International Journal of Cardiology 177 (2014) 736–737
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Hypertrophic cardiomyopathy: Genotype-positive, phenotype-“almost” negative. Diagnostic role of exercise in provocation of left ventricular outflow tract gradient Pawel Petkow Dimitrow a,⁎, Tsung O. Cheng b a b
2nd Department of Cardiology CMUJ, 31-501 Cracow, Poland Department of Medicine, The George Washington University Medical Center, 2150 Pennsylvania Avenue NW, Washington, DC 20037, USA
a r t i c l e
i n f o
Article history: Received 18 September 2014 Accepted 27 September 2014 Available online 30 October 2014 Keywords: Hypertrophic cardiomyopathy Genetics Exercise stress echocardiography Mutation carriers Left ventricular outflow tract obstruction
a b s t r a c t It has been proposed to use exercise stress echocardiography in the upright position with left ventricular outflow tract gradient monitoring both during and after exercise as a marker of genotype-positive/phenotype negative hypertrophic cardiomyopathy (HCM). Doppler measurement of gradient has been a very helpful and diagnostic examination in several subgroups of subjects (especially in young persons, athletes). Recently, many noninvasive (bio)markers have been found to be very helpful in screening patients suspected of HCM before full expression of phenotype. © 2014 Elsevier Ireland Ltd. All rights reserved.
The late and incomplete penetrance that characterizes hypertrophic cardiomyopathy (HCM), combined with the relatively low −50%-yield of genetic testing, has stimulated the search for morphologic markers of early disease in “pre-hypertrophic” relatives of index patients [1]. According to the very recent 2014 ESC guidelines [1], family screening in HCM carriers (usually young persons) is important and can be accomplished by several noninvasive studies. Another recent publication in International Journal of Cardiology [2] described a possible novel and clinical relevant marker of pre-hypertrophic stage of genotypepositive HCM. Authors have reported two pathogenic mutation carriers with neither hypertrophy nor SAM at resting condition, where a significant latent left ventricular outflow tract (LVOT) gradient was identified by treadmill stress echocardiography. LVOTG was recorded during and also immediately after exercise in orthostatic position [2]. The importance of upright position during exercise and recovery with continuous LVOTG monitoring has been recently recommended in meta-analysis [3] and rewiev paper [4,5]. Standing position, both at rest and during exercise, is a normal and fundamental activity of daily life, but may precipitate an unexpected fall in cardiac patients predisposed to syncope, especially in patients with unsuspected HCM. On the other hand, supine exercise is technically less demanding but also less physiological than upright exercise. It should be underscored that orthostatic exercise
⁎ Corresponding author. E-mail addresses: [email protected] (P.P. Dimitrow), [email protected] (T.O. Cheng).
http://dx.doi.org/10.1016/j.ijcard.2014.09.159 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
reflects physical exercise during everyday activity and reduces the preload more than supine exercise. In addition, upright exercise may provoke LVOTG in several other groups of subjects, including: – “healthy” youth with palpitation, WPW syndrome, shortness of breath, or chest pain [6]; – “symptomatic” athletes [7]; – “syndrome X” [8]. The first two groups are especially interesting, because these young patients may not have yet developed phenotypic expression of HCM. Apart from LVOTG as a primary phenotypic expression of HCM in mutation carriers without hypertrophy, many other approaches may be helpful in diagnostic evaluation: Noninvasive methods
Specific techniques
Abnormalities
Echocardiography
Upright treadmill exercise Speckle-tracking Tissue doppler Resting Gadolinium contrast
Peak, post exercise LVOTG Abnormal rotation LV diastolic dysfunction Various deviations Late enhancement-marker of fibrosis as arrhythmogenic substrate Abnormal rotation Reduced myocardial efficiency Profibrotic marker
ECG MRI
PET Biomarkers
Tagging Assessment of metabolism C-terminal propeptide of type I procollagen (PICP)
Editorial
Interestingly, a recent paper published in New England Journal of Medicine reported testing results with both morphological (contrast MRI) and biochemical (PICP) markers and found myocardial fibrosis to be an early manifestation of HCM [9]. Dynamically, the role of biomarkers has been explored in HCM [10]. In conclusion, given the potential for early presentation and potential clinical implications, the early identification of at-risk patients, even of sudden death, is vital in the management of these patients. The rapidly developing knowledge for markers heralding HCM has a very important and promising future.
737
[2]
[3]
[4]
[5]
Conflict of interest
[6]
The authors report no relationships that could be construed as a conflict of interest.
