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Diagnosis and screening of hypertrophic cardiomyopathy in children
Progress in Pediatric Cardiology 31 (2011) 21–27
Contents lists available at ScienceDirect
Progress in Pediatric Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p p e d c a r d
Diagnosis and screening of hypertrophic cardiomyopathy in children Gul H. Dadlani a,b,⁎, William G. Harmon c, Elimarys Perez-Colon b, Mary C. Sokoloski c, Ivan Wilmot a, Steven E. Lipshultz c a b c
All Children's Hospital Heart Institute, St. Petersburg, FL, United States University of South Florida, Department of Pediatrics, Tampa, FL, United States Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
a r t i c l e
i n f o
Keywords: Hypertrophic cardiomyopathy Sudden cardiac death Screening Pediatrics
a b s t r a c t Hypertrophic cardiomyopathy is the most common inherited cardiovascular disorder and the leading cause of sudden cardiac death in young people in the United States. Wide genetic heterogeneity and phenotypic expression are seen in hypertrophic cardiomyopathy and can make this disorder difficult to recognize in the general public. Population based screening for hypertrophic cardiomyopathy is aimed to allow for early detection, earlier treatment, promote complete family screening and to hopefully prevent some cases of sudden cardiac death in the community. A screening regimen consisting of a directed medical history and physical exam is currently recommended in the United States. The addition of electrocardiography is routine in some countries and can help guide the utilization of more expensive or invasive testing. Tools such as echocardiography, magnetic resonance imaging, serum biomarkers, and genetic testing are then directed to specific individuals to maximize their diagnostic and prognostic impact. Currently, no specific or widespread screening program has been uniformly adopted across the United States, as costs, benefits and the hazards of false positive diagnoses have yet to be balanced and decided. A working knowledge and appropriate suspicion for HCM remains fundamental for clinicians in order to diagnosis this important disorder. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hypertrophic cardiomyopathy (HCM) is an important disease affecting populations worldwide. It is the most common inherited cardiovascular disorder and the leading cause of sudden cardiac death in young people. HCM demonstrates wide genetic heterogeneity and variable phenotypic expression that can complicate recognition and diagnosis in the broad population. Screening for HCM could potentially allow for early detection, earlier treatment, screening for sub-clinical disease in family members, and may prevent some episodes of sudden cardiac death in the community. 2. Background: the nature of hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is a phenotypic label describing a heterogeneous group of disorders that produce ventricular hypertrophy in the absence of an identifiable hemodynamic cause [1]. Pediatric cardiomyopathies have been traditionally categorized by their dominant phenotypic subgroups as: (i) dilated, (ii) hypertrophic, or
⁎ Corresponding author. All Children's Hospital Heart Institute, Outpatient Care Center 2nd Floor, 501 6th Street South, St. Petersburg FL 33701, United States. Tel.: + 1 727 767 3333; fax: + 1 727 767 8990. E-mail address: [email protected] (G.H. Dadlani). 1058-9813/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2010.11.005
(iii) restrictive disease. Arrhythmogenic right ventricular dysplasia and left ventricular non-compaction have been increasingly recognized as other important clinical entities [1]. Considerable genetic commonality seems to exist between these disease subtypes, as similar gene mutations have been found in association with different phenotypic expression, seemingly to arise from variable effects of gene function, expression and control. The NHLBI-supported North American Pediatric Cardiomyopathy Registry (PCMR), the largest such registry globally, classifies pediatric hypertrophic cardiomyopathies in four distinct diagnostic categories: (i) disease found in association with inborn errors of metabolism, (ii) those identified as a component of a malformation syndrome, (iii) disease found in the setting of a neuromuscular disorder, and (iv) idiopathic disease. Idiopathic disease may be familial, and it may or may not be seen in association with a known myofilament or sarcomeric gene defect. Population-based data from the PCMR indicate the overall incidence of HCM to be 4.7 per 1 million children in two broad regions of North America [1]. The PCMR also recorded 42 specific identifiable causes in a cohort of 855 children less than 18 years of age [1]. Interestingly, in each of the major diagnostic categories a single disease process is shown to predominate: Pompe disease is the most common inborn error of metabolism, Noonan's Syndrome is the most commonly reported malformation syndrome, and Friedreich's ataxia dominates in the neuromuscular disease category.
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G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27
PCMR data demonstrate HCM to be most commonly diagnosed in the first year of life [1]. Among 328 infants presenting before age 1 year, 14.6% were identified with an inborn error of metabolism, 15.2% had malformation syndromes and 0.9% had neuromuscular disorders. The remaining 69.2% were classified with idiopathic disease. Death in HCM patients occurs in a bimodal distribution, with the highest frequencies in the first year of life, followed by a second peak during adolescence (Fig. 1). Infants and children with associated inborn errors of metabolism and malformation syndromes demonstrate the worst prognosis. Idiopathic HCM is the most common pediatric form. Survival for this subgroup was better than had been previously reported: children diagnosed or surviving after age 1 year have a mortality rate of just 1.0 per 100 patient-years [1]. Specific sarcomere and myofilament-related gene defects are more commonly identified in association with a later age of diagnosis. Between 35% and 65% of older, phenotypically-affected HCM patients will have an identifiable and disease-causing mutation in a myofilament protein. Genetic analysis has also identified causative mutations in Z-disc and calcium-handling proteins [2]. The molecular genetics of HCM are complex, involving at least 10 sarcomere-related genes in which more than 400 disease-causing missense mutations have been described [3]. Many of these sarcomeric mutations have been identified in either the myosin binding protein C or in the beta-myosin heavy chain [2,3]. These
mutations have been hypothesized to cause increased contractile function, altered myofilament calcium sensitivity, and impaired Myocyte-energetics that lead to inefficient ATP use and altered calcium homeostasis [3]. Interplay and alterations within the renin– angiotensin system and sex hormone polymorphisms have also been postulated to modify the development and time course of this disease process [2]. Recent research has shown that some sarcomeric mutations lead to increased myocardial collagen synthesis and early myocardial fibrosis [4,5]. This heterogeneous and perhaps transitional phenotype seems to be a common pathway that leads to variable degrees of left ventricular hypertrophy, myocardial fibrosis and myofibril disarray. Associated diastolic dysfunction, intramural coronary abnormalities and electrical myocardial instability further combine to raise the risk for ventricular tachyarrhythmias and sudden cardiac death [2–5]. The prevalence of HCM has been estimated to be at most 0.2% in the United States, affecting about 1 of every 500 adults [2,5]. Several community-based epidemiologic studies have estimated the risk of sudden cardiac death in teenagers and young adults with HCM to be approximately 1% per year [2]. Associated risk factors for sudden cardiac death in the adult HCM population include: (i) a family history of hypertrophic-cardiomyopathy-related premature death, (ii) unexplained syncope, (iii) a hypotensive or attenuated blood pressure response to exercise, (iv) recurrent nonsustained ventricular tachycardia as recorded by ambulatory Holter monitoring, and (v) massive left ventricular hypertrophy (a wall thickness N3 cm) [6]. 3. Screening for hypertrophic cardiomyopathy The primary purpose of screening for HCM is to identify affected patients before they experience sudden cardiac death. Early recognition of the disease, either in the pre-clinical stage (before left ventricular hypertrophy develops) or in the clinical stage (after left ventricular hypertrophy has developed) may allow for earlier treatment with the potential to alter disease progression (Fig. 2). A secondary aim of screening would be to identify family members with either pre-clinical or clinical disease, thus offering them the same therapeutic benefits as offered to the index case [7,8]. Registry and population data suggest that infants less than 1 year of age, adolescents, and athletes may be at particular risk for negative outcomes in association with HCM, and indeed, HCM is identified as the leading cause of sudden cardiac death in young athletes in the US (Fig. 3) [5]. Traditionally, the diagnosis of HCM has relied upon the identification of the left ventricular hypertrophic phenotype. However, the specific time-course of left ventricular hypertrophy is variable, age-dependent, and unpredictable, as described above. Many children and young adults, if put under the appropriate evaluation, will show pre-clinical evidence of HCM (i.e. myocardial fibrosis or diastolic dysfunction) years before developing overt left ventricular hypertrophy. As a result of these phenotypic and agerelated variations, any diagnostic or screening strategy for HCM must include a variety of components. These range from simple measures such as personal and family history, the physical examination, electrocardiography or echocardiography. More complex interventions such as cardiac magnetic resonance imaging, biomarkers, and genetic analyses (Table 1) may be appropriate for diagnosis and care in specific cases. The best application of these many modalities is yet to be determined, and will doubtless vary between location, population and availability. 4. Screening with the history and physical exam
Fig. 1. A) Age at death for 96 patients with hypertrophic cardiomyopathy and B) for 43 patients with idiopathic hypertrophic cardiomyopathy. [Source: Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation 2007;115:773–781. Epub 2007 Jan 29.]
