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Differences in Diagnostic Value of Four Electrocardiographic Voltage Criteria for Hypertrophic Cardiomyopathy in a Genotyped Population
Differences in Diagnostic Value of Four Electrocardiographic Voltage Criteria for Hypertrophic Cardiomyopathy in a Genotyped Population Tetsuo Konno, MD*, Masami Shimizu, MD, Hidekazu Ino, MD, Noboru Fujino, MD, Kenshi Hayashi, MD, Katsuharu Uchiyama, MD, Tomoya Kaneda, MD, Masaru Inoue, MD, Takashi Fujita, MD, Eiichi Masuta, MD, Akira Funada, MD, and Hiroshi Mabuchi, MD The diagnostic value of various classic electrocardiographic (ECG) voltage criteria for hypertrophic cardiomyopathy (HC) has not been established in a genotyped population. This study aimed to determine the most accurate diagnostic definition of classic ECG voltage criteria for detecting carriers of HC. ECG and echocardiographic findings were analyzed in 161 genotyped subjects (97 genetically affected, 64 unaffected) from 20 families with disease-causing mutations in 4 genes. The diagnostic value of 4 voltage criteria (Cornell, Sokolow-Lyon, Romhilt-Estes, and 12-lead QRS voltage) for detecting carriers of HC was investigated. In all subjects, the RomhiltEstes (point score >4) criterion and 12-lead QRS voltage (>240 mm) were most sensitive (37% and 36%, respectively), with high specificity (95% each), resulting in the greatest accuracy (60% and 59%, respectively). Using these criteria, in subjects without echocardiographic evidence of left ventricular hypertrophy, voltage abnormalities were found in 22.6% of carriers and 4.7% of noncarriers (p <0.01). In conclusion, these findings suggest that the Romhilt-Estes and the 12-lead QRS voltage criteria may be the most accurate diagnostic definitions for HC on the basis of molecular genetic diagnoses. Furthermore, this study demonstrated that voltage abnormalities may be found in prehypertrophic carriers. Even when genetic testing becomes widely available, it will be difficult to make genetic diagnoses in all patients with HC because of its genetic heterogeneity. Therefore, understanding the diagnostic value of classic ECG voltage criteria may be important in detecting carriers, including those without left ventricular hypertrophy. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96:1308 –1312)
In clinical practice, classic electrocardiographic (ECG) voltage criteria have been applied to the detection of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy (HC). However, differences in the diagnostic value of various voltage criteria for HC have not yet been clarified. Recent molecular genetic studies in HC have shown that some genetic carriers of the disease may have no demonstrable hypertrophy on 2-dimensional echocardiography.1 Previous studies have demonstrated that ECG abnormalities may be observed before the appearance of left ventricular hypertrophy in carriers with disease-causing mutations for HC.2,3 The first goal of the present study was to determine the most accurate diagnostic definition of classic ECG voltage criteria for HC on the basis of molecular genetic diagnoses, and the second goal was to apply classic
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. Manuscript received January 26, 2005; revised manuscript received and accepted June 15, 2005. * Corresponding author: Tel: 81-76-265-2254; fax: 81-76-234-4251. E-mail address: [email protected] (T. Konno). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.06.078
ECG voltage criteria to the identification of prehypertrophic carriers in clinically healthy subjects.
Methods Subjects: Twenty families with HC in which the disease-causing mutation was identified were studied. After the mutation was identified in the proband with HC, the family members were studied by 12-lead electrocardiography and echocardiography, and blood samples were obtained for genetic analysis. A total of 173 subjects were included in this study. Twelve subjects were excluded because of ⱖ1 of the following reasons: a history of old anterior myocardial infarction, preexcitation, hypertension, and conduction disturbance. Consequently, 161 subjects were analyzed. Informed consent was obtained from all subjects or their guardians in accordance with the guidelines of the Bioethical Committee on Medical Researches, School of Medicine, Kanazawa University. Detection of mutations: Deoxyribonucleic acid of the probands was isolated from peripheral white blood cells, as previously described.4 The amplification of genomic dewww.AJConline.org
Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy
oxyribonucleic acid was performed using a polymerase chain reaction. Oligonucleotide primers were used to amplify exons of the cardiac myosin-binding protein C gene, -myosin heavy chain gene, cardiac troponin T gene, and cardiac troponin I gene, as previously reported.5– 8 Singlestrand conformational polymorphism analysis of amplified deoxyribonucleic acid was then performed. For abnormal single-strand conformational polymorphism patterns, the nucleotide sequences of the cloned polymerase chain reaction products were determined on the 2 strands by the dye terminator cycle sequencing method using an automated fluorescent sequencer (ABI PRISM 310 Genetic Analyzer, PE Biosystems, Foster City, California). The sequence variations were confirmed by restriction enzyme digestion. Definition of classic ECG voltage criteria: Standard 12-lead electrocardiograms were recorded in all subjects in the supine position during quiet respiration. The ECG voltage criteria were defined as follows on the basis of previous studies: Cornell voltage criterion: R aVL ⫹ SV3, with 8 mm added in women, ⬎28 mm9; Sokolow-Lyon voltage criterion: SV1 ⫹ RV5 or RV6, whichever is larger, ⬎35 mm10; Romhilt-Estes voltage criterion: point score, described previously,11 ⱖ4; and sum of QRS voltages in all 12 leads ⬎175 mm.12 ECG abnormalities other than classic ECG voltage criteria were defined as follows: Q wave ⬎3 mm in depth and/or ⬎0.04 seconds in duration in ⱖ2 leads except aVR13; ST-segment depression of an upsloping type ⬎0.1 mV at 0.08 seconds after the J point, or those of horizontal or downsloping type ⬎0.05 mV2,13; and T-wave inversion ⬎0.1 mV except aVR and V1 to V2 leads in the absence of conduction disturbance.2,13 Echocardiographic criteria: Standard M-mode and 2dimensional echocardiographic studies were performed to identify and quantify morphologic features of the left ventricle. Left ventricular dimensions and the thickness of the septum and posterior wall were measured at the level of the tips of the mitral valve leaflets. Left ventricular maximum wall thickness ⱖ13 mm in adults and ⱖ95% confidence interval of the theoretic value in children were considered the diagnostic criteria for HC.14 Electrocardiography and echocardiography were performed at the time of genotyping and were analyzed without knowledge of the genetic status. Statistical analysis: Sensitivity was defined in percentage as true-positive results/(true-positive results ⫹ falsenegative results) ⫻ 100, specificity as true-negative results/ (true-negative results ⫹ false-positive results) ⫻ 100, positive predictive value as true-positive results/(true-positive results ⫹ false-positive results) ⫻ 100, negative predictive value as true-negative results/(true-negative results ⫹ false-negative results) ⫻ 100, and accuracy as (true-positive results ⫹ true-negative results)/(true-positive results ⫹ truenegative results ⫹ false-positive results ⫹ false-negative results) ⫻ 100.15 Continuous data are expressed as mean ⫾ SD and were analyzed with Student’s unpaired, 2-tailed t test.
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Table 1 Demographic and clinical characteristics of the study groups Characteristic
Carriers (n ⫽ 97)
Noncarriers (n ⫽ 64)
Age (yrs) Men/Women Genes TNNI3 TNNT2 MYBPC MYH7 Echocardiography MWT (mm) IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) FS (%) LAD (mm) Voltage criteria Sokolow-Lyon Cornel Romhilt-Estes 12-lead QRS
44.9 ⫾ 21.8 45/52
39.8 ⫾ 21.2 28/36
41 21 30 5
31 16 15 2
15.8 ⫾ 5.8* 15.1 ⫾ 5.7* 10.5 ⫾ 2.1* 43.9 ⫾ 5.3† 27.9 ⫾ 6.3 36.7 ⫾ 9.0 37.2 ⫾ 8.4‡
9.5 ⫾ 1.4 9.4 ⫾ 1.6 9.0 ⫾ 1.5 46.3 ⫾ 4.3 28.9 ⫾ 4.1 37.8 ⫾ 6.5 32.9 ⫾ 5.6
33 (34%) 29 (30%)* 36 (37%)* 76 (78%)*
15 (23%) 3 (4.9%) 3 (4.9%) 20 (31%)
* p ⬍0.0001; † p ⬍0.01; ‡ p ⬍0.001. FS ⫽ fractional shortening; IVST ⫽ interventricular wall thickness; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic dimension; LVDs ⫽ left ventricular end-systolic dimension; MYBPC3 ⫽ cardiac myosin-binding protein C; MYH7 ⫽ cardiac -myosin heavy chain; MWT ⫽ maximal wall thickness; PWT ⫽ left ventricular posterior wall thickness; TNNI3 ⫽ cardiac troponin I; TNNT2 ⫽ cardiac troponin T.
Categorical data were compared with the chi-square test. Differences were considered to be statistically significant at p ⬍0.05.
Results Genetic results and characteristics of subjects: Ten different mutations were identified in 20 families. Genetic analysis revealed that 97 of the 161 subjects enrolled were genetically affected, and 64 subjects were genetically unaffected. Of the 97 genetically affected subjects, 30 were associated with the cardiac myosin-binding protein C gene mutation (Del593C, n ⫽ 4; Int21DSG⫹1A, n ⫽ 14; Arg820Gln, n ⫽ 12), 5 were associated with the -myosin heavy chain gene mutation (Ala26Val, n ⫽ 3; Glu935Lys, n ⫽ 2), 21 were associated with the cardiac troponin T gene mutation (Arg92Trp, n ⫽ 8; Lys273Glu, n ⫽ 10; Val85Leu, n ⫽ 1; Phe110Ile, n ⫽ 2), and 41 were associated with the cardiac troponin I gene mutation (Lys183Del, n ⫽ 41). All mutations have been previously identified and described elsewhere.4,16 –21 The demographics and clinical characteristics of the study population are listed in Table 1. There were no statistically significant differences in the mean age and gender distribution between carriers and noncarriers. The frequency of voltage abnormalities assessed by the Cornell, Romhilt-Estes, and 12-lead QRS voltage criteria was significantly greater in carriers than noncarriers.