[7]
Acknowledgment This work has been supported by an NCN grant (grant no. 2011/01/ B/NZ5/02804). References [1] Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC Guidelines on diagnosis and management of
[8]
[9]
[10]
hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014 Oct 14;35:2733–79. Lopes LR, Cotrim C, Cruz I, Picano E, Pinto F, Pereira H. Left ventricular outflow tract obstruction as a primary phenotypic expression of hypertrophic cardiomyopathy in mutation carriers without hypertrophy. Int J Cardiol 2014 Oct 20;12:1264–7. Dimitrow PP, Cotrim C, Cheng TO. Need for a standardized protocol for stress echocardiography in provoking subaortic and valvular gradient in various cardiac conditions. Cardiovasc Ultrasound 2014 Jul 14;12:26. Dimitrow PP, Cheng TO. Standing position alone or in combination with exercise as a stress test to provoke left ventricular outflow tract gradient in hypertrophic cardiomyopathy and other conditions. Int J Cardiol 2010;143:219–22. Cotrim C, João I, Fazendas P, Almeida AR, Lopes L, Stuart B, et al. Clinical applications of exercise stress echocardiography in the treadmill with upright evaluation during and after exercise. Cardiovasc Ultrasound 2013;11:26. Wittlieb-Weber CA, Cohen MS, McBride MG, Paridon SM, Stephens Jr P. Elevated left ventricular outflow tract velocities on exercise stress echocardiography may be a normal physiologic response in healthy youth. J Am Soc Echocardiogr 2013;26: 1372–8. Cotrim C, Almeida AG, Carrageta M. Exercise-induced intra-ventricular gradients as a frequent potential cause of myocardial ischemia in cardiac syndrome X patients. Cardiovasc Ultrasound 2008;6:3. Cotrim C, Lopes LR, Almeida AR, Miranda R, Almeida AG, Cotrim H, et al. Efficacy of beta-blocker therapy in symptomatic athletes with exercise-induced intraventricular gradients. Cardiovasc Ultrasound 2010;8:38. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552–63. Dimitrow PP. Current and future roles of biochemical biomarkers in hypertrophic cardiomyopathy. Biomark Med 2014;8:81–3.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Editorial
Hypertrophic cardiomyopathy: Genotype-positive, phenotype-“almost” negative. Diagnostic role of exercise in provocation of left ventricular outflow tract gradient Pawel Petkow Dimitrow a,⁎, Tsung O. Cheng b a b
2nd Department of Cardiology CMUJ, 31-501 Cracow, Poland Department of Medicine, The George Washington University Medical Center, 2150 Pennsylvania Avenue NW, Washington, DC 20037, USA
a r t i c l e
i n f o
Article history: Received 18 September 2014 Accepted 27 September 2014 Available online 30 October 2014 Keywords: Hypertrophic cardiomyopathy Genetics Exercise stress echocardiography Mutation carriers Left ventricular outflow tract obstruction
a b s t r a c t It has been proposed to use exercise stress echocardiography in the upright position with left ventricular outflow tract gradient monitoring both during and after exercise as a marker of genotype-positive/phenotype negative hypertrophic cardiomyopathy (HCM). Doppler measurement of gradient has been a very helpful and diagnostic examination in several subgroups of subjects (especially in young persons, athletes). Recently, many noninvasive (bio)markers have been found to be very helpful in screening patients suspected of HCM before full expression of phenotype. © 2014 Elsevier Ireland Ltd. All rights reserved.
The late and incomplete penetrance that characterizes hypertrophic cardiomyopathy (HCM), combined with the relatively low −50%-yield of genetic testing, has stimulated the search for morphologic markers of early disease in “pre-hypertrophic” relatives of index patients [1]. According to the very recent 2014 ESC guidelines [1], family screening in HCM carriers (usually young persons) is important and can be accomplished by several noninvasive studies. Another recent publication in International Journal of Cardiology [2] described a possible novel and clinical relevant marker of pre-hypertrophic stage of genotypepositive HCM. Authors have reported two pathogenic mutation carriers with neither hypertrophy nor SAM at resting condition, where a significant latent left ventricular outflow tract (LVOT) gradient was identified by treadmill stress echocardiography. LVOTG was recorded during and also immediately after exercise in orthostatic position [2]. The importance of upright position during exercise and recovery with continuous LVOTG monitoring has been recently recommended in meta-analysis [3] and rewiev paper [4,5]. Standing position, both at rest and during exercise, is a normal and fundamental activity of daily life, but may precipitate an unexpected fall in cardiac patients predisposed to syncope, especially in patients with unsuspected HCM. On the other hand, supine exercise is technically less demanding but also less physiological than upright exercise. It should be underscored that orthostatic exercise
⁎ Corresponding author. E-mail addresses: [email protected] (P.P. Dimitrow), [email protected] (T.O. Cheng).
