 and in BAV relatives,4 the phenotype described by Schnell et al. lacks information regarding load-bearing characteristics of the aortic wall in their BAV relatives, hindering any consideration on its relation with shape and vortices. Nonetheless, on the basis of these findings, the above-mentioned hypotheses (i.e. haemodynamic and genetic) should no longer be considered as separated or even contradictory. Flow abnormalities may in fact be an early functional equivalent of abnormal aortic shape in some BAV relatives or may be an environmental factor interacting with the genetic background of the dilated/aneurismal aorta of BAV patients. Consistently with the endophenotypic character and the clinical heterogeneity of BAV and TAA, a univocal genetic interpretation of BAV syndrome is lacking.1,7 Moreover, although BAV often displays an autosomal dominant pattern of inheritance with incomplete penetrance and variable expressivity, the increased prevalence of BAV in males and in patients with Turner syndrome (along a spectrum of aortic valve morphology) underscores the potential of X-linked transmission in this disease.8 Other limitations of the study by Schnell et al. resides in the small number of families studied due to the fact that the largest number of subjects comes from one family and that there are a lot of missing information on familial subjects. Therefore, the familial character of BAV cannot be ascertained in most families. Thus, showed pedigrees confirm the acknowledged difficulties in attributing a pattern of inheritance to BAVs and precludes the generalizability of the present findings to the common BAV syndrome. Schnell et al. utilized an advanced method for studying the thoracic aorta, an approach to date confined for research purposes. Although transthoracic echocardiography plays a pivotal role in clinical detection and follow-up studies of patients with BAV and/or TAA, cardiovascular computed tomography and CMR are the elective techniques for the quantitative and semi-quantitative assessment of the entire thoracic aorta, including the aortic valve and the aortic
The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association, or the European Society of Cardiology.
* Corresponding author. Tel: +39 0444225111; Fax: +39 0444225199. E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
1249
Editorial
root in clinical practice. Even though the two techniques have been used for a long time and their technological development have been continuous until today, we still tend to use them in a very basic way. Unfortunately, it is not unusual to verify the tendency to measure the thoracic aorta on non-axial planes, although there is consensus on the fact that at least we should perform measurements in anatomically defined landmarks, always on ECG-synchronized images, perpendicular to the main axis of the vessel. This methodological aspect may be particularly relevant especially in serial assessments. The study by Schnell et al. underscores that considerations about flow patterns depending on anatomical pre-conditions are very important suggesting that, in the future, a proper definition of the aortic phenotype should include the aortic size as well as its shape. However, we should remind that extensive epidemiological studies of thoracic aorta phenotypes have not been performed. For instance, the largest series considering aortic size as endpoint have been performed on individuals undergoing calcium scoring assessment for primary prevention.9,10 Even in these large series (.4000 individuals), the correlation between the size of the ascending aorta and age, gender, and body surface area were present but weak and with large standard deviations/confidence intervals. We miss a thorough and comprehensive epidemiological assessment of aortic phenotypes, which we understand only marginally. The impact of different phenotypes such as cubic or gothic shapes of the aortic arch on 4D flow pattern is surely a step ahead, which adds up to the pathophysiological understanding of potential development of complications.11 From a clinical point of view, the study of Schnell et al., despite its limitations, confirms some practical implications. When studying BAV relatives, the clinical cardiologist should not only carefully check for aortic valve morphology by echocardiography, seeking all the spectrum of aortic valve malformations,8 but should also perform a very careful scrutiny of the entire thoracic aorta, including the arch, with accurate measurement of the aortic size and also looking for associated congenital heart diseases (e.g. aortic coarctation, patent ductus arteriosus). Consistently, when this focused visualization of the aortic root and aortic valve would be technically
inadequate by transthoracic echocardiography, cardiac computed tomography /CMR should be considered.8 Schnell et al. should be commended for adding a new piece in the mosaic of BAV syndrome underscoring that a great effort must be performed by the researchers in the future to better comprehend this complex genetic trait, including subjects with different phenotypes, outcomes, and prognoses, caused by the interaction among different genetic backgrounds and non-genetic factors, and that a personalized approach to each BAV patient and her/his family should be pursued by the clinical cardiologist in team with imaging experts and genetists.