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Table 2 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC Criterion Age ⬍30 yrs (n ⫽ 51) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes Age ⱖ30 yrs (n ⫽ 110) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes All subjects (n ⫽ 161) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
32 25 78 25
73 91 68 91
60 78 72 78
47 50 68 50
51 55 71 55
36 32 81 42
78 98 70 98
73 96 82 97
42 46 68 50
51 57 77 63
34 30 80 37
77 95 67 95
69 91 79 92
44 47 68 50
51 56 75 60
NPV ⫽ negative predictive value; PPV ⫽ positive predictive value.
Table 3 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC (with specificity adjustment) Criterion Age ⬍30 yrs (n ⫽ 51) Sokolow-Lyon (⬎45 mm) Cornell 12-lead QRS (⬎235 mm) Romhilt-Estes Age ⱖ30 yrs (n ⫽ 110) Sokolow-Lyon (⬎50 mm) Cornell 12-lead QRS (⬎275 mm) Romhilt-Estes All subjects (n ⫽ 161) Sokolow-Lyon (⬎48 mm) Cornell 12-lead QRS (⬎240 mm) Romhilt-Estes
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
14 25 37 25
91 91 91 91
67 78 83 78
47 50 53 50
49 55 60 55
14 32 19 42
98 98 98 98
91 96 93 97
40 46 41 50
45 57 48 63
13 30 36 37
95 95 95 95
81 91 92 92
42 48 49 50
36 56 59 60
Abbreviations as in Table 2.
Diagnostic value of various ECG voltage criteria: Table 2 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations. In the young and adult populations, the 12-lead QRS voltage criterion showed the greatest sensitivity but the least specificity. All 4 criteria showed greater diagnostic values in the adult population than in the young population, with greater sensitivity and greater specificity, resulting in greater accuracy. Comparison of sensitivity of various ECG voltage criteria: Table 3 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations, with adjustment of the specificity to compare the sensitivity. In the young population, the 12-lead QRS voltage criterion showed the greatest sensitivity of the 4 voltage criteria. In the adult population, the Romhilt-Estes criterion showed the greatest sensitivity of the 4 voltage criteria. In all subjects, the sensitivities of the 12-lead QRS voltage and
Romhilt-Estes criteria were greater than those of the Cornell and Sokolow-Lyon criteria. Age-related frequency of major ECG abnormalities: Figure 1 shows the ratio of major ECG abnormalities in different decades of life in carrier subjects. In teens, abnormal Q waves were most frequently found, gradually decreasing after 20 years of age. In contrast, ST-T abnormalities were the most frequently observed of the 3 major ECG abnormalities after 20 years of age. The frequency of left ventricular hypertrophy assessed by the Romhilt-Estes criterion increased after 20 years of age but decreased after 60 years of age. Voltage abnormalities in prehypertrophic carriers: The Romhilt-Estes (point score ⱖ4) and the 12-lead QRS voltage (ⱖ240 mm) criteria, which showed the greatest diagnostic value in all subjects at a specificity of 95%, were
Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy
Figure 1. Age-related frequencies of abnormal Q waves, voltage abnormalities assessed by the Romhilt-Estes criterion, and ST-T abnormalities. Open bars, the percentage of carriers with abnormal Q waves, hatched bars, the percentage of carriers with voltage abnormalities, and solid bars, the percentage of carriers with ST-T abnormalities.
applied to the identification of prehypertrophic carriers in clinically healthy subjects without echocardiographic evidence of left ventricular hypertrophy. Of the 97 genetically affected subjects, 31 did not manifest left ventricular hypertrophy on echocardiography, and they were defined as prehypertrophic carriers. The frequency of voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria was significantly greater in prehypertrophic carriers than noncarriers (22.6% in prehypertrophic carriers, n ⫽ 31; 4.7% in noncarriers, n ⫽ 64; p ⬍0.01). Maximal wall thickness and age were not significantly different between prehypertrophic carriers and noncarriers (maximal wall thickness 9.6 ⫾ 1.9 mm in prehypertrophic carriers, 9.5 ⫾ 1.4 mm in noncarriers, p ⫽ NS; age 31.0 ⫾ 22.4 years in prehypertrophic carriers, 39.8 ⫾ 21.2 years in noncarriers, p ⫽ NS). Five of 31 prehypertrophic carriers showed wall thickness of 12 to 13 mm, whereas 2 of 64 noncarriers exhibited this level of hypertrophy. In screening for prehypertrophic carriers in clinically healthy subjects without left ventricular hypertrophy, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Romhilt-Estes and 12-lead QRS voltage criteria were 23%, 95%, 70%, 72%, and 72%, respectively.