http://dx.doi.org/10.1016/j.ijcard.2014.09.159 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
reflects physical exercise during everyday activity and reduces the preload more than supine exercise. In addition, upright exercise may provoke LVOTG in several other groups of subjects, including: – “healthy” youth with palpitation, WPW syndrome, shortness of breath, or chest pain [6]; – “symptomatic” athletes [7]; – “syndrome X” [8]. The first two groups are especially interesting, because these young patients may not have yet developed phenotypic expression of HCM. Apart from LVOTG as a primary phenotypic expression of HCM in mutation carriers without hypertrophy, many other approaches may be helpful in diagnostic evaluation: Noninvasive methods
Specific techniques
Abnormalities
Echocardiography
Upright treadmill exercise Speckle-tracking Tissue doppler Resting Gadolinium contrast
Peak, post exercise LVOTG Abnormal rotation LV diastolic dysfunction Various deviations Late enhancement-marker of fibrosis as arrhythmogenic substrate Abnormal rotation Reduced myocardial efficiency Profibrotic marker
ECG MRI
PET Biomarkers
Tagging Assessment of metabolism C-terminal propeptide of type I procollagen (PICP)
Editorial
Interestingly, a recent paper published in New England Journal of Medicine reported testing results with both morphological (contrast MRI) and biochemical (PICP) markers and found myocardial fibrosis to be an early manifestation of HCM [9]. Dynamically, the role of biomarkers has been explored in HCM [10]. In conclusion, given the potential for early presentation and potential clinical implications, the early identification of at-risk patients, even of sudden death, is vital in the management of these patients. The rapidly developing knowledge for markers heralding HCM has a very important and promising future.
737
[2]
[3]
[4]
[5]
Conflict of interest
[6]
The authors report no relationships that could be construed as a conflict of interest.
[7]
Acknowledgment This work has been supported by an NCN grant (grant no. 2011/01/ B/NZ5/02804). References [1] Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC Guidelines on diagnosis and management of
[8]
[9]
[10]
hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014 Oct 14;35:2733–79. Lopes LR, Cotrim C, Cruz I, Picano E, Pinto F, Pereira H. Left ventricular outflow tract obstruction as a primary phenotypic expression of hypertrophic cardiomyopathy in mutation carriers without hypertrophy. Int J Cardiol 2014 Oct 20;12:1264–7. Dimitrow PP, Cotrim C, Cheng TO. Need for a standardized protocol for stress echocardiography in provoking subaortic and valvular gradient in various cardiac conditions. Cardiovasc Ultrasound 2014 Jul 14;12:26. Dimitrow PP, Cheng TO. Standing position alone or in combination with exercise as a stress test to provoke left ventricular outflow tract gradient in hypertrophic cardiomyopathy and other conditions. Int J Cardiol 2010;143:219–22. Cotrim C, João I, Fazendas P, Almeida AR, Lopes L, Stuart B, et al. Clinical applications of exercise stress echocardiography in the treadmill with upright evaluation during and after exercise. Cardiovasc Ultrasound 2013;11:26. Wittlieb-Weber CA, Cohen MS, McBride MG, Paridon SM, Stephens Jr P. Elevated left ventricular outflow tract velocities on exercise stress echocardiography may be a normal physiologic response in healthy youth. J Am Soc Echocardiogr 2013;26: 1372–8. Cotrim C, Almeida AG, Carrageta M. Exercise-induced intra-ventricular gradients as a frequent potential cause of myocardial ischemia in cardiac syndrome X patients. Cardiovasc Ultrasound 2008;6:3. Cotrim C, Lopes LR, Almeida AR, Miranda R, Almeida AG, Cotrim H, et al. Efficacy of beta-blocker therapy in symptomatic athletes with exercise-induced intraventricular gradients. Cardiovasc Ultrasound 2010;8:38. Ho CY, López B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010;363:552–63. Dimitrow PP. Current and future roles of biochemical biomarkers in hypertrophic cardiomyopathy. Biomark Med 2014;8:81–3.