References 1. Pepe G, De Cario R, Sticchi E, Giusti B, Abbate R, Gensini G et al. Bicuspid aortic valve syndrome and fibrillinopathies: potential impact on clinical approach. Int Cardiovasc Forum J 2015;1:167 – 74. 2. Schnell S, Smith DA, Barker AJ, Entezari P, Honarmand AR, Carr ML et al. Altered aortic shape in bicuspid aortic valve relatives influences blood flow patterns. Eur Heart J Cardiovasc Imaging 2016;17:1239 –47. 3. Mahadevia R, Barker AJ, Schnell S, Entezari P, Kansal P, Fedak PW et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation 2014;129:673 –82. 4. Biner S, Rafique AM, Ray I, Cuk O, Siegel RJ, Tolstrup K. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol 2009;53:2288 –95. 5. Loscalzo ML, Goh DLM, Loeys B, Kent KC, Spevak PJ, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A 2007;143:1960 –7. 6. Nistri S, Grande-Allen J, Noale M, Basso C, Siviero P, Maggi S et al. Aortic elasticity and size in bicuspid aortic valve syndrome. Eur Heart J 2008;29:472 –9. 7. Padang R, Bannon PG, Jeremy R, Richmond DR, Semsarian C, Vallely M et al. The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity. Ann Cardiothorac Surg 2013;2:83 –91. 8. Olivieri LJ, Baba RY, Arai AE, Bandettini WP, Rosing DR, Bakalov V et al. Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome. Circ Cardiovasc Imaging 2013;6:1018 –23. 9. Ka¨lsch H, Lehmann N, Mo¨hlenkamp S, Becker A, Moebus S, Schmermund A et al. Body-surface adjusted aortic reference diameters for improved identification of patients with thoracic aortic aneurysms: results from the population-based Heinz Nixdorf Recall study. Int J Cardiol 2013;163:72 –8. 10. Wolak A, Gransar H, Thomson LE, Friedman JD, Hachamovitch R, Gutstein A et al. Aortic size assessment by noncontrast cardiac computed tomography: normal limits by age, gender, and body surface area. JACC Cardiovasc Imaging 2008;1:200 –9. 11. Dyverfeldt P, Bissell M, Barker AJ, Bolger AF, Carlha¨ll CJ, Ebbers T et al. 4D flow cardiovascular magnetic resonance consensus statement. J Cardiovasc Magn Reson 2015;10:17–72.
EDITORIAL
Another piece in the puzzle of bicuspid aortic valve syndrome Stefano Nistri 1*, Betti Giusti 2, Guglielmina Pepe 2, and Filippo Cademartiri3,4 1 Cardiology Service, CMSR Veneto Medica, Via Vicenza 204, 36077 Altavilla Vicentina, Italy; 2Department of Experimental and Clinical Medicine, University of Florence—Regional (Tuscany) Referral Center for Marfan Syndrome and Related Disorders, Careggi Hospital, Firenze, Italy; 3Department of Radiology, Montreal Heart Institute, Universite` de Montreal, Montreal, Canada; and 4Department of Radiology, Erasmus Medical Center University, Rotterdam, The Netherlands
Online publish-ahead-of-print 7 August 2016
Bicuspid aortic valve (BAV) is a syndrome whose natural history is determined by valvular impairment (congenital or acquired) and/ or increased prevalence of aortic abnormalities ranging from reduced aortic elasticity to aortic dilatation/aneurysm [thoracic aortic aneurysm (TAA)] and dissection. Familial clustering has been documented in up to 20 –30% of patients with isolated BAV, supporting the notion of a relevant genetic background in BAV and highlighting the need for screening first-degree relatives of BAV patients.1 Schnell et al. 2 describe the 4D flow cardiovascular magnetic resonance (CMR) findings in 24 BAV relatives (mostly first-degree relatives) with trileaflet aortic valves and normal aortic size, in comparison with those obtained in 15 age-matched healthy individuals. A higher prevalence of cubic and gothic shaped aortas was found in BAV relatives, which were also associated with a significantly higher incidence of vortices in the ascending aortas of BAV relatives than in controls. This small study generates new intriguing perspectives. To