Discussion In patients with HC, the Romhilt-Estes criterion is conventionally applied to the detection of left ventricular hypertrophy in clinical practice, although its use has not been based on the evidence established. In this study, we demonstrated that the Romhilt-Estes and 12-lead QRS voltage criteria were most accurate for the diagnosis of carriers of HC and that voltage abnormalities may be observed, even in prehypertrophic carriers.
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The Romhilt-Estes criterion is a unique ECG voltage criterion, which is calculated by its original point-score system.11 Interestingly, the definition of not only QRScomplex amplitude but also the ST-T segment is included in the point-score system, in contrast with the Cornell and Sokolow-Lyon criteria. Probable left ventricular hypertrophy is defined as 4 of a maximum total of 13 points. Of note, 3 points will be given if the typical ST-T pattern of left ventricular strain is present without the use of digitalis. That is to say, patients with ST-T segment abnormalities tend to be diagnosed as “positive” by the Romhilt-Estes criterion. In the present study, ST-T abnormalities were commonly observed in carrier subjects after 20 years of age (Figure 1), which could have contributed to a high sensitivity for the Romhilt-Estes criterion, especially in the adult population. It was previously demonstrated that the 12-lead QRS voltage criterion shows the greatest sensitivity for HC in necropsy patients.12 Actually, using 175 mm as the cutoff point, the 12-lead QRS voltage criterion showed excellent sensitivity for HC in the genotyped population studied here (Table 2). Of note, the 12-lead QRS voltage criterion showed preferable sensitivity, even when the cutoff point was set to 240 mm to provide a specificity of 95% (Table 3). Our data may provide evidence of the clinical use of the Romhilt-Estes and 12-lead QRS voltage criteria as “standard voltage criteria” for HC on the basis of molecular genetic diagnoses. Establishing a clinical diagnosis in prehypertrophic carriers is of major importance, because sudden death occurs in young, asymptomatic patients with HC even in the absence of left ventricular hypertrophy.22,23 In our population, voltage abnormalities assessed by the Romhilt-Estes and 12lead QRS voltage criteria were observed at a significantly higher rate in prehypertrophic carriers than in noncarriers (22.6% in preclinical carriers, 4.7% in noncarriers, p ⬍0.01). These findings suggest that voltage abnormalities may be a useful predictor for prehypertrophic carriers in clinically healthy subjects. A simple, cheap, accessible, sensitive, and specific diagnostic test for HC is not available at present,24 especially for detecting prehypertrophic carriers. Ho et al25 reported that diastolic dysfunction assessed by tissue Doppler imaging may predict the genetic status in subjects without left ventricular hypertrophy. In their report, the diagnostic value of a combination of Ea velocity (ⱕ13.5 cm/s) and the left ventricular ejection fraction (ⱖ68%) shows a preferable sensitivity of 44%, with a specificity of 100%. However, in clinical practice, tissue Doppler techniques have not yet been widely used for screening prehypertrophic carriers because of their relatively complicated procedures and cost-related problems. From this point of view, electrocardiography is a clinically accessible method for the diagnosis of HC.13 Although voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria showed lower sensitivity for prehypertrophic carriers (23%) compared with the tissue Doppler techniques described previously, we suggest that ECG voltage criteria may still be useful in
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detecting prehypertrophic carriers, because of their excellent specificity, simplicity, and cost-effectiveness. 1. Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux AC, Isnard R, Hagege A, Langlard JM, Bonne G, et al. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation 1997;96:214 –219. 2. Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Kiyama M, Sakata K, Hayashi T, Inoue M, Kaneda T, et al. Chronologic electrocardiographic changes in patients with hypertrophic cardiomyopathy associated with cardiac troponin I mutation. Am Heart J 2002;143: 289 –293. 3. Ryan MP, Cleland JG, French JA, Joshi J, Choudhury L, Chojnowska L, Michalak E, al-Mahdawi S, Nihoyannopoulos P, Oakley CM. The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy. Am J Cardiol 1995;76:689 – 694. 4. Kokado H, Shimizu M, Yoshio H, Ino H, Okeie K, Emoto Y, Matsuyama T, Yamaguchi M, Yasuda T, Fujino N, et al. Clinical features of hypertrophic cardiomyopathy caused by a Lys183 deletion mutation in the cardiac troponin I gene. Circulation 2000;102:663– 669. 5. Carrier L, Bonne G, Bahrend E, Yu B, Richard P, Niel F, Hainque B, Cruaud C, Gary F, Labeit S, et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res 1997;80:427– 434. 6. Jaenicke T, Diederich KW, Haas W, Schleich J, Lichter P, Pfordt M, Bach A, Vosberg HP. The complete sequence of the human betamyosin heavy chain gene and a comparative analysis of its product. Genomics 1990;8:194 –206. 7. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994;77:701–712. 8. Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16:379 –382. 9. Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left ventricular mass by simple voltageduration products. J Am Coll Cardiol 1995;25:417– 423. 10. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949;37:161–186. 11. Romhilt DW, Estes EH. A point-score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 1968;75:752–758. 12. Dollar AL, Roberts WC. Usefulness of total 12-lead QRS voltage compared with other criteria for determining left ventricular hypertrophy in hypertrophic cardiomyopathy: analysis of 57 patients studies at necropsy. Am J Med 1989;87:377–381.