The utility of the history and physical exam can be variable in screening patients for HCM. In 2007, the American Heart Association advised screening children aged 12 to 18 years who planned to participate in competitive sports with a 12-item pre-participation
G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27
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Hypertrophic Cardiomyopathy
Pre-clinical Disease
Genetic Cause
Suspected Cellular Abnormalities:
Sarcomere gene defects Z-disc gene defects Calcium handling gene defects Non-myocyte gene defects
Abnormalities in energy ATP utilization Abnormal calcium handling Abnormal collagen
Primary Prevention Screening Genetic testing Biomarkers
Clinical Disease
Pre-Clinical Findings Myocardial fibrosis Diastolic dysfunction
Clinical Phenotypic Finding
Symptom at Onset of Presentation
Asymptomatic Left ventricular hypertrophy
Asymptomatic New heart murmur Chest pain Palpitations Syncope
Secondary Prevention Screening EKG findings of LVH or inverted T-waves Echo finding of diastolic dysfunction or LVH MRI finding of myocardial fibrosis or LVH
Therapeutic Intervention -Medical management (calcium channel blockers, betablockers, reninangiotensin system modification (ACE inhibitor, Angiotensin receptor blocker) or statin therapy -Device therapy: implantable automatic cardiac defibrillator -Surgical myectomyor alcohol catheter based ablation -Heart transplant
Fig. 2. Screening strategies for hypertrophic cardiomyopathy at each stage of disease.
cardiovascular checklist [8]. This medical history should query for a history for exertional chest pain, unexplained syncope or nearsyncope, exertional dyspnea or fatigue with exercise, and heart murmur or elevated systolic blood pressure. It also called for assessing the family history of death and disability from heart disease before age 50 years, hypertrophic or dilated cardiomyopathy, long QTc syndrome, other ion channelopathies, Marfan's syndrome, and clinically important arrhythmias [8]. Other important questions to screen for inherited cardiomyopathy or channelopathy include a query as to a family history of sudden infant death (SIDS), unexplained recurrent seizures or any unexplained sudden death (especially while driving, swimming or in otherwise healthy athletes). The development of a newly heard heart murmur in an otherwise healthy child or adolescent is the most common physical exam finding that prompts a new diagnosis of HCM. Cardiovascular screening with a thorough history and physical exam should be performed at all wellchild exams although the effectiveness has been debated [9]. Further testing may be indicated based on the history or physical exam findings. Clinicians should be aware of the importance of a thorough personal and family history in this disease and remember that many forms are dominantly inherited. Wheeler et al. recently demonstrated
that cardiovascular screening with a history and physical alone would be unlikely to be cost effective in the US, when compared with no screening, due to the poor sensitivity and specificity in detecting causes of sudden cardiac death in young athletes [10]. 5. Screening with electrocardiography Electrocardiography is a good screening modality for clinically present myocardial hypertrophy; electrocardiograms (ECGs) can also detect pre-clinical disease in some patients. Electrocardiography is abnormal in N90% of patients with HCM [9]. Therefore, in most cases, a normal ECG suggests the absence of cardiomyopathy. Other studies of electrocardiography report a sensitivity of about 68% and specificity of 94% for HCM, with a low positive predictive value (where an abnormal ECG indicates the presence of cardiomyopathy) of only 6% to 7% in the general population [6]. The low positive predictive value for ECG testing does imply that, using this modality alone, many normal (“false positive”) subjects would be identified. Several countries have used national electrocardiography screening programs to attempt to reduce the incidence of sudden cardiac death. Italy has a government mandated cardiovascular screening
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Fig. 3. Causes of sudden cardiac death in young competitive athletes in the US. [Source: Maron BJ. Sudden Death in Hypertrophic Cardiomyopathy. J Cardiovasc Trans Res 2009;(2):368–380. Epub 2009 Nov 13.]
program that incorporates a mandatory ECG along with a history and physical exam prior to participation in sports or military service [10]. This program has reduced the rate of sudden cardiac death in young athletes to comparable rates for age matched non-athletes [10]. Electrocardiography can also detect pre-clinical disease by revealing the presence of inverted T-waves before the development of left ventricular hypertrophy [10,11,12], as well as Wolff–Parkinson– White syndrome and long QTc syndrome. The European Society of Cardiology and the International Olympic Committee currently both recommend ECG screening in their respective cardiovascular screening programs [10].
