International Journal of Cardiology 176 (2014) 1264–1267
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Left ventricular outflow tract obstruction as a primary phenotypic expression of hypertrophic cardiomyopathy in mutation carriers without hypertrophy Luís R. Lopes a,b,⁎, Carlos Cotrim a,c, Inês Cruz a, Eugenio Picano d, Fátima Pinto e, Hélder Pereira a a
Serviço de Cardiologia, Hospital Garcia de Orta, Almada, Portugal Centro de Cardiologia da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal c Circulation Department - Hospital da Cruz Vermelha Portuguesa d CNR Institute of Clinical Physiology, Pisa, Italy e Serviço de Cardiologia Pediátrica, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central, Lisbon, Portugal b
a r t i c l e
i n f o
Article history: Received 21 June 2014 Accepted 27 July 2014 Available online 2 August 2014 Keywords: Hypertrophic cardiomyopathy Genetics Exercise stress echocardiography Mutation carriers Left ventricular outflow tract obstruction
The late and incomplete penetrance that characterizes hypertrophic cardiomyopathy (HCM) [1], combined with the relatively low – 40– 50% – yield of genetic testing [2], has stimulated the search for markers of early disease in “pre-hypertrophic” relatives of index patients [3]. The main suggested aims of those markers are to identify relatives at risk of developing HCM in families where a causal mutation is not identified, or to predict the risk of developing disease in carriers of a causal mutation in a non-hypertrophic stage. The clinical value of identifying these markers remains to be validated. We describe a possible novel and clinical relevant marker of this subclinical/pre-hypertrophic stage, as we report two pathogenic mutation carriers without hypertrophy, where a significant latent left ventricular outflow tract (LVOT) gradient was identified by treadmill stress echocardiography. The first patient was first evaluated at 14 years of age, and referred for a treadmill exercise stress echocardiogram because of atypical chest pain during and immediately after exercise at school, in the presence of unremarkable baseline cardiac investigations, including a normal ECG, normal rest echocardiogram and normal exercise test. ⁎ Corresponding author at: Serviço de Cardiologia do Hospital Garcia de Orta, Av. Torrado da Silva, 2801-951 Almada, Portugal. Tel.: +351 212 727168. E-mail address: [email protected] (L.R. Lopes).
http://dx.doi.org/10.1016/j.ijcard.2014.07.191 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
The stress echocardiography was performed with a previously published protocol that includes the evaluation of intraventricular gradients during and immediately after exercise in orthostatic position [4]. An LVOT gradient of 60 mm Hg at peak exercise and 96 mm Hg at recovery, with complete systolic anterior movement (SAM) of the mitral valve was identified (Fig. 1A, B, and C). Beta-blocker therapy was started (atenolol 25 mg bid) and the patient was kept under regular follow-up. Two years later, the patient was asymptomatic under beta-blocker, but the echocardiogram showed asymmetric septal hypertrophy, with a maximal wall thickness of 20 mm at the basal anterior septum; a significant intraventricular gradient of 64 mm Hg at the LVOT still occurred at peak exercise and an even higher gradient of 150 mm Hg was noted at recovery, with complete SAM (Fig. 1D). Atenolol was gradually uptitrated to 50 mg bid and 2 years later the stress echocardiogram revealed a significant 100-mm Hg LVOT gradient, but only at immediate recovery. Family screening was conducted (pedigree is shown in Fig. 2A). The 47-yearold mother's (I-1) ECG showed an incomplete right bundle branch block. The echocardiogram showed an angulated mild hypertrophy of the basal anterior septum (13 mm); when submitted to provocation with treadmill exercise, an LVOT gradient of 30 mm Hg and incomplete SAM was detected at immediate recovery (Fig. 1E). The 54-year-old father's (I-2) ECG showed a slow progression of the R waves at the right precordial leads. The echocardiogram showed a mild asymmetric septal hypertrophy of the basal anterior septum; when submitted to an exercise echocardiogram, a 28-mm Hg LVOT gradient with incomplete SAM was detected (Fig. 1F). An asymptomatic younger brother, first evaluated when 11 years old (II-2), showed no hypertrophy at the first echocardiographic evaluation (interventricular septum of 8 mm), but a significant intraventricular gradient at immediate recovery was detected when submitted to stress echocardiography. Atenolol 25 mg od was started. Two years later, an asymmetric septal hypertrophy at the anterior septum (15 mm) was noted. The ECG showed deep S waves at the right precordial leads, without hypertrophy criteria. When the subject was submitted to a stress echocardiogram using the same protocol, a latent LVOT gradient of 50 mm Hg with complete SAM was revealed at immediate recovery (Fig. 1G and H). Genetic testing was performed for eight sarcomere genes — MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1 and TPM1 on the index case,