13. Konno T, Shimizu M, Ino H, Yamaguchi M, Terai H, Uchiyama K, Oe K, Mabuchi T, Kaneda T, Mabuchi H. Diagnostic value of abnormal Q waves for identification of preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis. Eur Heart J 2004;25:246 – 452. 14. Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux AC, Isnard R, Hagege A, Langlard JM, Bonne G, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin binding protein C gene. Circulation 1998;97:2230 –2236. 15. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359:881– 884. 16. Konno T, Shimizu M, Ino H, Matsuyama T, Yamaguchi M, Terai H, Hayashi K, Mabuchi T, Kiyama M, Sakata K, et al. A novel missense mutation in the myosin binding protein-C gene is responsible hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients. J Am Coll Cardiol 2003;41:781–786. 17. Konno T, Shimizu M, Ino H, Terai H, Fujino N, Sakata K, Inoue M, Mabuchi H. A novel mutation (Int21DSG⫹1A) in the cardiac myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with severe left ventricular hypertrophy and a high degree of penetrance (abstr). Circulation 2003;108. 18. Nishi H, Kimura A, Harada H, Koga Y, Adachi K, Matsuyama K, Koyanagi T, Yasunaga S, Imaizumi T, Toshima H, et al. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation 1995;91:2911–2915. 19. Nishi H, Kimura A, Harada H, Adachi K, Koga Y, Sasazuki T, Toshima H. Possible gene dose effect of a mutant cardiac beta-myosin heavy chain gene on the clinical expression of familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun 1994;200:549 –556. 20. Fujino N, Shimizu M, Ino H, Okeie K, Yamaguchi M, Yasuda T, Kokado H, Mabuchi H. Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy. Clin Cardiol 2001;24:397– 402. 21. Fujino N, Shimizu M, Ino H, Yamaguchi M, Yasuda T, Nagata M, Konno T, Mabuchi H. A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. Am J Cardiol 2002;89:29 –33. 22. McKenna WJ, Stewart JT, Nihoyannopoulos P, McGinty F, Davies MJ. Hypertrophic cardiomyopathy without hypertrophy: two families with myocardial disarray in the absence of increased myocardial mass. Br Heart J 1990;63:287–290. 23. Maron BJ, Kragel AH, Roberts WC. Sudden death in hypertrophic cardiomyopathy with normal left ventricular mass. Br Heart J 1990; 63:308 –310. 24. Sigwart U. The diagnosis of familial hypertrophic cardiomyopathy in children. Eur Heart J 1998;19:1276 –1278. 25. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–2997.
In clinical practice, classic electrocardiographic (ECG) voltage criteria have been applied to the detection of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy (HC). However, differences in the diagnostic value of various voltage criteria for HC have not yet been clarified. Recent molecular genetic studies in HC have shown that some genetic carriers of the disease may have no demonstrable hypertrophy on 2-dimensional echocardiography.1 Previous studies have demonstrated that ECG abnormalities may be observed before the appearance of left ventricular hypertrophy in carriers with disease-causing mutations for HC.2,3 The first goal of the present study was to determine the most accurate diagnostic definition of classic ECG voltage criteria for HC on the basis of molecular genetic diagnoses, and the second goal was to apply classic
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. Manuscript received January 26, 2005; revised manuscript received and accepted June 15, 2005. * Corresponding author: Tel: 81-76-265-2254; fax: 81-76-234-4251. E-mail address: [email protected] (T. Konno). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.06.078
ECG voltage criteria to the identification of prehypertrophic carriers in clinically healthy subjects.
