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including sudden cardiac death &#40;SCD&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">1&#44;2</span></a> However&#44; in about 5-10&#37; of cases&#44; unexplained LVH can be caused by other non-genetic or rarer genetic disorders that may mimic sarcomeric HCM&#44; for some of which specific treatment is available&#46; This is the case with Fabry disease &#40;FD&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">3&#8211;5</span></a> a multisystem lysosomal storage disease caused by a deficiency of the enzyme alpha-galactosidase A &#40;&#945;-Gal A&#41;&#44; encoded by the <span class="elsevierStyleItalic">GLA</span> gene on the X chromosome&#46; The disease leads to accumulation of globotriaosylceramide &#40;Gb3&#41; and other glycosphingolipids in lysosomes&#44; resulting in progressive multiorgan damage&#44; with severe complications due to cardiac&#44; renal or cerebrovascular lesions&#44; and ultimately in decreased life expectancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">6&#8211;8</span></a> Although the classic form of FD affects multiple organs and occurs early in men &#40;hemizygotes&#41;&#44; some forms are found particularly &#40;though not exclusively&#41; in women &#40;heterozygotes&#41;&#44; manifesting as milder disease&#44; with a late-onset phenotype that is often confined to a single organ such as the heart&#44; kidney&#44; or brain&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">9&#8211;11</span></a> The frequent observation of exclusively cardiac involvement in FD suggests that the heart is the most susceptible organ to &#945;-Gal A deficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">12&#8211;14</span></a> Cardiac involvement is one of the main determinants of prognosis&#44;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">6&#44;9&#44;15&#44;16</span></a> and includes LVH &#40;the most common manifestation&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">17</span></a> arrhythmias&#44; small-vessel coronary disease and heart failure&#46; Electrocardiographic &#40;ECG&#41; abnormalities are frequent&#44; and brady- or tachyarrhythmias are a significant cause of morbidity and mortality&#44; including SCD&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The diagnosis of FD is difficult and requires a high level of clinical suspicion&#46; Many of the typical extracardiac features may not be evident in non-classical forms of the disease&#44; and in some patients cardiac involvement may predominate&#44; commonly mimicking sarcomeric HCM&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">20&#8211;22</span></a> Unlike the latter&#44; LVH is typically concentric in FD&#44;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">23&#44;24</span></a> but it may also manifest as asymmetric septal hypertrophy or even predominantly with involvement of other wall segments&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">11&#44;13&#44;21&#44;25&#8211;27</span></a> Left ventricular outflow obstruction &#40;a common feature in sarcomeric HCM&#41;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">1</span></a> may also exist in FD&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">21</span></a> hindering the differential diagnosis between the two conditions&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The accepted prevalence of FD in patients presenting with unexplained LVH is 0&#46;5&#37;-1&#37;&#44; although higher in some series&#44;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">20&#44;26&#44;28&#44;29</span></a> and its exclusion should be considered in this context&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">11&#44;28&#44;30</span></a> When initiated early&#44; enzyme replacement therapy with agalsidase alpha or agalsidase beta can halt the progression of FD and modify its prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">3&#44;4&#44;31&#44;32</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In men&#44; the first diagnostic test should be measurement of &#945;-Gal A &#40;in plasma&#44; white blood cells or dried blood spots&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">33</span></a> which is generally decreased or absent&#44; followed by <span class="elsevierStyleItalic">GLA</span> gene sequencing&#46; In women&#44; interpretation of enzyme activity results is difficult &#8211; only about 40&#37; of female patients have a low enzyme level&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">34</span></a> and sequencing of the <span class="elsevierStyleItalic">GLA</span> gene is necessary for diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">35</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In the Portuguese Registry of Hypertrophic Cardiomyopathy &#40;PRo-HCM&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">36</span></a> the possibility of FD was considered in the differential diagnosis of LVH&#46; The aim of the present study was to analyze the registry data in order to assess the awareness of cardiologists regarding the need to exclude this phenocopy in real-world scenarios&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">PRo-HCM was a national multicenter registry designed to collect information on the current approach to sarcomeric HCM in Portugal and to facilitate future improvements regarding diagnosis and therapeutic management of the condition&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">36</span></a> The registry was designed and implemented by the Working Group on Myocardial and Pericardial Diseases of the Portuguese Society of Cardiology &#40;SPC&#41;&#44; and centralized and managed at the SPC&#39;s National Center for Data Collection in Cardiology &#40;CNCDC&#41;&#46; It was an observational&#44; multicenter&#44; voluntary&#44; non-mandatory study&#44; with a two-year enrollment period &#40;from 25 April 2013 to 25 April 2015&#41;&#44; largely retrospective but also including a prospective update&#46; Participating centers &#40;n &#61; 29&#41; were asked to include all patients with a diagnosis of HCM followed at the center at that time or in the past &#40;with no retrospective time limit&#41;&#44; including those already deceased at the time of enrollment&#46; Included individuals were aged over 18 years at inclusion and had a diagnosis of HCM with LVH phenotype by imaging methods &#40;unexplained LVH with maximum left ventricular wall thickness of &#8805;15 mm in one or more myocardial segments in index patients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">1&#44;37</span></a> Criteria for non-inclusion in the registry were the presence of secondary LVH &#40;at least stage 2 hypertension&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">38</span></a> moderate or severe aortic valve stenosis&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">39</span></a> or a previously diagnosed cardiac or systemic disease associated with LVH&#41;&#46; However&#44; the electronic case report form included some information about the possible exclusion of FD&#46; This was a non-mandatory open-ended yes&#47;no question&#44; at the discretion of the investigator and not requiring any specific clinical or imaging characterization&#46; However&#44; if the answer was yes&#44; a reference to the specific tests carried out for that purpose &#40;measurement of &#945;-Gal A activity and&#47;or <span class="elsevierStyleItalic">GLA</span> gene sequencing&#41; was requested&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The registry complied with the principles of the Declaration of Helsinki &#40;October 2000&#41; and written informed consent was obtained from all living patients before inclusion&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">For the purpose of the present study&#44; only