L.R. Lopes et al. / International Journal of Cardiology 176 (2014) 1264–1267
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Fig. 1. Echocardiographic evaluation of family 1. A: Index patient (II-1): parasternal long axis at end-diastole showing normal wall thickness; B: Index patient (II-1): apical four-chamber view at peak exercise showing complete mitral SAM; C: Index patient (II-1): continuous wave Doppler tracing showing a 96-mm Hg gradient through the left ventricular outflow tract; D: Index patient (II-1) — follow-up echocardiogram: parasternal long axis at end-diastole showing asymmetric septal hypertrophy; E: Index patient's mother (I-1): parasternal long axis at end-diastole showing angulated and mildly hypertrophied basal septum; F: Index patient's father (I-2): parasternal long axis at end-diastole showing mildly hypertrophied basal septum; G: Index patient's younger brother (II-2): parasternal long axis at end-diastole showing asymmetric septal hypertrophy; F: Index patient's younger brother (II-2): continuous wave Doppler tracing showing a 50-mm Hg gradient through the left ventricular outflow tract.
revealing he was a compound heterozygote for c.772GN A (p.Glu258Lys) and c.836GN C (p.Gly279Ala) in MYBPC3. His brother carried the same two mutations. The mother was a carrier of c.772GN A (p.Glu258Lys) and the father was a carrier of c.836GNC (p.Gly279Ala). Both variants have been previously published [5,6]. Glu258Lys is well-established as
a causal mutation, including evidence for co-segregation [5]. The available evidence for pathogenicity of Gly279Ala is less convincing, and there is no published co-segregation. The second patient was a 16-year-old girl, under screening for the last 4 years. The index case of the family was her 52-year-old father,
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Fig. 2. A. Pedigree for family 1. B. Pedigree for family 2. Key: squares = males; circles = females; black-filled shapes = phenotype-positive individuals; empty shapes = healthy individuals; shapes with a dot = doubtful phenotype; arrows point to the proband; mutations are shown beside the symbol for the corresponding patient.
with HCM diagnosed 6 years before. Genetic testing of this index case for the above-mentioned genes showed a c.1624GNC (p.Glu542Gln) mutation. The pathogenicity of this previously published mutation has been established, including co-segregation [5] and functional studies [7]. The older son of the proband refused screening (Fig. 2B). The daughter is a carrier of the same mutation and was asymptomatic until her last clinic visit. Aside from a short PQ (0.10–0.16 s), her ECG has been unremarkable. The echocardiogram showed no hypertrophy or other remarkable findings. However, an exercise stress echocardiogram, performed due to dizziness symptoms while exercising at school, showed a significant 40 mm Hg LVOT gradient with complete SAM at immediate recovery. As more families undergo genetic testing for HCM, a new pre-clinical population (genotype-positive, phenotype-negative) is growing. A constellation of functional markers have been identified in carriers of mutations, including diastolic dysfunction evaluated with tissue Doppler [8], strain/torsion abnormalities [9], derangement of energy metabolism detected by magnetic resonance spectroscopy [10] and biomarkers of collagen metabolism [11]. The detection of morphological markers such as myocardial crypts, mitral valve leaflet dimension and increased trabeculae has followed [12,3]. Our data suggest that a dynamic echocardiographic evaluation with treadmill exercise echocardiography can reveal a yet-undescribed prehypertrophic trait — LVOT latent obstruction caused by mitral valve SAM. Similarly to what we have previously published regarding HCM patients [4], the highest and sometimes the only significant gradient