Methods Subjects: Twenty families with HC in which the disease-causing mutation was identified were studied. After the mutation was identified in the proband with HC, the family members were studied by 12-lead electrocardiography and echocardiography, and blood samples were obtained for genetic analysis. A total of 173 subjects were included in this study. Twelve subjects were excluded because of ⱖ1 of the following reasons: a history of old anterior myocardial infarction, preexcitation, hypertension, and conduction disturbance. Consequently, 161 subjects were analyzed. Informed consent was obtained from all subjects or their guardians in accordance with the guidelines of the Bioethical Committee on Medical Researches, School of Medicine, Kanazawa University. Detection of mutations: Deoxyribonucleic acid of the probands was isolated from peripheral white blood cells, as previously described.4 The amplification of genomic dewww.AJConline.org
Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy
oxyribonucleic acid was performed using a polymerase chain reaction. Oligonucleotide primers were used to amplify exons of the cardiac myosin-binding protein C gene, -myosin heavy chain gene, cardiac troponin T gene, and cardiac troponin I gene, as previously reported.5– 8 Singlestrand conformational polymorphism analysis of amplified deoxyribonucleic acid was then performed. For abnormal single-strand conformational polymorphism patterns, the nucleotide sequences of the cloned polymerase chain reaction products were determined on the 2 strands by the dye terminator cycle sequencing method using an automated fluorescent sequencer (ABI PRISM 310 Genetic Analyzer, PE Biosystems, Foster City, California). The sequence variations were confirmed by restriction enzyme digestion. Definition of classic ECG voltage criteria: Standard 12-lead electrocardiograms were recorded in all subjects in the supine position during quiet respiration. The ECG voltage criteria were defined as follows on the basis of previous studies: Cornell voltage criterion: R aVL ⫹ SV3, with 8 mm added in women, ⬎28 mm9; Sokolow-Lyon voltage criterion: SV1 ⫹ RV5 or RV6, whichever is larger, ⬎35 mm10; Romhilt-Estes voltage criterion: point score, described previously,11 ⱖ4; and sum of QRS voltages in all 12 leads ⬎175 mm.12 ECG abnormalities other than classic ECG voltage criteria were defined as follows: Q wave ⬎3 mm in depth and/or ⬎0.04 seconds in duration in ⱖ2 leads except aVR13; ST-segment depression of an upsloping type ⬎0.1 mV at 0.08 seconds after the J point, or those of horizontal or downsloping type ⬎0.05 mV2,13; and T-wave inversion ⬎0.1 mV except aVR and V1 to V2 leads in the absence of conduction disturbance.2,13 Echocardiographic criteria: Standard M-mode and 2dimensional echocardiographic studies were performed to identify and quantify morphologic features of the left ventricle. Left ventricular dimensions and the thickness of the septum and posterior wall were measured at the level of the tips of the mitral valve leaflets. Left ventricular maximum wall thickness ⱖ13 mm in adults and ⱖ95% confidence interval of the theoretic value in children were considered the diagnostic criteria for HC.14 Electrocardiography and echocardiography were performed at the time of genotyping and were analyzed without knowledge of the genetic status. Statistical analysis: Sensitivity was defined in percentage as true-positive results/(true-positive results ⫹ falsenegative results) ⫻ 100, specificity as true-negative results/ (true-negative results ⫹ false-positive results) ⫻ 100, positive predictive value as true-positive results/(true-positive results ⫹ false-positive results) ⫻ 100, negative predictive value as true-negative results/(true-negative results ⫹ false-negative results) ⫻ 100, and accuracy as (true-positive results ⫹ true-negative results)/(true-positive results ⫹ truenegative results ⫹ false-positive results ⫹ false-negative results) ⫻ 100.15 Continuous data are expressed as mean ⫾ SD and were analyzed with Student’s unpaired, 2-tailed t test.
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Table 1 Demographic and clinical characteristics of the study groups Characteristic
Carriers (n ⫽ 97)
Noncarriers (n ⫽ 64)
Age (yrs) Men/Women Genes TNNI3 TNNT2 MYBPC MYH7 Echocardiography MWT (mm) IVST (mm) PWT (mm) LVDd (mm) LVDs (mm) FS (%) LAD (mm) Voltage criteria Sokolow-Lyon Cornel Romhilt-Estes 12-lead QRS
44.9 ⫾ 21.8 45/52
39.8 ⫾ 21.2 28/36
41 21 30 5
31 16 15 2
15.8 ⫾ 5.8* 15.1 ⫾ 5.7* 10.5 ⫾ 2.1* 43.9 ⫾ 5.3† 27.9 ⫾ 6.3 36.7 ⫾ 9.0 37.2 ⫾ 8.4‡
9.5 ⫾ 1.4 9.4 ⫾ 1.6 9.0 ⫾ 1.5 46.3 ⫾ 4.3 28.9 ⫾ 4.1 37.8 ⫾ 6.5 32.9 ⫾ 5.6
33 (34%) 29 (30%)* 36 (37%)* 76 (78%)*
15 (23%) 3 (4.9%) 3 (4.9%) 20 (31%)
* p ⬍0.0001; † p ⬍0.01; ‡ p ⬍0.001. FS ⫽ fractional shortening; IVST ⫽ interventricular wall thickness; LAD ⫽ left atrial dimension; LVDd ⫽ left ventricular end-diastolic dimension; LVDs ⫽ left ventricular end-systolic dimension; MYBPC3 ⫽ cardiac myosin-binding protein C; MYH7 ⫽ cardiac -myosin heavy chain; MWT ⫽ maximal wall thickness; PWT ⫽ left ventricular posterior wall thickness; TNNI3 ⫽ cardiac troponin I; TNNT2 ⫽ cardiac troponin T.