The US has not implemented large-scale, population-based ECG screening. Cost has been the major issue limiting this within the United States. Debate remains as to such issues as the number and timing of ECG screenings needed in order to effectively detect the variety of cardiac conditions associated with sudden death. Effective single screening models have been described in competitive athletes with a total incremental cost of $89 per athlete. This proposal suggested a significant improvement in the cost effectiveness per lifeyear saved when compared to screening with a history and physical exam alone [10]. Other studies have assessed the cost of adding an ECG to as low as $44 per patient [8]. Other issues such as genetic heterogeneity have not been studied, making the benefits of an Italian-modeled system uncertain in a more diverse population like the United States. ECG screening criteria for HCM generally include voltages for left ventricular hypertrophy, pathologic Q-waves, and repolarization abnormalities (T-wave inversion in the precordial leads, V2 through V6). Electrocardiography is generally recommended to evaluate any patient with a personal history, family history, or a clinical exam suspicious for HCM. In addition, we recommend that first-degree relatives and probably “athletic” second-degree relatives of a newly-diagnosed patient with HCM be screened with electrocardiography and echocardiography [2]. Annual ECGs and echocardiograms have been recommended for adolescents, young adults, and athletes aged 12 to 25 years with an affected family member [2]. For family members older than 25 years, electrocardiography and echocardiography should be performed every 3 to 5 years unless a genetic analysis has ruled out the presence of a known, specific familial mutation [2]. 6. Screening with echocardiography Echocardiography is the reference standard for diagnosing left ventricular hypertrophy in patients with a phenotypical expression of HCM. Echocardiography can accurately detect symmetric or asymmetric hypertrophy throughout the ventricles. It can detect four distinct patterns of septal hypertrophy described in HCM: (i) sigmoidal, (ii) reverse curve, (iii) apical, and (iv) neutral contours. The presence of these anatomical forms helps guide genetic testing toward specific myofilament proteins [2]. Morphologic classification
Table 1 Summary of Possible Components of a Public Screening Program for Hypertrophic Cardiomyopathy. Screening modality
Description
Indication
Family history
Family member with hypertrophic cardiomyopathy, idiopathic hypertrophic sub-aortic stenosis, muscular subaorticstenosis, and hypertrophic obstructive cardiomyopathy. Family member with sudden death b50 years old (especially sudden infant death, otherwise health drowning, or low-velocity car accident) Exertional chest pain, unexplained or recurrent syncope, near syncope, or seizure, exertionaldyspnea or fatigue New heart murmur Voltage criteria for left ventricular hypertrophy Inverted T-waves in leads V2 through V6
All patients
Personal history Physical exam Electrocardiography
Echocardiography
Magnetic resonance imaging
Serum biomarkers Genetic testing
Tissue Doppler or strain evidence of diastolic dysfunction Left ventricular hypertrophy with or without outflow tract obstruction, mitral regurgitation. Left ventricular hypertrophy, especially in the apex and basal septum. Myocardial fibrosis identified with gadolinium late enhancement C-terminal pro-peptide of type 1 procollagen assessment for increased collagen synthesis Commercially available for the most common sarcomere or myofilament-related gene defects and non-myocyte causes such as: Noonan's syndrome, Pompes disease, Forbes disease, Barth syndrome, and PRKAG2 (hypertrophic cardiomyopathyor Wolff–Parkinson–White syndrome).
All patients All patients If family history is positive, personal history or physical exam. Consideration for general population based-screening for sudden cardiac death. If positive family history, personal history or physical exam.
If diagnosed with or suspicious for atypical left ventricular hypertrophy or arrhythmogenic right ventricular dysplasia If diagnosed with hypertrophic cardiomyopathy and evaluating for myocardial fibrosis. Not yet determined All patients diagnosed with hypertrophic cardiomyopathyby physical exam, electrocardiography, and echocardiography. Consider in all first-degree relatives of a family member with a positive genetic test to determine the need for ongoing screening and pre-clinical disease.
G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27
may also have some developing impact as to potential risk stratification. Echocardiography is not always fully diagnostic, as uncertainties may exist distinguishing abnormal hypertrophy, as if found in HCM, versus normal findings of hypertrophy as is seen in the athletic heart. The echocardiogram may also be non-diagnostic (a false negative) in patients with a family history/genetic defect who have yet to develop the clinical phenotype. Newer echocardiographic modalities, such as tissue Doppler and strain-rate imaging can help detect these clinically silent forms of HCM. Tissue Doppler imaging is useful for detecting left ventricular diastolic dysfunction, which can be caused by myocyte disarray, fibrosis, left ventricular hypertrophy, alterations in calcium homeostasis, and ongoing myocardial ischemia [12]. Strain and strain-rate imaging may also have the potential for risk stratification of sudden cardiac death in patients with HCM. Strain assesses the degree of deformation or change in the length of the ventricles, and strain-rate echo measures the rate of this deformation. These characteristics are load-independent, and the degree of fibrosis that affects strain is independent of wall thickness [12]. Increasing myocardial fibrosis in HCM has been associated with an increase in the burden of ventricular tachyarrhythmias and the increased potential for sudden cardiac death. The indications for screening echocardiograms are the same as for ECGs and are listed above [2]. 7. Screening with cardiac magnetic resonance imaging Cardiac magnetic resonance imaging (MRI) is also useful for detecting and following patients with HCM. Cardiac MRI can assess the structure and function of the left ventricle. It is able to detect atypical hypertrophy at the left ventricular apex, basal portions of the septum, or non-compaction that may not be detected on standard echocardiographic views. The use of gadolinium enhancement with cardiac MRI may allow patients with HCM to be stratified as to their risk of sudden cardiovascular death. Gadolinium has a high affinity for regions of increased interstitial space or fibrosis in the myocardium. This leads to “late enhancement” on the MRI. Late enhancement is most common in areas of hypertrophy greater than 10 mm, and seems to concentrate in affected areas in the mid-layer of the myocardium; it does not appear to follow any specific coronary artery distribution [12]. Late enhancement has been attributed to myocardial necrosis and progressive myocardial fibrosis. Increased myocardial scarring may be associated with an increased risk of sudden cardiac death from ventricular arrhythmias [4]. Interestingly, similar findings of late enhancement have been described in some patients with severe aortic valve stenosis, who also have a risk of sudden cardiac death [12]. Longitudinal follow-up using MRI may be beneficial in following the degree of fibrosis, myocardial viability and possibly determining the timing for therapeutic intervention with automatic implantable cardiac defibrillator or replacement therapy with heart transplant. Recommendations for routine MRI analysis have yet to be formalized, but will likely play an increasing a role in the diagnosis and management of this disease. 8. Screening with serum biomarkers Serum biomarkers may also play a role in the detection and risk stratification in HCM. As previously discussed, myocardial fibrosis is a common pathway in the development of HCM which has been attributed to alterations in collagen synthesis. Mouse models have revealed that sarcomere gene defects leading to increased collagen deposition and increased myocardial fibrosis [4]. The C-terminal propeptide of type-1 pro-collagen is a serum byproduct and marker of type-1 collagen synthesis. CT-pro-peptide collagen levels have been shown to be elevated in patients with HCM in the pre-clinical (no left ventricular hypertrophy) and clinical stages (left ventricular hyper-