index patients included in the registry were considered&#46; This population was first identified and characterized according to whether sarcomeric genetic testing had been performed and the results thereof&#46; They were then divided into three groups&#58; group A &#8211; patients with positive sarcomeric genetic testing&#44; in whom pathogenic or likely pathogenic mutation&#40;s&#41; were identified in genes encoding beta-myosin heavy chain &#40;<span class="elsevierStyleItalic">MYH7</span>&#41;&#44; myosin-binding protein C &#40;<span class="elsevierStyleItalic">MYBPC3</span>&#41;&#44; cardiac troponin I and T &#40;<span class="elsevierStyleItalic">TNNI3</span> and <span class="elsevierStyleItalic">TNNT2</span>&#41;&#44; tropomyosin alpha-1 chain &#40;<span class="elsevierStyleItalic">TPM1</span>&#41;&#44; myosin light chain 3 &#40;<span class="elsevierStyleItalic">MYL3</span>&#41;&#44; myosin regulatory light chain 2 &#40;<span class="elsevierStyleItalic">MYL2</span>&#41;&#44; alpha cardiac actin &#40;<span class="elsevierStyleItalic">ACTC1</span>&#41; and muscle LIM protein &#40;<span class="elsevierStyleItalic">CSRP3</span>&#41;&#59; group B &#8211; those with negative sarcomeric genetic testing&#44; in whom pathogenic or likely pathogenic mutation&#40;s&#41; were identified in none of the above nine genes&#59; and group C &#8211; those in whom genetic testing in sarcomeric genes had not been performed&#46; Each group was then characterized according to whether exclusion of FD had been considered &#40;and methods used in its exclusion&#41;&#44; associated extracardiac conditions&#44; ECG abnormalities and echocardiographic &#40;echo&#41; characteristics&#46; Finally&#44; the groups were analyzed for the presence of specific features that could potentially constitute red flags for FD&#46; These included clinical data&#44; specific ECG abnormalities &#40;short or prolonged PR interval&#44; intraventricular conduction disturbances&#44; or the need for pacemaker &#91;PM&#93; implantation for treatment of bradyarrhythmias&#41;&#44; or concentric LVH on echocardiographic imaging&#46; Data from group B &#40;patients with no identified sarcomeric mutations&#41; &#8211; the particular population of interest in this study &#8211; were compared with data from groups A and C&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Continuous variables are reported as means and standard deviations and comparisons were performed by ANOVA&#44; using the F test or Welch test&#46; The latter was used whenever the hypothesis of homogeneity of variance was rejected by Levene&#39;s test&#46; Normality was tested by the Shapiro-Wilks test&#46; Multiple comparisons between the two groups A and C and group B were performed using Dunnett&#39;s test or Dunnett&#39;s T3 test&#46; Male and female ages were compared within each group using the t test&#46; Categorical variables are expressed as absolute frequencies and percentages and differences were analyzed using Pearson&#39;s chi-square test&#46; When the conditions for a chi-square test were not met&#44; the Monte Carlo simulation method was used as an alternative&#46; Male and female percentages were compared within each group by a binomial test with test percentage 50&#37;&#46; All p-values reported are from two-tailed tests and regarded as statistically significant at a level of 5&#37;&#46; Multiple comparisons were performed using Pearson&#39;s chi-square test&#44; adjusting the significance level to 2&#46;5&#37; by Bonferroni&#39;s method&#46; All data analyses were performed using IBM SPSS Statistics version 19&#46;0&#46;0&#46;2&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Index patients and characteristics of study groups</span><p id="par0050" class="elsevierStylePara elsevierViewall">The flowchart of selection of index patients and division into groups is presented in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#46; A total of 1042 patients with unexplained LVH identified by imaging methods &#40;echocardiography in 97&#37; of cases&#41; and a diagnosis of HCM were included in the PRo-HCM registry&#46; Of these&#44; 887 were index patients&#46; Genetic testing in sarcomeric genes was performed in 48&#37; &#40;n &#61; 426&#41; of patients&#44; and not performed in 50&#46;6&#37; &#40;n &#61; 449&#41;&#59; 76 patients were excluded &#40;12 due to missing data&#44; 37 awaiting results and 27 due to unclear results&#41;&#46; The population included in the final analysis was composed of 811 index patients&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The characteristics of this population are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Males &#40;n &#61; 486&#41; predominated over females &#40;n &#61; 325&#41; &#40;p&#60;0&#46;001&#41;&#59; the overall median age was 55 &#177; 16 years at the time of diagnosis&#44; women being older than men &#40;p&#60;0&#46;001&#41;&#46; Familial HCM was documented in 198 &#40;24&#46;4&#37;&#41; patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Group A was composed of 128 patients &#40;35&#46;5&#37; of the population in whom sarcomeric genetic testing was performed&#41;&#44; mean age 49 &#177; 18 years&#44; 74 men &#40;48 &#177; 16 years&#41; and 54 women &#40;51 &#177; 20 years&#41;&#59; group B included 234 patients&#44; mean age 55 &#177; 14 years&#44; 146 men &#40;53 &#177; 14 years&#41; and 88 women &#40;59 &#177; 14 years&#41;&#59; and group C included 449 patients&#44; mean age 56 &#177; 15 years&#44; 266 men &#40;54 &#177; 15 years&#41;&#44; and 183 women &#40;59 &#177; 15 years&#41;&#46; Although no differences were observed regarding the number of male or female patients between groups &#40;p &#61; NS&#41;&#44; male gender predominated over female &#40;p &#60;0&#46;001&#41; in groups B and C&#44; but not in group A &#40;p &#61; NS&#41;&#46; Patients in group A were younger &#40;both genders&#41; than in the other two groups&#44; and more frequently had familial HCM &#40;53&#46;9&#37;&#41; compared to groups B &#40;20&#46;1&#37;&#41; and C &#40;18&#46;3&#37;&#41; &#40;p &#60;0&#46;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">There was no difference between groups A and B regarding the number of sarcomeric genes tested &#40;median 8&#46;0&#44; interquartile range 5-9&#44; p &#61; 0&#46;051&#41;&#59; at least five genes were sequenced in 82&#37; of patients in group A and in 88&#46;9&#37; of patients in group B&#44; and all nine genes were screened in 35&#46;2&#37; of patients in group A and in 34&#46;2&#37; of patients in group B&#46; Screening of the <span class="elsevierStyleItalic">MYH7</span>&#44; <span class="elsevierStyleItalic">MYBPC3</span>&#44; <span class="elsevierStyleItalic">MYL2</span>&#44; <span class="elsevierStyleItalic">TNNI3</span>&#44; and <span class="elsevierStyleItalic">CSRP3</span> genes was performed in the same number of patients in both groups &#40;p &#61; NS&#41;&#44; but in group B &#40;patients with no identified pathogenic or likely pathogenic mutations&#41;&#44; four genes were screened in a larger number of patients than in group A&#58; <span class="elsevierStyleItalic">TNNT2</span> &#40;88&#46;9&#37; vs&#46; 80&#46;5&#37;&#44; p &#61; 0&#46;028&#41;&#44; <span class="elsevierStyleItalic">TPM1</span> &#40;70&#46;1&#37; vs&#46; 58&#46;6&#37;&#44; p &#61; 0&#46;027&#41;&#44; <span class="elsevierStyleItalic">MYL3</span> &#40;76&#46;9&#37; vs&#46; 67&#46;2&#37;&#44; p &#61; 0&#46;045&#41;&#44; and <span class="elsevierStyleItalic">ACTC1</span> &#40;69&#46;2&#37; vs&#46; 53&#46;1&#37;&#44; p &#61; 0&#46;002&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Exclusion of Fabry disease</span><p id="par0070" class="elsevierStylePara elsevierViewall">Reported data on exclusion of FD are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Overall&#44; FD was reported to