date, there are two main pathogenetic hypotheses of BAV-related aortopathy, i.e. the haemodynamic and the genetic ones.3 Flow abnormalities have been attributed to the inherently dysfunctioning BAV shape, and the critical blood flow pattern in the ascending aorta of BAV patients is considered to be responsible for the development and progression of aneurysm. Schnell et al. show that abnormal flow in the ascending aorta may not be solely due to abnormal valvular shape or to aortic dilatation, suggesting a relationship between aortic shape and vortices in BAV relatives with trileaflet aortic valve and normally sized thoracic aorta. Functional and dimensional abnormalities of the ascending aorta have been previously reported in BAV relatives,4 and some data suggested that BAV and TAA may be independent manifestations of a single gene defect.5 Thus, individuals with normally functioning and normally shaped aortic valve, with normally sized but abnormally shaped thoracic aorta causing abnormal flow vortices, might be one end of a spectrum of an heritable condition having BAV in association with TAA at the other end, with patients with isolated BAV or TAA somewhere between these extremities. Unfortunately,
Schnell et al. could not derive data on aortic compliance due to limited spatial resolution of 4D flow data. Since abnormal stiffness is a recognized and independent feature of BAV aortopathy in patients6 and in BAV relatives,4 the phenotype described by Schnell et al. lacks information regarding load-bearing characteristics of the aortic wall in their BAV relatives, hindering any consideration on its relation with shape and vortices. Nonetheless, on the basis of these findings, the above-mentioned hypotheses (i.e. haemodynamic and genetic) should no longer be considered as separated or even contradictory. Flow abnormalities may in fact be an early functional equivalent of abnormal aortic shape in some BAV relatives or may be an environmental factor interacting with the genetic background of the dilated/aneurismal aorta of BAV patients. Consistently with the endophenotypic character and the clinical heterogeneity of BAV and TAA, a univocal genetic interpretation of BAV syndrome is lacking.1,7 Moreover, although BAV often displays an autosomal dominant pattern of inheritance with incomplete penetrance and variable expressivity, the increased prevalence of BAV in males and in patients with Turner syndrome (along a spectrum of aortic valve morphology) underscores the potential of X-linked transmission in this disease.8 Other limitations of the study by Schnell et al. resides in the small number of families studied due to the fact that the largest number of subjects comes from one family and that there are a lot of missing information on familial subjects. Therefore, the familial character of BAV cannot be ascertained in most families. Thus, showed pedigrees confirm the acknowledged difficulties in attributing a pattern of inheritance to BAVs and precludes the generalizability of the present findings to the common BAV syndrome. Schnell et al. utilized an advanced method for studying the thoracic aorta, an approach to date confined for research purposes. Although transthoracic echocardiography plays a pivotal role in clinical detection and follow-up studies of patients with BAV and/or TAA, cardiovascular computed tomography and CMR are the elective techniques for the quantitative and semi-quantitative assessment of the entire thoracic aorta, including the aortic valve and the aortic
The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association, or the European Society of Cardiology.
* Corresponding author. Tel: +39 0444225111; Fax: +39 0444225199. E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: [email protected].