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trophy present) of the disease [4]. Further work is needed to define the clinical utility of pro-collagen markers for either population screening or individual patient management. 9. Screening with genetic tests Genetic testing for HCM has advanced from the bench to the bedside in the last decade. Sarcomeric genes causing HCM include those involved with myofilament, Z-disc, and calcium-handling proteins [2]. Non-sarcomeric proteins can also be causative for HCM, such as those seen with glycogen storage diseases (Pompe's disease), Fabry's disease, Noonan's Syndrome and Barth Syndrome [1,2]. Transcription factors and other regulatory proteins may also influence the phenotypic expression of HCM and may be important areas for genetic screening in the future (Fig. 4). The most common of the sarcomeremyofilament gene abnormalities detected in HCM occur in the beta-myosin heavy chain or in myosin binding protein C. Together these account for 30% to 50% of HCM cases in several adult series [2,5]. Several clinical and echocardiographic HCM subtypes have been strongly associated with specific gene mutations. For example, a “reverse curve” septal morphology is described in 80% of patients with myofilament gene defects, whereas a sigmoidal septal configuration is seen in only 10% of such patients [2]. Thus, it seems that echocardiographic findings may predict or correlate to specific genetic defects in at least some subsets of patients. Gene testing offers the promise to guide risk stratification for some patients. For example, HCM associated with myofilament defects is associated with an increased risk of cardiac death, stroke, congestive heart failure, left ventricular systolic dysfunction, and restrictive diastolic filling. As more data are collected we will hopefully be able to better stratify patients by risk to prevent sudden cardiac death. Genetic testing may also become important in treating patients with HCM by helping to define specific intracellular mechanisms, which may give clues toward treatment and prevention. Modifier proteins and polymorphisms in the renin–angiotensin system and sex hormone may be found to be important for treating and inhibiting progressive remodeling, fibrosis and hypertrophy [2]. Currently genetic testing can confirm a diagnosis of HCM, but has not yet modified most therapies or the clinical course of the disease. Despite this, the presence of a genetic diagnosis is desirable in order to confirm a diagnosis in the index patient, serve as the reference standard for screening first-degree relatives if the index case is positive, and potentially exempting gene-specific, negative family members from ongoing surveillance [2]. Clinicians must be cautious when interpreting a genetic test for HCM. It is important to recognize that a negative genetic test does not exclude a diagnosis of HCM. In the future, genetic analysis will be needed to improve our understanding of the genotype-phenotype relationships in HCM. Genetic counseling is important for patients and families to understand the benefits and limitations of the testing available today. 10. Current screening programs in the US Various local cardiovascular screening programs exist in the US with a common goal of detecting occult cardiovascular disease that may predispose to sudden cardiac death and saving lives within their local community. In the State of Florida, a potential model for nationalized cardiovascular screening was started in March 2010. The SafeBeat Initiative is a comprehensive, free and voluntary cardiovascular screening program offered to high school students from the 9th and 12th grades [13]. It utilizes a personal history, family medical history, height, weight, blood pressure, and ECG for each student. Both athletic and non-athletic students are encouraged to participate. All students receive cardiovascular education on risk factors, symptom recognition, and the advantages of a healthy diet and exercise. Longitudinal data will
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Fig. 4. A decision tree for genetic and echocardiographic-based screening for hypertrophic cardiomyopathy. [Source: Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am CollCardiol. 2009 Jul 14;54 (3):201–11.]
be collected on abnormal ECGs to assess the effectiveness of the program. The study aims to examine the incidence of occult cardiac conditions that predispose to sudden cardiac death (such as HCM) and to further examine the effectiveness of ECG screening in a large population-based cohort of children within the US. The incidence of childhood obesity and hypertension will also be tracked. This project is sponsored by the Cardiac Arrhythmia Syndromes Foundation, a community organization created to support research and interventions aimed at reducing sudden death in children. 11. Conclusion Large-scale screening programs in the general public for HCM must consider genetic and phenotypic heterogeneity, age-based differential diagnoses, the ability to reliably detect pre-clinical disease, and the presence of other causes of sudden cardiac death besides HCM. Electrocardiography screening programs have been effective in other countries. Currently, a thorough personal history, family history, and ECG are the best components of cardiovascular screening for HCM in the general public. The ages at which to screen children and adults will need to be determined in the US. The estimated cost of a physical exam, history, and ECG is as low as $44 [7]. As genetic testing becomes more available, less expensive, and free of the need for blood draws (depending instead on buccal swabs or saliva) it may be added to a general population-based
screening programs. The National Heart Lung and Blood Institute recently convened a working group to assess screening options for sudden cardiac death in the US [14]. This group concluded that, although such screening is important, further studies need to be conducted to assess the epidemiology and causes of sudden cardiac death in the general population, the accuracy of screening modalities in the general population, how asymptomatic heart disease discovered with screening should be managed, and the overall impact of ECG screening on the individual, family, community, and society. As a nation, we need to draw on the experience of other nations and ongoing genetic research to develop a cost-effective, comprehensive cardiovascular screening program able to identify HCM and other cardiovascular disorders, in the hope of preventing sudden cardiac death. References [1] Colan SD, Lipshultz SE, Lowe AM, et al. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children. Findings from the pediatric cardiomyopathy registry. Circulation 2007;115:773–81. [2] Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54(3):201–11. [3] Ferrantini C, Belus A, Piroddi N, et al. Mechanical and energetic consequences of HCM-causing mutations. J Cardiovasc Transl Res 2009;2:441–51. [4] 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.
G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27 [5] Maron BJ. Sudden death in hypertrophic cardiomyopathy. J Cardiovasc Transl Res Dec. 2009;2(4):368–80. [6] Nistri S, Olivotto I, Girolami F, Torricelli F, Cecchi F, Yacoub MH. Looking for hypertrophic cardiomyopathy in the community: why is it important? J CardiovascTransl Res 2009(2):392–7. [7] Wren C. Screening for potentially fatal heart disease in children and teenagers. Heart 2009;95:2040–6. [8] Maron BJ, Thompson PD, Ackerman MJ, et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 2007;115:1643–55. [9] Wilson MG, Basavarajaiah S, Whyte G, et al. Efficacy of personal symptom and family history questionnaires when screening for inherited cardiac pathologies? The role of electrocardiography. Br J Sports Med 2007:039420.
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[10] Wheeler MT, Heidenreich PA, Froelicher VF, et al. Cost effectiveness of preparticipation screening for prevention of sudden cardiac death in young athletes. Ann Intern Med 2010;152(5):276–86. [11] Pelliccia A, DiPaolo FM, Quattrini FM, et al. Outcomes in athletes with marked ECG repolarization abnormalities. N Engl J Med 2008;358:152–61. [12] Fuster V, Vander Zee S, Miller MA. Evolving anatomic, functional, and molecular imaging in the early detection and prognosis of hypertrophic cardiomyopathy. J CardiovascTransl Res 2009(2):398–406. [13] Cardiac Arrhythmia Syndromes Foundation. www.thecasfoundation.org. [14] National Heart Lung and blood Institute, National Institutes of Health. NHLBI working group screening for sudden cardiac death, executive summary. www. nhlbi.nih.gov.