have been excluded in 217 out of 811 patients &#40;26&#46;8&#37;&#41;&#44; in similar proportions in male &#40;135&#47;486&#59; 27&#46;8&#37;&#41; and in females &#40;82&#47;325&#59; 25&#46;2&#37;&#41;&#44; females being older than males &#40;overall median age at diagnosis was 56 &#177; 15 years and 49 &#177; 14 years respectively&#59; p &#61; 0&#46;001&#41;&#46; There were no differences between groups regarding the number of males or females in whom exclusion of FD was reported&#44; and the age of males was similar in all groups&#44; as was the age of females&#46; However&#44; when compared within groups&#44; females were older than males in groups B and C&#44; but not in group A&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">GLA</span> gene testing</span><p id="par0075" class="elsevierStylePara elsevierViewall">Genetic testing of the <span class="elsevierStyleItalic">GLA</span> gene was carried out in 50 out of 217 patients&#44; overall more frequently in women than in men &#40;36&#46;6&#37; vs&#46; 14&#46;8&#37;&#44; p &#60; 0&#46;001&#41;&#46; However&#44; <span class="elsevierStyleItalic">GLA</span> gene testing was performed in only 25&#46;7&#37; of patients in group B&#44; with a significant difference &#40;p &#61; 0&#46;019&#41; in comparison with group A &#40;<span class="elsevierStyleItalic">GLA</span> testing in 48&#46;6&#37; of patients&#41;&#44; but similar to group C &#40;13&#46;4&#37; of patients&#59; p &#61; NS&#41;&#59; these differences between groups B and A were observed for both men &#40;p &#61; 0&#46;001&#41; and women &#40;p &#61; 0&#46;020&#41;&#46; In groups B and C&#44; <span class="elsevierStyleItalic">GLA</span> gene testing was performed significantly more frequently in women than in men &#40;respectively 46&#37; vs&#46; 13&#46;6&#37;&#44; p &#61; 0&#46;003&#59; and 23&#37; vs&#46; 7&#46;2&#37;&#44; p &#61; 0&#46;016&#41;&#44; with no age difference between genders&#46; In group A&#44; <span class="elsevierStyleItalic">GLA</span> gene testing was carried out as frequently in women as in men &#40;61&#46;5&#37; vs&#46; 40&#46;9&#37;&#44; p &#61; NS&#41;&#44; also with no observed differences in age between genders&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In the 50 patients who underwent <span class="elsevierStyleItalic">GLA</span> gene testing&#44; no pathogenic mutations were identified in 33&#59; in 17 patients &#40;10 in group B and 7 in group C&#41; genetic results were missing in the registry&#46; <span class="elsevierStyleItalic">GLA</span> gene screening was not performed in 74&#46;3&#37; of patients in group B &#40;including in 53&#46;8&#37; of female patients in this group&#41; and in 86&#46;6&#37; of patients in group C &#40;including in 76&#46;7&#37; of female patients in this group&#41;&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Alpha-galactosidase A activity</span><p id="par0085" class="elsevierStylePara elsevierViewall">Alpha-Gal A enzyme activity was assessed in only 39&#47;217 &#40;18&#37;&#41; of patients&#44; with no difference between groups &#40;p &#61; NS&#41;&#44; and more often in men than in women &#40;23&#46;7&#37; vs&#46; 8&#46;5&#37;&#44; p &#61; 0&#46;005&#41;&#46; In patients with a borderline &#945;-Gal A value&#44; no pathogenic mutations were identified in the <span class="elsevierStyleItalic">GLA</span> gene&#46; &#945;-Gal A activity was not determined in 85&#46;7&#37; of patients in group B&#44; or in 79&#46;5&#37; of patients in group C &#40;&#8776;77&#37; of the male population in both groups&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In summary&#44; when exclusion of FD was considered&#44; a specific diagnostic method &#40;<span class="elsevierStyleItalic">GLA</span> gene testing and&#47;or determination of &#945;-Gal A activity&#41; was carried out in 38&#46;6&#37; of patients in group B &#40;patients with no identified mutations in sarcomeric genes&#41;&#44; and in 32&#46;1&#37; of patients in group C &#40;patients who did not undergo sarcomeric genetic testing&#41;&#59; in the other patients in these two groups&#44; cardiologists relied solely on clinical and&#47;or imaging criteria for exclusion of FD&#46; Overall&#44; exclusion of FD was not considered in 73&#46;2&#37; of the population&#44; with no difference between groups&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Associated disorders &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Supplementary Table 1</a>&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Systemic hypertension &#40;stage 1&#41; was common&#44; affecting 403&#47;811 &#40;49&#46;7&#37;&#41; of patients &#40;mean age 62 &#177; 12 years at HCM diagnosis&#41;&#44; 225&#47;486 &#40;46&#46;3&#37;&#41; of men&#44; and 178&#47;325 &#40;54&#46;8&#37;&#41; of women&#46; Hypertension was more frequent in patients in groups B &#40;58&#46;1&#37;&#41; and C &#40;49&#46;9&#37;&#41; than in group A &#40;33&#46;6&#37;&#41; &#40;p &#60; 0&#46;001&#41;&#46; Other non-cardiovascular diseases were present in 40&#46;2&#37; of patients overall&#44; with no difference between groups &#40;p &#61; NS&#41;&#59; the prevalence of cerebrovascular disease&#44; renal disease&#44; and diseases of other organs or systems was similar between groups&#44; affecting both genders equally in all groups&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Electrocardiographic and echocardiographic data</span><p id="par0100" class="elsevierStylePara elsevierViewall">An abnormal ECG was present in around 95&#37; of patients&#46; Overall&#44; the three groups did not differ in terms of the presence of LVH criteria &#40;&#8776;64&#37;&#41;&#44; repolarization &#40;ST-T&#41; abnormalities &#40;&#8776;82&#37;&#41;&#44; atrial fibrillation &#40;&#8776;10&#37;&#41;&#44; left anterior fascicular block &#40;13&#37;&#41;&#44; short PR interval &#40;3&#46;3&#37;&#41;&#44; prolonged PR interval &#40;1&#46;4&#37;&#41;&#44; left bundle branch block &#40;4&#46;7&#37;&#41;&#44; right bundle branch block &#40;10&#37;&#41;&#44; or need for PM implantation &#40;6&#46;5&#37;&#41; due to bradyarrhythmias or advanced atrioventricular &#40;AV&#41; block&#46; Regarding gender&#44; the groups were generally similar in the numbers of males or females with these abnormalities&#44; although LVH criteria were more often observed in males in group B &#40;p &#61; 0&#46;019 for B vs&#46; C&#41;&#44; and left bundle branch block was more common in females in group B &#40;p &#61; 0&#46;001 for B vs&#46; C&#41;&#46; PM implantation was more frequently needed in older patients &#40;mean age 63 &#177; 14 years&#44; p &#61; 0&#46;016 between groups&#41; &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Supplementary Table 2</a>&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A pattern of concentric LVH on echo imaging was described in 7&#46;8&#37; of patients&#44; with no difference between groups&#46; Left ventricular outflow tract or intraventricular obstruction was diagnosed in about 40&#37; of patients&#44; also with no difference between groups&#46; Both of these features affected both genders equally &#40;<a class="elsevierStyleCrossRef" href="#sec0095">Supplementary Table 3</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Exclusion of Fabry disease in patients with potential red flags</span><p id="par0110" class="elsevierStylePara elsevierViewall">A further analysis was performed comparing the three groups of patients with regard to exclusion of FD but including only those with potential red flags for the condition&#46; These included references in the registry to prespecified clinical conditions &#40;cerebrovascular disease&#44; other neurological disease&#44; or renal disease&#41; and&#47;or other nonspecific conditions &#40;gastrointestinal symptoms&#44; chronic fatigue&#44; chronic limb pain&#44; hearing impairment&#44; and