was only detected at immediate recovery in the upright position. Stress echocardiography might play a role in identifying functional abnormalities of documented pathogenic and prognostic value in these subjects. This may include the development of critical LVOT gradients after stress, especially evident in the orthostatic position after treadmill exercise. Possible explanations for the development of obstruction without hypertrophy include mitral valve leaflet dimensions, recognized as larger in both HCM patients [13] and relatives at the pre-hypertrophic stage [12,3] and anomalies of the papillary muscles [13], also described in HCM cases. We hypothesize that both could predispose to latent mitral valve SAM, before the development of the full phenotype. These subtle structural changes are probably related to cardiac development changes induced by genetic variants [14], which occur before the development of hypertrophy. Furthermore, significant LVOT gradients have been described in other populations with apparently structurally normal hearts, such as athletes [15]. As such, our current findings also raise the hypothesis that some of those individuals are carriers of rare sarcomere variants, perhaps not pathogenic enough to cause a hypertrophied phenotype, but able to provoke those dynamic changes and symptoms. Only a long follow-up of these individuals can elucidate that question. In our cases, the development of hypertrophy was apparently not affected by beta-blocker therapy, which was started to control mild exercise-induced symptoms such as atypical chest pain on effort or dizziness after exercise, and was associated with a striking reduction
L.R. Lopes et al. / International Journal of Cardiology 176 (2014) 1264–1267
in gradients. Although clearly limited by small sample size and requiring more substantial confirmation from larger series, these data suggest that the development of LVOT gradients does not play a triggering role in the development of left ventricular hypertrophy and is not affected by starting beta-blocker therapy at a pre-hypertrophic initial stage of disease. For now, the main implication of our findings is that genetic result-driven stress echo testing can be helpful to link genetic findings of uncertain clinical relevance to the risk of developing HCM. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004;363:1881–91. [2] Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart 2013;99:1800–11. [3] Captur G, Lopes L, Patel V, et al. Abnormal cardiac formation in hypertrophic cardiomyopathy — fractal analysis of trabeculae and preclinical gene expression. Circ Cardiovasc Genet 2014;7:241–8. [4] Miranda R, Cotrim C, Cardim N, et al. Evaluation of left ventricular outflow tract gradient during treadmill exercise and in recovery period in orthostatic position, in patients with hypertrophic cardiomyopathy. Cardiovasc Ultrasound 2008;6:19. [5] Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:1903–10.
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[6] Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227–32. [7] Flavigny J, Souchet M, Sebillon P, et al. COOH-terminal truncated cardiac myosinbinding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. J Mol Biol 1999;294:443–56. [8] Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–7. [9] Russel IK, Brouwer WP, Germans T, et al. Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness. J Cardiovasc Magn Reson 2011;13:3. [10] Crilley JG, Boehm EA, Blair E, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol 2003;41:1776–82. [11] Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552–63. [12] Maron MS, Olivotto I, Harrigan C, et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation 2011;124:40–7. [13] Kim DH, Handschumacher MD, Levine RA, et al. In vivo measurement of mitral leaflet surface area and subvalvular geometry in patients with asymmetrical septal hypertrophy: insights into the mechanism of outflow tract obstruction. Circulation 2010;122:1298–307. [14] Olivotto I, Cecchi F, Poggesi C, et al. Developmental origins of hypertrophic cardiomyopathy phenotypes: a unifying hypothesis. Nat Rev Cardiol 2009;6:317–21. [15] Cotrim C, Almeida AR, Miranda R, et al. Stress-induced intraventricular gradients in symptomatic athletes during upright exercise continuous wave Doppler echocardiography. Am J Cardiol 2010;106:1808–12.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Left ventricular outflow tract obstruction as a primary phenotypic expression of hypertrophic cardiomyopathy in mutation carriers without hypertrophy Luís R. Lopes a,b,⁎, Carlos Cotrim a,c, Inês Cruz a, Eugenio Picano d, Fátima Pinto e, Hélder Pereira a a