Contents lists available at ScienceDirect
Progress in Pediatric Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p p e d c a r d
Diagnosis and screening of hypertrophic cardiomyopathy in children Gul H. Dadlani a,b,⁎, William G. Harmon c, Elimarys Perez-Colon b, Mary C. Sokoloski c, Ivan Wilmot a, Steven E. Lipshultz c a b c
All Children's Hospital Heart Institute, St. Petersburg, FL, United States University of South Florida, Department of Pediatrics, Tampa, FL, United States Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
a r t i c l e
i n f o
Keywords: Hypertrophic cardiomyopathy Sudden cardiac death Screening Pediatrics
a b s t r a c t Hypertrophic cardiomyopathy is the most common inherited cardiovascular disorder and the leading cause of sudden cardiac death in young people in the United States. Wide genetic heterogeneity and phenotypic expression are seen in hypertrophic cardiomyopathy and can make this disorder difficult to recognize in the general public. Population based screening for hypertrophic cardiomyopathy is aimed to allow for early detection, earlier treatment, promote complete family screening and to hopefully prevent some cases of sudden cardiac death in the community. A screening regimen consisting of a directed medical history and physical exam is currently recommended in the United States. The addition of electrocardiography is routine in some countries and can help guide the utilization of more expensive or invasive testing. Tools such as echocardiography, magnetic resonance imaging, serum biomarkers, and genetic testing are then directed to specific individuals to maximize their diagnostic and prognostic impact. Currently, no specific or widespread screening program has been uniformly adopted across the United States, as costs, benefits and the hazards of false positive diagnoses have yet to be balanced and decided. A working knowledge and appropriate suspicion for HCM remains fundamental for clinicians in order to diagnosis this important disorder. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hypertrophic cardiomyopathy (HCM) is an important disease affecting populations worldwide. It is the most common inherited cardiovascular disorder and the leading cause of sudden cardiac death in young people. HCM demonstrates wide genetic heterogeneity and variable phenotypic expression that can complicate recognition and diagnosis in the broad population. Screening for HCM could potentially allow for early detection, earlier treatment, screening for sub-clinical disease in family members, and may prevent some episodes of sudden cardiac death in the community. 2. Background: the nature of hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is a phenotypic label describing a heterogeneous group of disorders that produce ventricular hypertrophy in the absence of an identifiable hemodynamic cause [1]. Pediatric cardiomyopathies have been traditionally categorized by their dominant phenotypic subgroups as: (i) dilated, (ii) hypertrophic, or
⁎ Corresponding author. All Children's Hospital Heart Institute, Outpatient Care Center 2nd Floor, 501 6th Street South, St. Petersburg FL 33701, United States. Tel.: + 1 727 767 3333; fax: + 1 727 767 8990. E-mail address: [email protected] (G.H. Dadlani). 1058-9813/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ppedcard.2010.11.005
(iii) restrictive disease. Arrhythmogenic right ventricular dysplasia and left ventricular non-compaction have been increasingly recognized as other important clinical entities [1]. Considerable genetic commonality seems to exist between these disease subtypes, as similar gene mutations have been found in association with different phenotypic expression, seemingly to arise from variable effects of gene function, expression and control. The NHLBI-supported North American Pediatric Cardiomyopathy Registry (PCMR), the largest such registry globally, classifies pediatric hypertrophic cardiomyopathies in four distinct diagnostic categories: (i) disease found in association with inborn errors of metabolism, (ii) those identified as a component of a malformation syndrome, (iii) disease found in the setting of a neuromuscular disorder, and (iv) idiopathic disease. Idiopathic disease may be familial, and it may or may not be seen in association with a known myofilament or sarcomeric gene defect. Population-based data from the PCMR indicate the overall incidence of HCM to be 4.7 per 1 million children in two broad regions of North America [1]. The PCMR also recorded 42 specific identifiable causes in a cohort of 855 children less than 18 years of age [1]. Interestingly, in each of the major diagnostic categories a single disease process is shown to predominate: Pompe disease is the most common inborn error of metabolism, Noonan's Syndrome is the most commonly reported malformation syndrome, and Friedreich's ataxia dominates in the neuromuscular disease category.
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G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27
PCMR data demonstrate HCM to be most commonly diagnosed in the first year of life [1]. Among 328 infants presenting before age 1 year, 14.6% were identified with an inborn error of metabolism, 15.2% had malformation syndromes and 0.9% had neuromuscular disorders. The remaining 69.2% were classified with idiopathic disease. Death in HCM patients occurs in a bimodal distribution, with the highest frequencies in the first year of life, followed by a second peak during adolescence (Fig. 1). Infants and children with associated inborn errors of metabolism and malformation syndromes demonstrate the worst prognosis. Idiopathic HCM is the most common pediatric form. Survival for this subgroup was better than had been previously reported: children diagnosed or surviving after age 1 year have a mortality rate of just 1.0 per 100 patient-years [1]. Specific sarcomere and myofilament-related gene defects are more commonly identified in association with a later age of diagnosis. Between 35% and 65% of older, phenotypically-affected HCM patients will have an identifiable and disease-causing mutation in a myofilament protein. Genetic analysis has also identified causative mutations in Z-disc and calcium-handling proteins [2]. The molecular genetics of HCM are complex, involving at least 10 sarcomere-related genes in which more than 400 disease-causing missense mutations have been described [3]. Many of these sarcomeric mutations have been identified in either the myosin binding protein C or in the beta-myosin heavy chain [2,3]. These
mutations have been hypothesized to cause increased contractile function, altered myofilament calcium sensitivity, and impaired Myocyte-energetics that lead to inefficient ATP use and altered calcium homeostasis [3]. Interplay and alterations within the renin– angiotensin system and sex hormone polymorphisms have also been postulated to modify the development and time course of this disease process [2]. Recent research has shown that some sarcomeric mutations lead to increased myocardial collagen synthesis and early myocardial fibrosis [4,5]. This heterogeneous and perhaps transitional phenotype seems to be a common pathway that leads to variable degrees of left ventricular hypertrophy, myocardial fibrosis and myofibril disarray. Associated diastolic dysfunction, intramural coronary abnormalities and electrical myocardial instability further combine to raise the risk for ventricular tachyarrhythmias and sudden cardiac death [2–5]. The prevalence of HCM has been estimated to be at most 0.2% in the United States, affecting about 1 of every 500 adults [2,5]. Several community-based epidemiologic studies have estimated the risk of sudden cardiac death in teenagers and young adults with HCM to be approximately 1% per year [2]. Associated risk factors for sudden cardiac death in the adult HCM population include: (i) a family history of hypertrophic-cardiomyopathy-related premature death, (ii) unexplained syncope, (iii) a hypotensive or attenuated blood pressure response to exercise, (iv) recurrent nonsustained ventricular tachycardia as recorded by ambulatory Holter monitoring, and (v) massive left ventricular hypertrophy (a wall thickness N3 cm) [6]. 3. Screening for hypertrophic cardiomyopathy The primary purpose of screening for HCM is to identify affected patients before they experience sudden cardiac death. Early recognition of the disease, either in the pre-clinical stage (before left ventricular hypertrophy develops) or in the clinical stage (after left ventricular hypertrophy has developed) may allow for earlier treatment with the potential to alter disease progression (Fig. 2). A secondary aim of screening would be to identify family members with either pre-clinical or clinical disease, thus offering them the same therapeutic benefits as offered to the index case [7,8]. Registry and population data suggest that infants less than 1 year of age, adolescents, and athletes may be at particular risk for negative outcomes in association with HCM, and indeed, HCM is identified as the leading cause of sudden cardiac death in young athletes in the US (Fig. 3) [5]. Traditionally, the diagnosis of HCM has relied upon the identification of the left ventricular hypertrophic phenotype. However, the specific time-course of left ventricular hypertrophy is variable, age-dependent, and unpredictable, as described above. Many children and young adults, if put under the appropriate evaluation, will show pre-clinical evidence of HCM (i.e. myocardial fibrosis or diastolic dysfunction) years before developing overt left ventricular hypertrophy. As a result of these phenotypic and agerelated variations, any diagnostic or screening strategy for HCM must include a variety of components. These range from simple measures such as personal and family history, the physical examination, electrocardiography or echocardiography. More complex interventions such as cardiac magnetic resonance imaging, biomarkers, and genetic analyses (Table 1) may be appropriate for diagnosis and care in specific cases. The best application of these many modalities is yet to be determined, and will doubtless vary between location, population and availability. 4. Screening with the history and physical exam
Fig. 1. A) Age at death for 96 patients with hypertrophic cardiomyopathy and B) for 43 patients with idiopathic hypertrophic cardiomyopathy. [Source: Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation 2007;115:773–781. Epub 2007 Jan 29.]