eye or skin problems&#41; and&#47;or specific ECG abnormalities &#40;short or prolonged PR interval&#44; intraventricular conduction abnormalities&#44; or need for PM implantation due to bradyarrhythmias&#41; and&#47;or a pattern of concentric LVH on echo&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Data on exclusion of FD in patients with HCM and potential red flags are summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Four hundred and twenty index patients &#8211; 64 &#40;15&#46;23&#37;&#41; patients in group A&#44; 122 &#40;29&#46;0&#37;&#41; in group B&#44; and 234 &#40;55&#46;71&#37;&#41; in group C &#40;p&#60;0&#46;001 for comparison between groups&#41; &#8211; had at least one of the above features&#46; In this sub-analysis&#44; exclusion of FD was reported in 122 &#40;29&#37;&#41; patients&#44; more frequently in group B patients with these features compared to group C &#40;37&#46;7&#37; vs&#46; 25&#46;6&#37;&#44; p &#61; 0&#46;018&#41;&#44; but with no difference compared to group A &#40;25&#37;&#44; p &#61; NS&#41;&#46; However&#44; exclusion of FD relied on <span class="elsevierStyleItalic">GLA</span> gene testing in only 25&#46;4&#37; of patients&#44; with no difference between groups &#40;p &#61; NS&#41;&#44; more commonly in females than males in groups B and C&#59; and &#945;-Gal A activity was assessed in 21&#46;3&#37; of patients&#44; also with no differences between groups &#40;p &#61; NS&#41;&#44; and mostly in men&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Therefore&#44; in patients with red flags for FD and in whom the disease was reported as having been excluded&#44; a specific test was performed in 46&#46;7&#37; of patients &#40;including 45&#46;6&#37; of those in group B and 40&#37; of those in Group C&#41;&#59; in the other patients exclusion of FD relied solely on clinical and&#47;or imaging criteria&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Overall&#44; exclusion of FD was not considered in 298 &#40;71&#37;&#41; patients with red flags for FD&#44; with no difference between groups &#40;p &#61; NS&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">In this descriptive&#44; observational analysis of a subpopulation of 811 index patients included in the PRo-HCM registry with a diagnosis of HCM on the basis of classic criteria&#44;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">37&#44;40&#44;41</span></a> genetic testing in sarcomeric genes was performed in &#8776;45&#37; of patients&#44; and a pathogenic or likely pathogenic mutation associated with HCM was identified in 35&#46;5&#37;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A definitive diagnosis of sarcomeric HCM can only be made when a pathogenic or likely pathogenic mutation associated with the disease is identified&#46; However&#44; when genetic testing targeting the most common mutated genes is performed&#44; findings are negative in up to 50&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">1</span></a> It may be hypothesized that older patients with a late HCM phenotype may have mutations in other &#40;uncommon&#41; sarcomeric genes that are not usually screened&#44; but it is also possible that FD is the cause of that phenotype&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">According to data from the registry&#44; exclusion of FD was infrequent and relied on specific diagnostic tests in less than 40&#37; of patients&#46; When sarcomeric genetic testing was negative or was not performed&#44; consideration of FD predominantly involved older women&#46; Clinical presentation of FD may occur later and be more variable in women than in men&#44; and women are more likely to develop a variant characterized by isolated cardiac involvement only&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">6&#8211;8&#44;10</span></a> Interestingly&#44; the <span class="elsevierStyleItalic">GLA</span> gene was most often tested in patients with identified sarcomeric mutations&#44; probably because a large panel of genes was used&#59; but it was the only gene tested in 13&#37; of patients in group C&#44; possibly due to economic restraints&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">However&#44; genetic testing for FD was not performed in more than 50&#37; of female patients in group B&#44; or in more than 70&#37; of females in group C&#46; Furthermore&#44; &#945;-Gal A activity was only assessed in a minority of patients&#44; although&#44; appropriately&#44; mainly in males&#59; but it was not assessed in the majority of men in groups B and C&#46; Overall&#44; specific tests for FD exclusion were performed in less than 50&#37; of patients in whom the disease was reported as having been excluded&#46; <span class="elsevierStyleItalic">GLA</span> testing results&#44; when available&#44; were negative&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">These data support the conclusion that many cardiologists rely only on clinical or imaging data for exclusion of FD&#44; and consider that in most patients with an HCM phenotype specific tests are not indicated or necessary&#46; However&#44; this may be a misconception&#46; In patients with no male-to-male transmission of unexplained LVH&#44; FD should be considered as a potential diagnosis and specific tests need to be performed&#44; a decision supported by any other additional personal and&#47;or family feature suggesting the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">35</span></a> Needless to say&#44; in the absence of a family history of FD&#44; such features in family members &#40;kidney disease&#44; acroparesthesias&#44; cornea verticillata&#44; etc&#46;&#41; may be absent&#44; difficult to ascertain&#44; or simply overlooked in patients with a predominantly or exclusively cardiac phenotype&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The ECG abnormalities observed in this analysis are commonly described in patients with LVH&#44; whatever the cause&#44; patients with sarcomeric HCM or FD included&#46; A short PR interval is classically described in 21&#37;-40&#37; of patients with FD&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">42</span></a> particularly in its early stages but&#44; although less common&#44; it is also described in HCM &#40;3&#46;3&#37; in the study population&#41;&#46; Likewise&#44; a tendency for PR prolongation and AV block is described in the later stages of FD&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">43</span></a> and these abnormalities may also occur during the natural history of sarcomeric HCM&#46; They were found with similar prevalence in all groups of the study population&#46; Conduction abnormalities may always be considered an additional warning for the cardiologist when excluding FD&#44; but they are in no way a decisive diagnostic marker of FD&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">All echo patterns of LVH can be observed in sarcomeric HCM&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">44&#8211;46</span></a> Concentric LVH &#40;the most common form in FD&#41; was described in less than 10&#37; of patients in the study population&#46; Conversely&#44; obstruction &#40;infrequent in FD&#41; was diagnosed in about 40&#37; of patients&#46; Both echo features were observed similarly&#44; whether or not sarcomeric genetic testing had been carried out&#44; and regardless of its result&#44; but none of them is key to the diagnosis&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; in this population there was no clear evidence of non-cardiac features suggesting FD&#44; but symptoms or signs may be subtle and non-specific in non-classical forms&#46; The subpopulations studied were relatively elderly for sarcomeric HCM and potentially prone to what is termed Fabry cardiomyopathy &#8211; despite the rarity of this disease &#8211; particularly considering the female gender and the forms that can be expressed with a late and predominantly cardiac phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">13&#44;20</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The findings herein highlight the need to be alert for both conditions&#58; sarcomeric HCM &#40;the purpose of the PRo-HCM registry&#41;&#44; which is often diagnosed late as it frequently evolves without symptoms&#59; and FD&#44; which needs to be systematically considered in the differential diagnosis of most cases of LVH&#44; especially when the proband is negative for sarcomeric mutations&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In the genetic era&#44; it seems reasonable to include <span class="elsevierStyleItalic">GLA</span> in the panel of genes to be tested when HCM is investigated&#46; When genetic testing is not possible&#44; &#945;-Gal A activity should be assessed&#44; because it may be diagnostic in male patients&#44; with <span class="elsevierStyleItalic">GLA</span> testing being reserved as a second step if appropriate&#46; In females&#44; particularly if middle-aged or older and bearing in mind the possibility of a predominantly cardiac phenotype&#44; <span class="elsevierStyleItalic">GLA</span> gene testing is advisable even if it is the only gene that can be tested due to economic constraints or other reasons&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">LVH occurs late in FD&#44; but enzyme replacement treatment can favorably modify the long-term prognosis of the disease&#44; reducing the incidence of and&#47;or progression to serious clinical events&#44;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">3&#44;4&#44;31&#44;32</span></a> and when a diagnosis is made in the index patient&#44; early diagnosis in affected relatives is facilitated<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">47</span></a> and may be associated with better outcomes&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Limitations</span><p id="par0190" class="elsevierStylePara elsevierViewall">The PRo-HCM registry was designed for the study of patients with a previous diagnosis of sarcomeric HCM on the basis of classical criteria&#44; and not according to a genetic diagnosis&#46; It cannot be excluded that patients with no identified pathogenic mutations in common sarcomeric genes have HCM associated with mutations in other rarer genes that are not usually screened&#46; But it also cannot be ruled out that in fact some of the cases of HCM included in the registry are atypical FD with a late expression and a predominantly or exclusively cardiac phenotype&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">We considered as potential red flags for FD clinical features that were not fully characterized in PRo-HCM&#44; because the registry was not designed for investigation of unexplained LVH&#46; However&#44; considering the similarities in clinical&#44; ECG and echocardiographic profile observed in the three patient groups&#44; rare genetic diseases such as FD seem unlikely as a cause of HCM in this population&#46; Also&#44; systemic hypertension was a common finding&#44; as expected considering its prevalence worldwide and the age of the population&#44;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">48&#44;49</span></a> although it is improbable that stage 1 hypertension could explain the observed &#8805;15 mm LVH on echo imaging&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">However&#44; the aim of this descriptive analysis&#44; which we consider original in design and objectives&#44; was neither to assess the yield of genetic testing in sarcomeric HCM nor to determine the prevalence of FD in patients with unexplained LVH detected by imaging techniques&#44; but only to assess the awareness of cardiologists of a potential diagnosis of FD&#44; and in clinical practice this awareness seems to be lower than empirically suspected&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusions</span><p id="par0205" class="elsevierStylePara elsevierViewall">Analysis of data from subpopulations of patients included in the PRo-HCM registry revealed a low awareness among cardiologists of the need to exclude FD in patients without a genetic diagnosis of sarcomeric HCM&#46; When exclusion of FD was undertaken&#44; it relied mainly on clinical or imaging features&#44; with specific diagnostic tests performed in fewer than 50&#37; of cases in which they could hypothetically be justified&#46; These data&#44; in a cardiology setting&#44; should be taken as an indication for a broader approach to patients with unexplained HCM&#44; aimed at the exclusion of a disease that&#44; although rare&#44; may benefit from specific therapy that has a favorable impact on prognosis&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0210" class="elsevierStylePara elsevierViewall">The Portuguese Registry of Hypertrophic Cardiomyopathy was supported by the following companies &#40;in alphabetical order&#41;&#58; Jaba Recordati&#44; Medinfar&#44; Merck Serono&#44; Sanofi Genzyme&#44; Servier&#44; Shire Human Genetic Therapies&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">This article was sponsored by a grant from Sanofi Genzyme&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authors&#8217; contributions</span><p id="par0220" class="elsevierStylePara elsevierViewall">DB&#44; NC&#44; and LR-L conceived and designed the research&#44; and drafted the manuscript&#59; AB performed the statistical analysis&#59; JM&#44; LG&#44; and HM performed critical revisions of the manuscript for drafting and key intellectual content&#46; All authors contribute to revising the paper and gave final approval of the version to be published&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of interest</span><p id="par0225" class="elsevierStylePara elsevierViewall">DB reports consultancy and lecture fees from Sanofi Genzyme&#44; and attended meetings sponsored by Shire Human Genetic Therapies&#59; LRL attended meetings sponsored by Shire Human Genetic Therapies and Sanofi Genzyme&#59; the other authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Results"
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              "titulo" => "Index patients and characteristics of study groups"
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              "titulo" => "Exclusion of Fabry disease"
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              "identificador" => "sec0035"
              "titulo" => "GLA gene testing"
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            3 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Alpha-galactosidase A activity"
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              "titulo" => "Associated disorders &#40;Supplementary Table 1&#41;"
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              "identificador" => "sec0050"
              "titulo" => "Electrocardiographic and echocardiographic data"
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              "identificador" => "sec0055"
              "titulo" => "Exclusion of Fabry disease in patients with potential red flags"
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          "titulo" => "Discussion"
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    "fechaRecibido" => "2017-10-18"
    "fechaAceptado" => "2018-03-11"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Fabry disease"
            1 => "Hypertrophic cardiomyopathy"
            2 => "Registry"
            3 => "Left ventricular hypertrophy"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec999221"
          "palabras" => array:4 [
            0 => "Doen&#231;a de Fabry"
            1 => "Miocardiopatia hipertr&#243;fica"
            2 => "Registo"