Serviço de Cardiologia, Hospital Garcia de Orta, Almada, Portugal Centro de Cardiologia da Universidade de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal c Circulation Department - Hospital da Cruz Vermelha Portuguesa d CNR Institute of Clinical Physiology, Pisa, Italy e Serviço de Cardiologia Pediátrica, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central, Lisbon, Portugal b
a r t i c l e
i n f o
Article history: Received 21 June 2014 Accepted 27 July 2014 Available online 2 August 2014 Keywords: Hypertrophic cardiomyopathy Genetics Exercise stress echocardiography Mutation carriers Left ventricular outflow tract obstruction
The late and incomplete penetrance that characterizes hypertrophic cardiomyopathy (HCM) [1], combined with the relatively low – 40– 50% – yield of genetic testing [2], has stimulated the search for markers of early disease in “pre-hypertrophic” relatives of index patients [3]. The main suggested aims of those markers are to identify relatives at risk of developing HCM in families where a causal mutation is not identified, or to predict the risk of developing disease in carriers of a causal mutation in a non-hypertrophic stage. The clinical value of identifying these markers remains to be validated. We describe a possible novel and clinical relevant marker of this subclinical/pre-hypertrophic stage, as we report two pathogenic mutation carriers without hypertrophy, where a significant latent left ventricular outflow tract (LVOT) gradient was identified by treadmill stress echocardiography. The first patient was first evaluated at 14 years of age, and referred for a treadmill exercise stress echocardiogram because of atypical chest pain during and immediately after exercise at school, in the presence of unremarkable baseline cardiac investigations, including a normal ECG, normal rest echocardiogram and normal exercise test. ⁎ Corresponding author at: Serviço de Cardiologia do Hospital Garcia de Orta, Av. Torrado da Silva, 2801-951 Almada, Portugal. Tel.: +351 212 727168. E-mail address: [email protected] (L.R. Lopes).
http://dx.doi.org/10.1016/j.ijcard.2014.07.191 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
The stress echocardiography was performed with a previously published protocol that includes the evaluation of intraventricular gradients during and immediately after exercise in orthostatic position [4]. An LVOT gradient of 60 mm Hg at peak exercise and 96 mm Hg at recovery, with complete systolic anterior movement (SAM) of the mitral valve was identified (Fig. 1A, B, and C). Beta-blocker therapy was started (atenolol 25 mg bid) and the patient was kept under regular follow-up. Two years later, the patient was asymptomatic under beta-blocker, but the echocardiogram showed asymmetric septal hypertrophy, with a maximal wall thickness of 20 mm at the basal anterior septum; a significant intraventricular gradient of 64 mm Hg at the LVOT still occurred at peak exercise and an even higher gradient of 150 mm Hg was noted at recovery, with complete SAM (Fig. 1D). Atenolol was gradually uptitrated to 50 mg bid and 2 years later the stress echocardiogram revealed a significant 100-mm Hg LVOT gradient, but only at immediate recovery. Family screening was conducted (pedigree is shown in Fig. 2A). The 47-yearold mother's (I-1) ECG showed an incomplete right bundle branch block. The echocardiogram showed an angulated mild hypertrophy of the basal anterior septum (13 mm); when submitted to provocation with treadmill exercise, an LVOT gradient of 30 mm Hg and incomplete SAM was detected at immediate recovery (Fig. 1E). The 54-year-old father's (I-2) ECG showed a slow progression of the R waves at the right precordial leads. The echocardiogram showed a mild asymmetric septal hypertrophy of the basal anterior septum; when submitted to an exercise echocardiogram, a 28-mm Hg LVOT gradient with incomplete SAM was detected (Fig. 1F). An asymptomatic younger brother, first evaluated when 11 years old (II-2), showed no hypertrophy at the first echocardiographic evaluation (interventricular septum of 8 mm), but a significant intraventricular gradient at immediate recovery was detected when submitted to stress echocardiography. Atenolol 25 mg od was started. Two years later, an asymmetric septal hypertrophy at the anterior septum (15 mm) was noted. The ECG showed deep S waves at the right precordial leads, without hypertrophy criteria. When the subject was submitted to a stress echocardiogram using the same protocol, a latent LVOT gradient of 50 mm Hg with complete SAM was revealed at immediate recovery (Fig. 1G and H). Genetic testing was performed for eight sarcomere genes — MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1 and TPM1 on the index case,