The utility of the history and physical exam can be variable in screening patients for HCM. In 2007, the American Heart Association advised screening children aged 12 to 18 years who planned to participate in competitive sports with a 12-item pre-participation
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Hypertrophic Cardiomyopathy
Pre-clinical Disease
Genetic Cause
Suspected Cellular Abnormalities:
Sarcomere gene defects Z-disc gene defects Calcium handling gene defects Non-myocyte gene defects
Abnormalities in energy ATP utilization Abnormal calcium handling Abnormal collagen
Primary Prevention Screening Genetic testing Biomarkers
Clinical Disease
Pre-Clinical Findings Myocardial fibrosis Diastolic dysfunction
Clinical Phenotypic Finding
Symptom at Onset of Presentation
Asymptomatic Left ventricular hypertrophy
Asymptomatic New heart murmur Chest pain Palpitations Syncope
Secondary Prevention Screening EKG findings of LVH or inverted T-waves Echo finding of diastolic dysfunction or LVH MRI finding of myocardial fibrosis or LVH
Therapeutic Intervention -Medical management (calcium channel blockers, betablockers, reninangiotensin system modification (ACE inhibitor, Angiotensin receptor blocker) or statin therapy -Device therapy: implantable automatic cardiac defibrillator -Surgical myectomyor alcohol catheter based ablation -Heart transplant
Fig. 2. Screening strategies for hypertrophic cardiomyopathy at each stage of disease.
cardiovascular checklist [8]. This medical history should query for a history for exertional chest pain, unexplained syncope or nearsyncope, exertional dyspnea or fatigue with exercise, and heart murmur or elevated systolic blood pressure. It also called for assessing the family history of death and disability from heart disease before age 50 years, hypertrophic or dilated cardiomyopathy, long QTc syndrome, other ion channelopathies, Marfan's syndrome, and clinically important arrhythmias [8]. Other important questions to screen for inherited cardiomyopathy or channelopathy include a query as to a family history of sudden infant death (SIDS), unexplained recurrent seizures or any unexplained sudden death (especially while driving, swimming or in otherwise healthy athletes). The development of a newly heard heart murmur in an otherwise healthy child or adolescent is the most common physical exam finding that prompts a new diagnosis of HCM. Cardiovascular screening with a thorough history and physical exam should be performed at all wellchild exams although the effectiveness has been debated [9]. Further testing may be indicated based on the history or physical exam findings. Clinicians should be aware of the importance of a thorough personal and family history in this disease and remember that many forms are dominantly inherited. Wheeler et al. recently demonstrated
that cardiovascular screening with a history and physical alone would be unlikely to be cost effective in the US, when compared with no screening, due to the poor sensitivity and specificity in detecting causes of sudden cardiac death in young athletes [10]. 5. Screening with electrocardiography Electrocardiography is a good screening modality for clinically present myocardial hypertrophy; electrocardiograms (ECGs) can also detect pre-clinical disease in some patients. Electrocardiography is abnormal in N90% of patients with HCM [9]. Therefore, in most cases, a normal ECG suggests the absence of cardiomyopathy. Other studies of electrocardiography report a sensitivity of about 68% and specificity of 94% for HCM, with a low positive predictive value (where an abnormal ECG indicates the presence of cardiomyopathy) of only 6% to 7% in the general population [6]. The low positive predictive value for ECG testing does imply that, using this modality alone, many normal (“false positive”) subjects would be identified. Several countries have used national electrocardiography screening programs to attempt to reduce the incidence of sudden cardiac death. Italy has a government mandated cardiovascular screening
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Fig. 3. Causes of sudden cardiac death in young competitive athletes in the US. [Source: Maron BJ. Sudden Death in Hypertrophic Cardiomyopathy. J Cardiovasc Trans Res 2009;(2):368–380. Epub 2009 Nov 13.]
program that incorporates a mandatory ECG along with a history and physical exam prior to participation in sports or military service [10]. This program has reduced the rate of sudden cardiac death in young athletes to comparable rates for age matched non-athletes [10]. Electrocardiography can also detect pre-clinical disease by revealing the presence of inverted T-waves before the development of left ventricular hypertrophy [10,11,12], as well as Wolff–Parkinson– White syndrome and long QTc syndrome. The European Society of Cardiology and the International Olympic Committee currently both recommend ECG screening in their respective cardiovascular screening programs [10].