            3 => "Hipertrofia ventricular esquerda"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In adults&#44; unexplained left ventricular hypertrophy is usually due to sarcomeric hypertrophic cardiomyopathy &#40;HCM&#41;&#46; Fabry disease &#40;FD&#41; is rare but may mimic sarcomeric HCM&#44; and has an adverse prognosis in the absence of specific treatment&#46; We aimed to assess cardiologists&#8217; awareness of FD based on data from the Portuguese Registry of Hypertrophic Cardiomyopathy&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A total of 811 index patients&#44; aged 55 &#177; 16 years&#44; 486 &#40;59&#46;9&#37;&#41; male&#44; were included&#46; Three groups were characterized&#58; A &#8211; 128 patients&#44; 74 &#40;57&#46;8&#37;&#41; male&#44; with pathogenic or likely pathogenic mutation&#40;s&#41; in sarcomeric genes&#59; B &#8211; 234 patients&#44; 146 &#40;62&#46;4&#37;&#41; male&#44; with negative genetic testing&#59; and C &#8211; 449 patients&#44; 266 &#40;59&#46;2&#37;&#41; male&#44; no genetic testing performed&#46; The groups were compared in terms of whether FD was excluded in the registry&#46; Potential red flags for FD were also analyzed and compared between groups&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patients in group A were younger and more frequently had familial HCM &#40;A &#8211; 53&#46;9&#37; vs&#46; B &#8211; 20&#46;1&#37; vs&#46; C &#8211; 18&#46;3&#37;&#59; p &#60;0&#46;001&#41;&#46; FD was recorded as excluded in 217 &#40;26&#46;8&#37;&#41;&#44; similar in all groups&#59; <span class="elsevierStyleItalic">GLA</span> gene testing was performed in only 50&#47;217 patients &#40;A &#8211; 48&#46;6&#37;&#44; B &#8211; 25&#46;7&#37;&#44; p &#61; 0&#46;019&#59; C &#8211; 13&#46;4&#37;&#44; p &#61; 0&#46;036 for B vs&#46; C&#41;&#44; mostly in women &#40;p &#60;0&#46;001&#41; in groups B and C&#46; Alpha-galactosidase A &#40;&#945;-Gal A&#41; activity was assessed in 39&#47;217 &#40;18&#37;&#41; patients&#44; with no difference between groups&#44; but more often in men &#40;p &#61; 0&#46;005&#41;&#46; Among patients with potential red flags for FD&#44; only 46&#46;7&#37; underwent specific tests &#40;<span class="elsevierStyleItalic">GLA</span> gene testing and&#47;or &#945;-Gal A activity&#41;&#46; When <span class="elsevierStyleItalic">GLA</span> genotyping was performed no mutations were identified&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There is a need to improve cardiologists&#8217; alertness for the identification of FD among the Portuguese HCM population&#46;</p></span>"
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            "titulo" => "Introduction"
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            "titulo" => "Methods"
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          2 => array:2 [
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Em adultos&#44; hipertrofia ventricular esquerda inexplicada &#233; geralmente devida a miocardiopatia hipertr&#243;fica sarcom&#233;rica &#40;MH&#41;&#46; A doen&#231;a de Fabry &#40;DF&#41;&#44; rara&#44; pode mimetizar MH e tem progn&#243;stico adverso na aus&#234;ncia de tratamento espec&#237;fico&#46; Avali&#225;mos a perce&#231;&#227;o dos cardiologistas para DF com base no Registo Portugu&#234;s de Miocardiopatia Hipertr&#243;fica&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Inclu&#237;mos 811 doentes-&#237;ndice&#44; 55 &#177; 16 anos&#44; 486 &#40;59&#44;9&#37;&#41; homens &#40;H&#41;&#46; Caracteriz&#225;mos tr&#234;s grupos&#58; A-128 doentes&#44; 74 &#40;57&#44;8&#37;&#41; H&#44; com muta&#231;&#227;o patog&#233;nica&#47;provavelmente patog&#233;nica em genes sarcom&#233;ricos&#59; B-234 doentes&#44; 146 &#40;62&#44;4&#37;&#41; H&#44; com teste gen&#233;tico negativo&#59; C-449 doentes&#44; 266 &#40;59&#44;2&#37;&#41; H&#44; sem teste gen&#233;tico efetuado&#46; Os grupos foram comparados em rela&#231;&#227;o &#224; exclus&#227;o de DF&#44; segundo a informa&#231;&#227;o do registo&#46; Sinais potenciais de alerta para DF foram tamb&#233;m avaliados e comparados entre os tr&#234;s grupos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Os doentes do grupo A eram mais novos e tinham mais frequentemente MH familiar &#40;A-53&#44;9&#37; <span class="elsevierStyleItalic">versus</span> B-20&#44;1&#37; <span class="elsevierStyleItalic">versus</span> C-18&#44;3&#37;&#59; p&#60;0&#44;001&#41;&#46; DF foi dada como exclu&#237;da em 217 &#40;26&#44;8&#37;&#41; doentes&#44; sem diferen&#231;a entre grupos&#59; sequencia&#231;&#227;o do gene GLA foi efetuada apenas em 50&#47;217 doentes &#91;A-48&#44;6&#37;&#44; B-25&#44;7&#37;&#44; p &#61; 0&#44;019&#59; C-13&#44;4&#37;&#44; p &#40;B <span class="elsevierStyleItalic">versus</span> C&#41; &#61; 0&#44;036&#93;&#44; predominantemente em mulheres &#40;p &#60; 0&#44;001&#41; nos grupos B e C&#59; atividade enzim&#225;tica da &#945;-Gal A foi avaliada em 39&#47;217 &#40;18&#37;&#41; doentes&#44; sem diferen&#231;a entre grupos&#44; mas predominantemente em H &#40;p &#61; 0&#44;005&#41;&#46; Dos doentes com sinais potenciais de alerta para DF&#44; apenas 46&#44;7&#37; foram submetidos a testes espec&#237;ficos &#40;GLA e&#47;ou &#945;-Gal A&#41;&#46; Quando o gene GLA foi estudado&#44; o resultado foi negativo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">&#201; necess&#225;rio melhorar a perce&#231;&#227;o dos cardiologistas para a identifica&#231;&#227;o da DF na popula&#231;&#227;o portuguesa com MH&#46;</p></span>"
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            "apendice" => "<p id="par0235" class="elsevierStylePara elsevierViewall">Centro Hospitalar de Leiria - Joana Correia &#40;PI&#41;&#44; Catarina Ruivo&#44; Fernando S&#225;&#59; Centro Hospitalar de Lisboa Norte&#44; Hospital de Santa Maria&#44; Lisbon - Dulce Brito &#40;PI&#41;&#44; Ana Rita Francisco&#44; Tatiana Guimar&#227;es&#44; Miguel Nobre Menezes&#44; Oana Moldovan&#44; M&#243;nica Mendes Pedro&#44; Gustavo Lima da Silva&#59; Centro Hospitalar de Lisboa Ocidental&#44; Servi&#231;o de Cardiologia - Jo&#227;o Abecasis &#40;PI&#41;&#44; Francisco Moscoso Costa&#44; Helder Dores&#59; Centro Hospitalar de Lisboa Ocidental&#44; Hospital S&#227;o Francisco Xavier&#44; Servi&#231;o de Medicina III&#58; C&#226;ndida Fonseca &#40;PI&#41;&#44; In&#234;s Ara&#250;jo&#44; Filipa Marques&#59; Centro Hospitalar de Tr&#225;s os Montes e Alto Douro&#44; Hospital de S&#227;o Pedro&#44; Vila Real - Carla Alexandra R&#46; Ara&#250;jo &#40;PI&#41;&#44; Ana Isabel Baptista&#44; Sofia Silva Carvalho&#44; Filipa Cordeiro&#44; Catarina Ferreira&#44; S&#237;lvia Le&#227;o&#44; Pedro Magalh&#227;es&#44; Renato Margato&#59; Centro Hospitalar de Vila Nova de Gaia&#47;Espinho - Concei&#231;&#227;o Fonseca &#40;PI&#41;&#44; Jo&#227;o Tiago Almeida&#44; Ricardo Fontes-Carvalho&#44; Rita Faria&#44; Paulo Fonseca&#44; Olga Sousa&#59; Centro Hospitalar do Algarve&#44; Hospital de Faro - Nuno Marques &#40;PI&#41;&#44; Jos&#233; Amado&#44; Joana Chin&#44; Walter Santos&#59; Centro Hospitalar do Alto Ave&#44; Hospital da Senhora da Oliveira&#44; Guimar&#226;es - Olga Azevedo &#40;PI&#41;&#44; Margarida Oliveira&#44; Lucy Calvo&#44; Jo&#227;o Portugu&#234;s&#59; Centro Hospitalar do Baixo Vouga&#44; Hospital Infante D&#46; Pedro&#44; Aveiro - Jos&#233; Ant&#243;nio Nobre dos Santos &#40;PI&#41;&#44; Tiago Cardoso&#44; Ana Raquel Ferreira&#44; Jos&#233; Luis Martins&#59; Centro Hospitalar do Oeste Norte&#44; Centro Hospitalar das Caldas da Rainha - Ana Filipa Pereira Rodrigues &#40;PI&#41;&#59; Centro Hospitalar do Porto&#44; Hospital de Santo Ant&#243;nio - Patr&#237;cia Fernandes Rodrigues &#40;PI&#41;&#44; Paulo Palma&#44; M&#225;rio Santos&#44; Maria Jo&#227;o Monteiro e Sousa&#59; Centro Hospitalar do T&#226;mega e Sousa&#44; Unidade Padre