L.R. Lopes et al. / International Journal of Cardiology 176 (2014) 1264–1267
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Fig. 1. Echocardiographic evaluation of family 1. A: Index patient (II-1): parasternal long axis at end-diastole showing normal wall thickness; B: Index patient (II-1): apical four-chamber view at peak exercise showing complete mitral SAM; C: Index patient (II-1): continuous wave Doppler tracing showing a 96-mm Hg gradient through the left ventricular outflow tract; D: Index patient (II-1) — follow-up echocardiogram: parasternal long axis at end-diastole showing asymmetric septal hypertrophy; E: Index patient's mother (I-1): parasternal long axis at end-diastole showing angulated and mildly hypertrophied basal septum; F: Index patient's father (I-2): parasternal long axis at end-diastole showing mildly hypertrophied basal septum; G: Index patient's younger brother (II-2): parasternal long axis at end-diastole showing asymmetric septal hypertrophy; F: Index patient's younger brother (II-2): continuous wave Doppler tracing showing a 50-mm Hg gradient through the left ventricular outflow tract.
revealing he was a compound heterozygote for c.772GN A (p.Glu258Lys) and c.836GN C (p.Gly279Ala) in MYBPC3. His brother carried the same two mutations. The mother was a carrier of c.772GN A (p.Glu258Lys) and the father was a carrier of c.836GNC (p.Gly279Ala). Both variants have been previously published [5,6]. Glu258Lys is well-established as
a causal mutation, including evidence for co-segregation [5]. The available evidence for pathogenicity of Gly279Ala is less convincing, and there is no published co-segregation. The second patient was a 16-year-old girl, under screening for the last 4 years. The index case of the family was her 52-year-old father,
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L.R. Lopes et al. / International Journal of Cardiology 176 (2014) 1264–1267
Fig. 2. A. Pedigree for family 1. B. Pedigree for family 2. Key: squares = males; circles = females; black-filled shapes = phenotype-positive individuals; empty shapes = healthy individuals; shapes with a dot = doubtful phenotype; arrows point to the proband; mutations are shown beside the symbol for the corresponding patient.
with HCM diagnosed 6 years before. Genetic testing of this index case for the above-mentioned genes showed a c.1624GNC (p.Glu542Gln) mutation. The pathogenicity of this previously published mutation has been established, including co-segregation [5] and functional studies [7]. The older son of the proband refused screening (Fig. 2B). The daughter is a carrier of the same mutation and was asymptomatic until her last clinic visit. Aside from a short PQ (0.10–0.16 s), her ECG has been unremarkable. The echocardiogram showed no hypertrophy or other remarkable findings. However, an exercise stress echocardiogram, performed due to dizziness symptoms while exercising at school, showed a significant 40 mm Hg LVOT gradient with complete SAM at immediate recovery. As more families undergo genetic testing for HCM, a new pre-clinical population (genotype-positive, phenotype-negative) is growing. A constellation of functional markers have been identified in carriers of mutations, including diastolic dysfunction evaluated with tissue Doppler [8], strain/torsion abnormalities [9], derangement of energy metabolism detected by magnetic resonance spectroscopy [10] and biomarkers of collagen metabolism [11]. The detection of morphological markers such as myocardial crypts, mitral valve leaflet dimension and increased trabeculae has followed [12,3]. Our data suggest that a dynamic echocardiographic evaluation with treadmill exercise echocardiography can reveal a yet-undescribed prehypertrophic trait — LVOT latent obstruction caused by mitral valve SAM. Similarly to what we have previously published regarding HCM patients [4], the highest and sometimes the only significant gradient