The US has not implemented large-scale, population-based ECG screening. Cost has been the major issue limiting this within the United States. Debate remains as to such issues as the number and timing of ECG screenings needed in order to effectively detect the variety of cardiac conditions associated with sudden death. Effective single screening models have been described in competitive athletes with a total incremental cost of $89 per athlete. This proposal suggested a significant improvement in the cost effectiveness per lifeyear saved when compared to screening with a history and physical exam alone [10]. Other studies have assessed the cost of adding an ECG to as low as $44 per patient [8]. Other issues such as genetic heterogeneity have not been studied, making the benefits of an Italian-modeled system uncertain in a more diverse population like the United States. ECG screening criteria for HCM generally include voltages for left ventricular hypertrophy, pathologic Q-waves, and repolarization abnormalities (T-wave inversion in the precordial leads, V2 through V6). Electrocardiography is generally recommended to evaluate any patient with a personal history, family history, or a clinical exam suspicious for HCM. In addition, we recommend that first-degree relatives and probably “athletic” second-degree relatives of a newly-diagnosed patient with HCM be screened with electrocardiography and echocardiography [2]. Annual ECGs and echocardiograms have been recommended for adolescents, young adults, and athletes aged 12 to 25 years with an affected family member [2]. For family members older than 25 years, electrocardiography and echocardiography should be performed every 3 to 5 years unless a genetic analysis has ruled out the presence of a known, specific familial mutation [2]. 6. Screening with echocardiography Echocardiography is the reference standard for diagnosing left ventricular hypertrophy in patients with a phenotypical expression of HCM. Echocardiography can accurately detect symmetric or asymmetric hypertrophy throughout the ventricles. It can detect four distinct patterns of septal hypertrophy described in HCM: (i) sigmoidal, (ii) reverse curve, (iii) apical, and (iv) neutral contours. The presence of these anatomical forms helps guide genetic testing toward specific myofilament proteins [2]. Morphologic classification
Table 1 Summary of Possible Components of a Public Screening Program for Hypertrophic Cardiomyopathy. Screening modality
Description
Indication
Family history
Family member with hypertrophic cardiomyopathy, idiopathic hypertrophic sub-aortic stenosis, muscular subaorticstenosis, and hypertrophic obstructive cardiomyopathy. Family member with sudden death b50 years old (especially sudden infant death, otherwise health drowning, or low-velocity car accident) Exertional chest pain, unexplained or recurrent syncope, near syncope, or seizure, exertionaldyspnea or fatigue New heart murmur Voltage criteria for left ventricular hypertrophy Inverted T-waves in leads V2 through V6
All patients
Personal history Physical exam Electrocardiography
Echocardiography
Magnetic resonance imaging
Serum biomarkers Genetic testing
Tissue Doppler or strain evidence of diastolic dysfunction Left ventricular hypertrophy with or without outflow tract obstruction, mitral regurgitation. Left ventricular hypertrophy, especially in the apex and basal septum. Myocardial fibrosis identified with gadolinium late enhancement C-terminal pro-peptide of type 1 procollagen assessment for increased collagen synthesis Commercially available for the most common sarcomere or myofilament-related gene defects and non-myocyte causes such as: Noonan's syndrome, Pompes disease, Forbes disease, Barth syndrome, and PRKAG2 (hypertrophic cardiomyopathyor Wolff–Parkinson–White syndrome).
All patients All patients If family history is positive, personal history or physical exam. Consideration for general population based-screening for sudden cardiac death. If positive family history, personal history or physical exam.
If diagnosed with or suspicious for atypical left ventricular hypertrophy or arrhythmogenic right ventricular dysplasia If diagnosed with hypertrophic cardiomyopathy and evaluating for myocardial fibrosis. Not yet determined All patients diagnosed with hypertrophic cardiomyopathyby physical exam, electrocardiography, and echocardiography. Consider in all first-degree relatives of a family member with a positive genetic test to determine the need for ongoing screening and pre-clinical disease.
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may also have some developing impact as to potential risk stratification. Echocardiography is not always fully diagnostic, as uncertainties may exist distinguishing abnormal hypertrophy, as if found in HCM, versus normal findings of hypertrophy as is seen in the athletic heart. The echocardiogram may also be non-diagnostic (a false negative) in patients with a family history/genetic defect who have yet to develop the clinical phenotype. Newer echocardiographic modalities, such as tissue Doppler and strain-rate imaging can help detect these clinically silent forms of HCM. Tissue Doppler imaging is useful for detecting left ventricular diastolic dysfunction, which can be caused by myocyte disarray, fibrosis, left ventricular hypertrophy, alterations in calcium homeostasis, and ongoing myocardial ischemia [12]. Strain and strain-rate imaging may also have the potential for risk stratification of sudden cardiac death in patients with HCM. Strain assesses the degree of deformation or change in the length of the ventricles, and strain-rate echo measures the rate of this deformation. These characteristics are load-independent, and the degree of fibrosis that affects strain is independent of wall thickness [12]. Increasing myocardial fibrosis in HCM has been associated with an increase in the burden of ventricular tachyarrhythmias and the increased potential for sudden cardiac death. The indications for screening echocardiograms are the same as for ECGs and are listed above [2]. 7. Screening with cardiac magnetic resonance imaging Cardiac magnetic resonance imaging (MRI) is also useful for detecting and following patients with HCM. Cardiac MRI can assess the structure and function of the left ventricle. It is able to detect atypical hypertrophy at the left ventricular apex, basal portions of the septum, or non-compaction that may not be detected on standard echocardiographic views. The use of gadolinium enhancement with cardiac MRI may allow patients with HCM to be stratified as to their risk of sudden cardiovascular death. Gadolinium has a high affinity for regions of increased interstitial space or fibrosis in the myocardium. This leads to “late enhancement” on the MRI. Late enhancement is most common in areas of hypertrophy greater than 10 mm, and seems to concentrate in affected areas in the mid-layer of the myocardium; it does not appear to follow any specific coronary artery distribution [12]. Late enhancement has been attributed to myocardial necrosis and progressive myocardial fibrosis. Increased myocardial scarring may be associated with an increased risk of sudden cardiac death from ventricular arrhythmias [4]. Interestingly, similar findings of late enhancement have been described in some patients with severe aortic valve stenosis, who also have a risk of sudden cardiac death [12]. Longitudinal follow-up using MRI may be beneficial in following the degree of fibrosis, myocardial viability and possibly determining the timing for therapeutic intervention with automatic implantable cardiac defibrillator or replacement therapy with heart transplant. Recommendations for routine MRI analysis have yet to be formalized, but will likely play an increasing a role in the diagnosis and management of this disease. 8. Screening with serum biomarkers Serum biomarkers may also play a role in the detection and risk stratification in HCM. As previously discussed, myocardial fibrosis is a common pathway in the development of HCM which has been attributed to alterations in collagen synthesis. Mouse models have revealed that sarcomere gene defects leading to increased collagen deposition and increased myocardial fibrosis [4]. The C-terminal propeptide of type-1 pro-collagen is a serum byproduct and marker of type-1 collagen synthesis. CT-pro-peptide collagen levels have been shown to be elevated in patients with HCM in the pre-clinical (no left ventricular hypertrophy) and clinical stages (left ventricular hyper-