Categorical data were compared with the chi-square test. Differences were considered to be statistically significant at p ⬍0.05.
Results Genetic results and characteristics of subjects: Ten different mutations were identified in 20 families. Genetic analysis revealed that 97 of the 161 subjects enrolled were genetically affected, and 64 subjects were genetically unaffected. Of the 97 genetically affected subjects, 30 were associated with the cardiac myosin-binding protein C gene mutation (Del593C, n ⫽ 4; Int21DSG⫹1A, n ⫽ 14; Arg820Gln, n ⫽ 12), 5 were associated with the -myosin heavy chain gene mutation (Ala26Val, n ⫽ 3; Glu935Lys, n ⫽ 2), 21 were associated with the cardiac troponin T gene mutation (Arg92Trp, n ⫽ 8; Lys273Glu, n ⫽ 10; Val85Leu, n ⫽ 1; Phe110Ile, n ⫽ 2), and 41 were associated with the cardiac troponin I gene mutation (Lys183Del, n ⫽ 41). All mutations have been previously identified and described elsewhere.4,16 –21 The demographics and clinical characteristics of the study population are listed in Table 1. There were no statistically significant differences in the mean age and gender distribution between carriers and noncarriers. The frequency of voltage abnormalities assessed by the Cornell, Romhilt-Estes, and 12-lead QRS voltage criteria was significantly greater in carriers than noncarriers.
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Table 2 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC Criterion Age ⬍30 yrs (n ⫽ 51) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes Age ⱖ30 yrs (n ⫽ 110) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes All subjects (n ⫽ 161) Sokolow-Lyon Cornell 12-lead QRS Romhilt-Estes
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
32 25 78 25
73 91 68 91
60 78 72 78
47 50 68 50
51 55 71 55
36 32 81 42
78 98 70 98
73 96 82 97
42 46 68 50
51 57 77 63
34 30 80 37
77 95 67 95
69 91 79 92
44 47 68 50
51 56 75 60
NPV ⫽ negative predictive value; PPV ⫽ positive predictive value.
Table 3 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC (with specificity adjustment) Criterion Age ⬍30 yrs (n ⫽ 51) Sokolow-Lyon (⬎45 mm) Cornell 12-lead QRS (⬎235 mm) Romhilt-Estes Age ⱖ30 yrs (n ⫽ 110) Sokolow-Lyon (⬎50 mm) Cornell 12-lead QRS (⬎275 mm) Romhilt-Estes All subjects (n ⫽ 161) Sokolow-Lyon (⬎48 mm) Cornell 12-lead QRS (⬎240 mm) Romhilt-Estes
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
14 25 37 25
91 91 91 91
67 78 83 78
47 50 53 50
49 55 60 55
14 32 19 42
98 98 98 98
91 96 93 97
40 46 41 50
45 57 48 63
13 30 36 37
95 95 95 95
81 91 92 92
42 48 49 50
36 56 59 60
Abbreviations as in Table 2.
Diagnostic value of various ECG voltage criteria: Table 2 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations. In the young and adult populations, the 12-lead QRS voltage criterion showed the greatest sensitivity but the least specificity. All 4 criteria showed greater diagnostic values in the adult population than in the young population, with greater sensitivity and greater specificity, resulting in greater accuracy. Comparison of sensitivity of various ECG voltage criteria: Table 3 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations, with adjustment of the specificity to compare the sensitivity. In the young population, the 12-lead QRS voltage criterion showed the greatest sensitivity of the 4 voltage criteria. In the adult population, the Romhilt-Estes criterion showed the greatest sensitivity of the 4 voltage criteria. In all subjects, the sensitivities of the 12-lead QRS voltage and
Romhilt-Estes criteria were greater than those of the Cornell and Sokolow-Lyon criteria. Age-related frequency of major ECG abnormalities: Figure 1 shows the ratio of major ECG abnormalities in different decades of life in carrier subjects. In teens, abnormal Q waves were most frequently found, gradually decreasing after 20 years of age. In contrast, ST-T abnormalities were the most frequently observed of the 3 major ECG abnormalities after 20 years of age. The frequency of left ventricular hypertrophy assessed by the Romhilt-Estes criterion increased after 20 years of age but decreased after 60 years of age. Voltage abnormalities in prehypertrophic carriers: The Romhilt-Estes (point score ⱖ4) and the 12-lead QRS voltage (ⱖ240 mm) criteria, which showed the greatest diagnostic value in all subjects at a specificity of 95%, were
Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy
Figure 1. Age-related frequencies of abnormal Q waves, voltage abnormalities assessed by the Romhilt-Estes criterion, and ST-T abnormalities. Open bars, the percentage of carriers with abnormal Q waves, hatched bars, the percentage of carriers with voltage abnormalities, and solid bars, the percentage of carriers with ST-T abnormalities.