Am&#233;rico&#44; Penafiel - Maria Concei&#231;&#227;o Queir&#243;s &#40;PI&#41;&#44; Alexandra Castro&#44; Adriana Pereira&#59; Centro Hospitalar e Universit&#225;rio de Coimbra&#44; Cardiologia B&#44; Hospital Geral - Joana Delgado Silva &#40;PI&#41;&#44; Ana Botelho&#44; Liliana Reis Teles&#59; Centro Hospitalar Tondela Viseu&#44; Hospital de S&#227;o Teot&#243;nio - Carlos Emanuel Correia &#40;PI&#41;&#44; Luis Abreu&#44; Davide Moreira&#59; CUF Infante Santo Hospital&#44; Lisbon - Pedro Matos &#40;PI&#41;&#59; Hospital Beatriz &#194;ngelo&#44; Loures - Luis Sargento &#40;PI&#41;&#44; Miguel Almeida Ribeiro&#59; Hospital da Luz&#44; Lisbon - Nuno Cardim &#40;PI&#41;&#59; Hospital das For&#231;as Armadas&#44; Lisbon - Sara Ferreira &#40;PI&#41;&#59; Hospital de Braga&#58; Nuno Salom&#233; &#40;PI&#41;&#44; Carina Arantes&#44; Carlos Braga&#44; Ant&#243;nio Costeira&#44; Catarina Vieira&#59; Hospital de Santa Maria Maior de Barcelos&#44; Servi&#231;o Cardiologia - Alexandra Sousa &#40;PI&#41;&#44; Mariana Paiva&#59; Hospital de Santo Esp&#237;rito de Angra do Hero&#237;smo&#44; A&#231;ores - Rute Couto &#40;PI&#41;&#59; Hospital de S&#227;o Jo&#227;o&#44; Porto - Elisabete Martins &#40;PI&#41;&#44; Ana Lebreiro&#44; S&#233;rgio Leite&#44; Carla Sousa&#59; Hospital do Esp&#237;rito Santo&#44; &#201;vora - Agostinho Caeiro &#40;PI&#41;&#44; Jo&#227;o Filipe Carvalho&#44; Bruno Pi&#231;arra&#59; Hospital Garcia de Orta&#44; Almada - Luis Rocha Lopes &#40;PI&#41;&#44; Ana Rita Almeida&#44; In&#234;s Cruz&#59; Hospital Prof&#46; Doutor Fernando Fonseca&#44; Amadora - Francisco Madeira &#40;PI&#41;&#44; Mariana Faustino&#59; Hospital SAMS&#44; Lisbon - Berta Car&#244;la &#40;PI&#41;&#44; Rui Conduto&#44; Paulo Pedro&#59; HPP Hospital de Cascais&#44; Hospital Dr&#46; Jos&#233; de Almeida - Gon&#231;alo Proen&#231;a &#40;PI&#41;&#44; &#201;lia Batista&#44; Sara Eira&#44; Carla Matias&#59; Unidade Local de Sa&#250;de da Guarda&#44; Hospital Sousa Martins - Maria Cristina Gamboa &#40;PI&#41;&#44; Maria Isabel Santos&#46;</p> <p id="par0240" class="elsevierStylePara elsevierViewall">Centers are in alphabetical order&#46; PI&#58; Principal Investigator&#46;</p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Participating centers and investigators"
            "identificador" => "sec0090"
          ]
          1 => array:4 [
            "apendice" => "<p id="par0250" class="elsevierStylePara elsevierViewall">The following are the supplementary material to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix B"
            "titulo" => "Supplementary material"
            "identificador" => "sec0100"
          ]
        ]
      ]
    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1923
            "Ancho" => 2167
            "Tamanyo" => 157891
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of selection of index patients and division into groups for analysis and comparisons&#46; <span class="elsevierStyleSup">a</span> See text for details&#46; <span class="elsevierStyleSup">b</span> Genetic test&#58; positive&#47;negative&#58; identification&#47;non-identification of pathogenic or likely pathogenic mutation&#40;s&#41; in sarcomeric genes encoding beta-myosin heavy chain &#40;<span class="elsevierStyleItalic">MYH7</span>&#41;&#44; myosin-binding protein C &#40;<span class="elsevierStyleItalic">MYBPC3</span>&#41;&#44; cardiac troponin I and T &#40;<span class="elsevierStyleItalic">TNNI3</span> and <span class="elsevierStyleItalic">TNNT2</span>&#41;&#44; tropomyosin alpha-1 chain &#40;<span class="elsevierStyleItalic">TPM1</span>&#41;&#44; myosin light chain 3 &#40;<span class="elsevierStyleItalic">MYL3</span>&#41;&#44; myosin regulatory light chain 2 &#40;<span class="elsevierStyleItalic">MYL2</span>&#41;&#44; alpha cardiac actin &#40;<span class="elsevierStyleItalic">ACTC1</span>&#41;&#44; and muscle LIM protein &#40;<span class="elsevierStyleItalic">CSRP3</span>&#41;&#46; PRo-HCM&#58; Portuguese Registry of Hypertrophic Cardiomyopathy&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Group A&#58; patients with identified pathogenic or likely pathogenic mutation&#40;s&#41; in sarcomeric genes &#40;see text for details&#41;&#59; Group B&#58; patients with no identified pathogenic or likely pathogenic mutations in sarcomeric genes&#59; Group C&#58; patients who did not undergo genetic testing for sarcomeric genes&#46; HCM&#58; hypertrophic cardiomyopathy&#59; SD&#58; standard deviation&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">811&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">128&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">449&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Male&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">486 &#40;59&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74 &#40;57&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">146 &#40;62&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">266 &#40;59&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;632&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age at HCM diagnosis&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49 &#177; 18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&#44; mean &#177; SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;005<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&#44; mean &#177; SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">58 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51 &#177; 20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;017<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Familial HCM&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">198 &#40;24&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;53&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47 &#40;20&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82 &#40;18&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "notaPie" => array:4 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">p &#61; 0&#46;002 for A vs&#46; B&#44; p &#61; 0&#46;893 for C vs&#46; B&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">p &#61; 0&#46;013 for A vs&#46; B&#44; p &#61; 0&#46;921 for C vs&#46; B&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">p &#61; 0&#46;042 for A vs&#46; B&#44; p &#61; 0&#46;972 for C vs&#46; B&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">p &#60; 0&#46;001 for A vs&#46; B&#44; p &#61; 0&#46;564 for C vs&#46; B&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Index patients with hypertrophic cardiomyopathy included in the study&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at2"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">&#945;-Gal A&#58; alpha-galactosidase A activity&#59; F&#58; females&#59; FD&#58; Fabry disease&#59; Group A&#58; patients with identified pathogenic or likely pathogenic mutation&#40;s&#41; in sarcomeric genes &#40;see text for details&#41;&#59; Group B&#58; patients with no identified pathogenic or likely pathogenic mutations in sarcomeric genes&#59; Group C&#58; patients who did not undergo genetic testing for sarcomeric genes&#59; HCM&#58; hypertrophic cardiomyopathy&#59; M&#58; males&#59; SD&#58; standard deviation&#59; yes&#58; when <span class="elsevierStyleItalic">GLA</span> gene testing was performed&#44; or &#945;-Gal A activity was assessed&#46;</p>"