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trophy present) of the disease [4]. Further work is needed to define the clinical utility of pro-collagen markers for either population screening or individual patient management. 9. Screening with genetic tests Genetic testing for HCM has advanced from the bench to the bedside in the last decade. Sarcomeric genes causing HCM include those involved with myofilament, Z-disc, and calcium-handling proteins [2]. Non-sarcomeric proteins can also be causative for HCM, such as those seen with glycogen storage diseases (Pompe's disease), Fabry's disease, Noonan's Syndrome and Barth Syndrome [1,2]. Transcription factors and other regulatory proteins may also influence the phenotypic expression of HCM and may be important areas for genetic screening in the future (Fig. 4). The most common of the sarcomeremyofilament gene abnormalities detected in HCM occur in the beta-myosin heavy chain or in myosin binding protein C. Together these account for 30% to 50% of HCM cases in several adult series [2,5]. Several clinical and echocardiographic HCM subtypes have been strongly associated with specific gene mutations. For example, a “reverse curve” septal morphology is described in 80% of patients with myofilament gene defects, whereas a sigmoidal septal configuration is seen in only 10% of such patients [2]. Thus, it seems that echocardiographic findings may predict or correlate to specific genetic defects in at least some subsets of patients. Gene testing offers the promise to guide risk stratification for some patients. For example, HCM associated with myofilament defects is associated with an increased risk of cardiac death, stroke, congestive heart failure, left ventricular systolic dysfunction, and restrictive diastolic filling. As more data are collected we will hopefully be able to better stratify patients by risk to prevent sudden cardiac death. Genetic testing may also become important in treating patients with HCM by helping to define specific intracellular mechanisms, which may give clues toward treatment and prevention. Modifier proteins and polymorphisms in the renin–angiotensin system and sex hormone may be found to be important for treating and inhibiting progressive remodeling, fibrosis and hypertrophy [2]. Currently genetic testing can confirm a diagnosis of HCM, but has not yet modified most therapies or the clinical course of the disease. Despite this, the presence of a genetic diagnosis is desirable in order to confirm a diagnosis in the index patient, serve as the reference standard for screening first-degree relatives if the index case is positive, and potentially exempting gene-specific, negative family members from ongoing surveillance [2]. Clinicians must be cautious when interpreting a genetic test for HCM. It is important to recognize that a negative genetic test does not exclude a diagnosis of HCM. In the future, genetic analysis will be needed to improve our understanding of the genotype-phenotype relationships in HCM. Genetic counseling is important for patients and families to understand the benefits and limitations of the testing available today. 10. Current screening programs in the US Various local cardiovascular screening programs exist in the US with a common goal of detecting occult cardiovascular disease that may predispose to sudden cardiac death and saving lives within their local community. In the State of Florida, a potential model for nationalized cardiovascular screening was started in March 2010. The SafeBeat Initiative is a comprehensive, free and voluntary cardiovascular screening program offered to high school students from the 9th and 12th grades [13]. It utilizes a personal history, family medical history, height, weight, blood pressure, and ECG for each student. Both athletic and non-athletic students are encouraged to participate. All students receive cardiovascular education on risk factors, symptom recognition, and the advantages of a healthy diet and exercise. Longitudinal data will
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Fig. 4. A decision tree for genetic and echocardiographic-based screening for hypertrophic cardiomyopathy. [Source: Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am CollCardiol. 2009 Jul 14;54 (3):201–11.]
be collected on abnormal ECGs to assess the effectiveness of the program. The study aims to examine the incidence of occult cardiac conditions that predispose to sudden cardiac death (such as HCM) and to further examine the effectiveness of ECG screening in a large population-based cohort of children within the US. The incidence of childhood obesity and hypertension will also be tracked. This project is sponsored by the Cardiac Arrhythmia Syndromes Foundation, a community organization created to support research and interventions aimed at reducing sudden death in children. 11. Conclusion Large-scale screening programs in the general public for HCM must consider genetic and phenotypic heterogeneity, age-based differential diagnoses, the ability to reliably detect pre-clinical disease, and the presence of other causes of sudden cardiac death besides HCM. Electrocardiography screening programs have been effective in other countries. Currently, a thorough personal history, family history, and ECG are the best components of cardiovascular screening for HCM in the general public. The ages at which to screen children and adults will need to be determined in the US. The estimated cost of a physical exam, history, and ECG is as low as $44 [7]. As genetic testing becomes more available, less expensive, and free of the need for blood draws (depending instead on buccal swabs or saliva) it may be added to a general population-based
screening programs. The National Heart Lung and Blood Institute recently convened a working group to assess screening options for sudden cardiac death in the US [14]. This group concluded that, although such screening is important, further studies need to be conducted to assess the epidemiology and causes of sudden cardiac death in the general population, the accuracy of screening modalities in the general population, how asymptomatic heart disease discovered with screening should be managed, and the overall impact of ECG screening on the individual, family, community, and society. As a nation, we need to draw on the experience of other nations and ongoing genetic research to develop a cost-effective, comprehensive cardiovascular screening program able to identify HCM and other cardiovascular disorders, in the hope of preventing sudden cardiac death. References [1] Colan SD, Lipshultz SE, Lowe AM, et al. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children. Findings from the pediatric cardiomyopathy registry. Circulation 2007;115:773–81. [2] Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol 2009;54(3):201–11. [3] Ferrantini C, Belus A, Piroddi N, et al. Mechanical and energetic consequences of HCM-causing mutations. J Cardiovasc Transl Res 2009;2:441–51. [4] 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.
G.H. Dadlani et al. / Progress in Pediatric Cardiology 31 (2011) 21–27 [5] Maron BJ. Sudden death in hypertrophic cardiomyopathy. J Cardiovasc Transl Res Dec. 2009;2(4):368–80. [6] Nistri S, Olivotto I, Girolami F, Torricelli F, Cecchi F, Yacoub MH. Looking for hypertrophic cardiomyopathy in the community: why is it important? J CardiovascTransl Res 2009(2):392–7. [7] Wren C. Screening for potentially fatal heart disease in children and teenagers. Heart 2009;95:2040–6. [8] Maron BJ, Thompson PD, Ackerman MJ, et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 2007;115:1643–55. [9] Wilson MG, Basavarajaiah S, Whyte G, et al. Efficacy of personal symptom and family history questionnaires when screening for inherited cardiac pathologies? The role of electrocardiography. Br J Sports Med 2007:039420.
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[10] Wheeler MT, Heidenreich PA, Froelicher VF, et al. Cost effectiveness of preparticipation screening for prevention of sudden cardiac death in young athletes. Ann Intern Med 2010;152(5):276–86. [11] Pelliccia A, DiPaolo FM, Quattrini FM, et al. Outcomes in athletes with marked ECG repolarization abnormalities. N Engl J Med 2008;358:152–61. [12] Fuster V, Vander Zee S, Miller MA. Evolving anatomic, functional, and molecular imaging in the early detection and prognosis of hypertrophic cardiomyopathy. J CardiovascTransl Res 2009(2):398–406. [13] Cardiac Arrhythmia Syndromes Foundation. www.thecasfoundation.org. [14] National Heart Lung and blood Institute, National Institutes of Health. NHLBI working group screening for sudden cardiac death, executive summary. www. nhlbi.nih.gov.