1249
Editorial
root in clinical practice. Even though the two techniques have been used for a long time and their technological development have been continuous until today, we still tend to use them in a very basic way. Unfortunately, it is not unusual to verify the tendency to measure the thoracic aorta on non-axial planes, although there is consensus on the fact that at least we should perform measurements in anatomically defined landmarks, always on ECG-synchronized images, perpendicular to the main axis of the vessel. This methodological aspect may be particularly relevant especially in serial assessments. The study by Schnell et al. underscores that considerations about flow patterns depending on anatomical pre-conditions are very important suggesting that, in the future, a proper definition of the aortic phenotype should include the aortic size as well as its shape. However, we should remind that extensive epidemiological studies of thoracic aorta phenotypes have not been performed. For instance, the largest series considering aortic size as endpoint have been performed on individuals undergoing calcium scoring assessment for primary prevention.9,10 Even in these large series (.4000 individuals), the correlation between the size of the ascending aorta and age, gender, and body surface area were present but weak and with large standard deviations/confidence intervals. We miss a thorough and comprehensive epidemiological assessment of aortic phenotypes, which we understand only marginally. The impact of different phenotypes such as cubic or gothic shapes of the aortic arch on 4D flow pattern is surely a step ahead, which adds up to the pathophysiological understanding of potential development of complications.11 From a clinical point of view, the study of Schnell et al., despite its limitations, confirms some practical implications. When studying BAV relatives, the clinical cardiologist should not only carefully check for aortic valve morphology by echocardiography, seeking all the spectrum of aortic valve malformations,8 but should also perform a very careful scrutiny of the entire thoracic aorta, including the arch, with accurate measurement of the aortic size and also looking for associated congenital heart diseases (e.g. aortic coarctation, patent ductus arteriosus). Consistently, when this focused visualization of the aortic root and aortic valve would be technically
inadequate by transthoracic echocardiography, cardiac computed tomography /CMR should be considered.8 Schnell et al. should be commended for adding a new piece in the mosaic of BAV syndrome underscoring that a great effort must be performed by the researchers in the future to better comprehend this complex genetic trait, including subjects with different phenotypes, outcomes, and prognoses, caused by the interaction among different genetic backgrounds and non-genetic factors, and that a personalized approach to each BAV patient and her/his family should be pursued by the clinical cardiologist in team with imaging experts and genetists.
References 1. Pepe G, De Cario R, Sticchi E, Giusti B, Abbate R, Gensini G et al. Bicuspid aortic valve syndrome and fibrillinopathies: potential impact on clinical approach. Int Cardiovasc Forum J 2015;1:167 – 74. 2. Schnell S, Smith DA, Barker AJ, Entezari P, Honarmand AR, Carr ML et al. Altered aortic shape in bicuspid aortic valve relatives influences blood flow patterns. Eur Heart J Cardiovasc Imaging 2016;17:1239 –47. 3. Mahadevia R, Barker AJ, Schnell S, Entezari P, Kansal P, Fedak PW et al. Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. Circulation 2014;129:673 –82. 4. Biner S, Rafique AM, Ray I, Cuk O, Siegel RJ, Tolstrup K. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol 2009;53:2288 –95. 5. Loscalzo ML, Goh DLM, Loeys B, Kent KC, Spevak PJ, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A 2007;143:1960 –7. 6. Nistri S, Grande-Allen J, Noale M, Basso C, Siviero P, Maggi S et al. Aortic elasticity and size in bicuspid aortic valve syndrome. Eur Heart J 2008;29:472 –9. 7. Padang R, Bannon PG, Jeremy R, Richmond DR, Semsarian C, Vallely M et al. The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity. Ann Cardiothorac Surg 2013;2:83 –91. 8. Olivieri LJ, Baba RY, Arai AE, Bandettini WP, Rosing DR, Bakalov V et al. Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome. Circ Cardiovasc Imaging 2013;6:1018 –23. 9. Ka¨lsch H, Lehmann N, Mo¨hlenkamp S, Becker A, Moebus S, Schmermund A et al. Body-surface adjusted aortic reference diameters for improved identification of patients with thoracic aortic aneurysms: results from the population-based Heinz Nixdorf Recall study. Int J Cardiol 2013;163:72 –8. 10. Wolak A, Gransar H, Thomson LE, Friedman JD, Hachamovitch R, Gutstein A et al. Aortic size assessment by noncontrast cardiac computed tomography: normal limits by age, gender, and body surface area. JACC Cardiovasc Imaging 2008;1:200 –9. 11. Dyverfeldt P, Bissell M, Barker AJ, Bolger AF, Carlha¨ll CJ, Ebbers T et al. 4D flow cardiovascular magnetic resonance consensus statement. J Cardiovasc Magn Reson 2015;10:17–72.