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Exclusion of FD</span><a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">217&#47;811 &#40;26&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35&#47;128&#40;27&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70&#47;234 &#40;29&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">112&#47;449 &#40;24&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;374&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Age&#44; years &#177; SD<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 &#177; 18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;089&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M&#47;total M&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">135&#47;486 &#40;27&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22&#47;74 &#40;29&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#47;146 &#40;30&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69&#47;266 &#40;25&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;609&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>F&#47;total F&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">82&#47;325 &#40;25&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#47;54 &#40;24&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#47;88 &#40;29&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43&#47;183 &#40;23&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;549&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">GLA gene testing &#40;yes&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#47;217 &#40;23&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#47;35 &#40;48&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#47;70 &#40;25&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#47;112 &#40;13&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Age&#44; years &#177; SD<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49 &#177; 8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44 &#177; 20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;051&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M&#47;total M&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;135 &#40;14&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#47;22 &#40;40&#46;9&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;44 &#40;13&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;69 &#40;7&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>F&#47;total F&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#47;82 &#40;36&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#47;13 &#40;61&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;26 &#40;46&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;43 &#40;23&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">&#945;-Gal A testing &#40;yes&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39&#47;217 &#40;18&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;35 &#40;17&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;70 &#40;14&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#47;112 &#40;20&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;560&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Age&#44; years &#177; SD<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51 &#177; 13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#177; 17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">47 &#177; 12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">55 &#177; 11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;052&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M&#47;total M&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#47;135 &#40;23&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;22 &#40;27&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#47;44 &#40;22&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#47;69 &#40;23&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;910&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>F&#47;total F&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;82 &#40;8&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;43 &#40;16&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">GLA and&#47;or &#945;-Gal A testing &#40;yes&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">83&#47;217 &#40;38&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#47;35 &#40;57&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27&#47;70 &#40;38&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36&#47;112 &#40;32&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;029<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Non-exclusion of FD</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">e</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">594&#47;811 &#40;73&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">93&#47;128&#40;72&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">164&#47;234&#40;70&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">337&#47;449 &#40;75&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;374&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Age&#44; years &#177; SD<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56 &#177; 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50 &#177; 17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">&#945;-Gal A&#58; alpha-galactosidase A activity&#59; F&#58; females&#59; FD&#58; Fabry disease&#59; Group A&#58; patients with identified pathogenic or likely pathogenic mutation&#40;s&#41; in sarcomeric genes &#40;see text for details&#41;&#59; Group B&#58; patients with no identified pathogenic or likely pathogenic mutations in sarcomeric genes&#59; Group C&#58; patients who did not undergo genetic testing for sarcomeric genes&#59; HCM&#58; hypertrophic cardiomyopathy&#59; M&#58; males&#59; SD&#58; standard deviation&#59; yes&#58; when <span class="elsevierStyleItalic">GLA</span> gene testing was performed&#44; or &#945;-Gal A activity was assessed&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Patients&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">420&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64 &#40;15&#46;23&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">122 &#40;29&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">234 &#40;55&#46;71&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; years &#177; SD</span><a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">54 &#177; 18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57 &#177; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">59 &#177; 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;062&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Exclusion of FD</span><a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">122&#47;420 &#40;29&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#47;64 &#40;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46&#47;122 &#40;37&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60&#47;234 &#40;25&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;044<a class="elsevierStyleCrossRef" href="#tblfn0060"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">GLA gene testing</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#47;122 &#40;25&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;16 &#40;43&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;46 &#40;26&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#47;60 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;151&nbsp;\t\t\t\t\t\t\n
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                          "etal" => true
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                          "colaboracion" => "FOS Investigators"
                          "etal" => true
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        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0230" class="elsevierStylePara elsevierViewall">We thank the Portuguese Society of Cardiology&#39;s National Center for Data Collection in Cardiology &#40;CNCDC&#41; team&#58; Sandra Corker&#44; Adriana Belo&#44; Lino Gon&#231;alves &#40;Head of CNCDC&#41; and Jorge Mimoso&#44; and investigators from the participating centers &#40;see <a class="elsevierStyleCrossRef" href="#sec0090">Appendix A</a>&#41;&#46;</p>"
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