applied to the identification of prehypertrophic carriers in clinically healthy subjects without echocardiographic evidence of left ventricular hypertrophy. Of the 97 genetically affected subjects, 31 did not manifest left ventricular hypertrophy on echocardiography, and they were defined as prehypertrophic carriers. The frequency of voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria was significantly greater in prehypertrophic carriers than noncarriers (22.6% in prehypertrophic carriers, n ⫽ 31; 4.7% in noncarriers, n ⫽ 64; p ⬍0.01). Maximal wall thickness and age were not significantly different between prehypertrophic carriers and noncarriers (maximal wall thickness 9.6 ⫾ 1.9 mm in prehypertrophic carriers, 9.5 ⫾ 1.4 mm in noncarriers, p ⫽ NS; age 31.0 ⫾ 22.4 years in prehypertrophic carriers, 39.8 ⫾ 21.2 years in noncarriers, p ⫽ NS). Five of 31 prehypertrophic carriers showed wall thickness of 12 to 13 mm, whereas 2 of 64 noncarriers exhibited this level of hypertrophy. In screening for prehypertrophic carriers in clinically healthy subjects without left ventricular hypertrophy, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Romhilt-Estes and 12-lead QRS voltage criteria were 23%, 95%, 70%, 72%, and 72%, respectively.
Discussion In patients with HC, the Romhilt-Estes criterion is conventionally applied to the detection of left ventricular hypertrophy in clinical practice, although its use has not been based on the evidence established. In this study, we demonstrated that the Romhilt-Estes and 12-lead QRS voltage criteria were most accurate for the diagnosis of carriers of HC and that voltage abnormalities may be observed, even in prehypertrophic carriers.
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The Romhilt-Estes criterion is a unique ECG voltage criterion, which is calculated by its original point-score system.11 Interestingly, the definition of not only QRScomplex amplitude but also the ST-T segment is included in the point-score system, in contrast with the Cornell and Sokolow-Lyon criteria. Probable left ventricular hypertrophy is defined as 4 of a maximum total of 13 points. Of note, 3 points will be given if the typical ST-T pattern of left ventricular strain is present without the use of digitalis. That is to say, patients with ST-T segment abnormalities tend to be diagnosed as “positive” by the Romhilt-Estes criterion. In the present study, ST-T abnormalities were commonly observed in carrier subjects after 20 years of age (Figure 1), which could have contributed to a high sensitivity for the Romhilt-Estes criterion, especially in the adult population. It was previously demonstrated that the 12-lead QRS voltage criterion shows the greatest sensitivity for HC in necropsy patients.12 Actually, using 175 mm as the cutoff point, the 12-lead QRS voltage criterion showed excellent sensitivity for HC in the genotyped population studied here (Table 2). Of note, the 12-lead QRS voltage criterion showed preferable sensitivity, even when the cutoff point was set to 240 mm to provide a specificity of 95% (Table 3). Our data may provide evidence of the clinical use of the Romhilt-Estes and 12-lead QRS voltage criteria as “standard voltage criteria” for HC on the basis of molecular genetic diagnoses. Establishing a clinical diagnosis in prehypertrophic carriers is of major importance, because sudden death occurs in young, asymptomatic patients with HC even in the absence of left ventricular hypertrophy.22,23 In our population, voltage abnormalities assessed by the Romhilt-Estes and 12lead QRS voltage criteria were observed at a significantly higher rate in prehypertrophic carriers than in noncarriers (22.6% in preclinical carriers, 4.7% in noncarriers, p ⬍0.01). These findings suggest that voltage abnormalities may be a useful predictor for prehypertrophic carriers in clinically healthy subjects. A simple, cheap, accessible, sensitive, and specific diagnostic test for HC is not available at present,24 especially for detecting prehypertrophic carriers. Ho et al25 reported that diastolic dysfunction assessed by tissue Doppler imaging may predict the genetic status in subjects without left ventricular hypertrophy. In their report, the diagnostic value of a combination of Ea velocity (ⱕ13.5 cm/s) and the left ventricular ejection fraction (ⱖ68%) shows a preferable sensitivity of 44%, with a specificity of 100%. However, in clinical practice, tissue Doppler techniques have not yet been widely used for screening prehypertrophic carriers because of their relatively complicated procedures and cost-related problems. From this point of view, electrocardiography is a clinically accessible method for the diagnosis of HC.13 Although voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria showed lower sensitivity for prehypertrophic carriers (23%) compared with the tissue Doppler techniques described previously, we suggest that ECG voltage criteria may still be useful in
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