was only detected at immediate recovery in the upright position. Stress echocardiography might play a role in identifying functional abnormalities of documented pathogenic and prognostic value in these subjects. This may include the development of critical LVOT gradients after stress, especially evident in the orthostatic position after treadmill exercise. Possible explanations for the development of obstruction without hypertrophy include mitral valve leaflet dimensions, recognized as larger in both HCM patients [13] and relatives at the pre-hypertrophic stage [12,3] and anomalies of the papillary muscles [13], also described in HCM cases. We hypothesize that both could predispose to latent mitral valve SAM, before the development of the full phenotype. These subtle structural changes are probably related to cardiac development changes induced by genetic variants [14], which occur before the development of hypertrophy. Furthermore, significant LVOT gradients have been described in other populations with apparently structurally normal hearts, such as athletes [15]. As such, our current findings also raise the hypothesis that some of those individuals are carriers of rare sarcomere variants, perhaps not pathogenic enough to cause a hypertrophied phenotype, but able to provoke those dynamic changes and symptoms. Only a long follow-up of these individuals can elucidate that question. In our cases, the development of hypertrophy was apparently not affected by beta-blocker therapy, which was started to control mild exercise-induced symptoms such as atypical chest pain on effort or dizziness after exercise, and was associated with a striking reduction
L.R. Lopes et al. / International Journal of Cardiology 176 (2014) 1264–1267
in gradients. Although clearly limited by small sample size and requiring more substantial confirmation from larger series, these data suggest that the development of LVOT gradients does not play a triggering role in the development of left ventricular hypertrophy and is not affected by starting beta-blocker therapy at a pre-hypertrophic initial stage of disease. For now, the main implication of our findings is that genetic result-driven stress echo testing can be helpful to link genetic findings of uncertain clinical relevance to the risk of developing HCM. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004;363:1881–91. [2] Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype–phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart 2013;99:1800–11. [3] Captur G, Lopes L, Patel V, et al. Abnormal cardiac formation in hypertrophic cardiomyopathy — fractal analysis of trabeculae and preclinical gene expression. Circ Cardiovasc Genet 2014;7:241–8. [4] Miranda R, Cotrim C, Cardim N, et al. Evaluation of left ventricular outflow tract gradient during treadmill exercise and in recovery period in orthostatic position, in patients with hypertrophic cardiomyopathy. Cardiovasc Ultrasound 2008;6:19. [5] Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:1903–10.
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[6] Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003;107:2227–32. [7] Flavigny J, Souchet M, Sebillon P, et al. COOH-terminal truncated cardiac myosinbinding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. J Mol Biol 1999;294:443–56. [8] Ho CY, Sweitzer NK, McDonough B, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–7. [9] Russel IK, Brouwer WP, Germans T, et al. Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness. J Cardiovasc Magn Reson 2011;13:3. [10] Crilley JG, Boehm EA, Blair E, et al. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy. J Am Coll Cardiol 2003;41:1776–82. [11] Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552–63. [12] Maron MS, Olivotto I, Harrigan C, et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation 2011;124:40–7. [13] Kim DH, Handschumacher MD, Levine RA, et al. In vivo measurement of mitral leaflet surface area and subvalvular geometry in patients with asymmetrical septal hypertrophy: insights into the mechanism of outflow tract obstruction. Circulation 2010;122:1298–307. [14] Olivotto I, Cecchi F, Poggesi C, et al. Developmental origins of hypertrophic cardiomyopathy phenotypes: a unifying hypothesis. Nat Rev Cardiol 2009;6:317–21. [15] Cotrim C, Almeida AR, Miranda R, et al. Stress-induced intraventricular gradients in symptomatic athletes during upright exercise continuous wave Doppler echocardiography. Am J Cardiol 2010;106:1808–12.
