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(Circulation. 1997;96:214-219.)
© 1997 American Heart Association, Inc.

Articles

Diagnostic Value of Electrocardiography and Echocardiography for Familial Hypertrophic Cardiomyopathy in a Genotyped Adult Population

Philippe Charron, MD; Olivier Dubourg, MD; Michel Desnos, MD; Richard Isnard, MD; Albert Hagege, MD; Alain Millaire, MD; Lucie Carrier, PhD; Gisele Bonne, PhD; Frédérique Tesson, PhD; Pascale Richard, PhD; Jean-Brieuc Bouhour, MD; Ketty Schwartz, PhD; ; Michel Komajda, MD

From the Service de Cardiologie (Ph.C., R.I., M.K.), INSERM U 153 (L.C., G.B., F.T., K.S.), and Service de Biochimie (P.R.), Hôpital Pitié-Salpêtrière, Paris; Service de Cardiologie, Hôpital Ambroise Paré, Boulogne (O.D.); Service de Cardiologie, Hôpital Boucicaut, Paris (M.D., A.H.); Service de Cardiologie, Hôpital Cardiologique, Lille (A.M.); and Service de Cardiologie, Hôpital Laennec, Nantes (J-B.B.), France.

Correspondence to Pr Michel Komajda, Service de Cardiologie, Pavillon Rambuteau, Hôpital Pitié-Salpêtrière, 47 Blvd de l'Hôpital, 75651 Paris Cedex 13, France.

	Abstract

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Background The diagnostic value of ECG and echocardiography for familial hypertrophic cardiomyopathy (FHC) has not been reassessed since the development of molecular genetics. The aim of the study was to evaluate it in adults, with the genetic status used as the criterion of reference.

Methods and Results Ten families with previously identified mutations were studied (9 mutations in 3 genes). ECG and echocardiography were analyzed in 155 adults, of whom 77 were genetically affected and 78 unaffected. The major diagnostic criteria were, for echocardiography, a left ventricular wall thickness >13 mm and, for ECG, abnormal Q waves, left ventricular hypertrophy, and marked ST-T changes. Minor ECG and echographic abnormalities were also analyzed. (1) Sensitivity and specificity of major criteria were 61% and 97% for ECG and 62% and 100% for echocardiography. (2) Sensitivity but not specificity was age related (from 50% at <30 years to 94% at >50 years old, P<.01) and sex related (83% in men versus 57% in women, P=.01). (3) Sensitivity was improved by the addition of minor criteria and by the association of ECG and echocardiography. The negative predictive value was therefore very good (95%) at >30 years of age. (4) Healthy carriers without any ECG or echocardiographic abnormality represented 17% of genetically affected adults.

Conclusions ECG and echocardiography have similar diagnostic values for FHC in adults, with an excellent specificity and a lower sensitivity. The association of the two techniques allows a better evaluation of the risk of being genetically affected in families with hypertrophic cardiomyopathy.

Key Words: tests • cardiomyopathy • echocardiography • genetics • electrocardiography • diagnosis • hypertrophy

	Introduction

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Hypertrophic cardiomyopathy is characterized by a hypertrophied and nondilated left ventricle with predominant involvement of the interventricular septum in the absence of known causes of hypertrophy.¹ The diagnosis of FHC is usually based on ECG and echo, and it is generally considered that echo is a more accurate technique than ECG for the diagnosis in adults.² However, the diagnostic value of both techniques is based on premolecular studies.

The clinical features of the disease vary greatly, particularly the degree of ventricular hypertrophy,² making clinical diagnosis sometimes difficult. The left ventricular hypertrophy is not always expressed at birth and may occur during childhood and adolescence,³ whereas progression of hypertrophy apparently does not occur in adults.⁴ In some cases, it has been suspected that adults could be affected by FHC in the absence of cardiac hypertrophy on necropsies or on premortem data because of unexplained sudden death and myocardial disarray on histology⁵ or because of the status of "obligated carriers" in families affected by the disease.⁶

Recent developments in the molecular genetics of FHC have identified several genes responsible for the disease, which all encode for proteins of the sarcomere: the ß-myosin heavy chain gene,⁷ the cardiac troponin T gene,⁸ the -tropomyosin gene,⁸ the cardiac C-protein gene,^{9 10} and the essential and regulatory light chain of myosin.¹¹ Based on preliminary data, genotype-phenotype analyses have confirmed the existence of healthy carriers of mutation without any ECG or echo abnormalities and the possibility of a dissociation between ECG and echo abnormalities.^{12 13 14 15 16}

Nevertheless, these data are limited and concern only a few individuals. The sensitivity and specificity of ECG and echo remain to be reassessed in a large and completely genotyped population. Using the genetic status as the criterion of reference, the aim of our study was therefore to evaluate in adults the diagnostic value of the classic ECG and echo criteria for FHC in families with identified mutations.

	Methods

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Selection and Characterization of Subjects
Subjects from families involved in genetic studies in whom genetic analyses had been performed and the causative mutation identified were screened for inclusion in the study. All adults (18 years old) included in the study were at risk of inheriting the disease gene, ie, they had a first-degree relative clinically affected by hypertrophic cardiomyopathy. Among the 165 subjects asked to participate in the study, 8 could not be included because of refusal (personal or geographic considerations). For the 157 subjects included in the study, informed consent was obtained in accordance with a study protocol approved by the Comité d'Ethique du Centre Hospitalier Universitaire de la Pitié-Salpêtrière (Paris). Clinical evaluation was performed, and blood samples were obtained. ECG and echo were performed at the time of genotyping. Individuals with another cause of ventricular hypertrophy, such as valvular heart disease, were excluded from the study. One subject was excluded because of poor echo quality and one because the echo showed aortic stenosis, leaving 155 for analysis. One of the genetically unaffected subjects and three of the genetically affected subjects had a history of hypertension but were not excluded because blood pressure had been well controlled for many years and could not account for hypertrophy when it was present (2 subjects).

Determination of Genotype
The genotypic assessment was previously determined and is described elsewhere.^{9 12 17 18 19} Ten families with nine different mutations were studied. Among the 77 genetically affected adults, 40 were associated with a mutation in the ß-myosin heavy chain gene (mutation Asn²³²Ser, n=6; Arg⁴⁰³Leu, n=14; Arg⁴⁰³Trp, n=6; Arg⁷²³Cys, n=6; Ile²⁶³Thr, n=2; Arg⁷¹⁹Trp, n=3; and Del⁹³⁰GAG, n=3); 34 were associated with a mutation in the cardiac myosin binding protein-C gene (all with the same mutation: SASint [AG] in two families); and 3 were associated with a mutation in the cardiac troponin T gene (mutation Arg⁹²Leu). No family was found to be linked to the -tropomyosin gene.

Echo Procedure and Criteria
Echos were performed at the time of genotyping, at different institutions, according to a standardized procedure.²⁰ Subjects underwent M-mode, two-dimensional echo (including parasternal short- and long-axis views and apical four- and two-chamber views) and Doppler ultrasonography. Echo was performed with a 2.5- or 3.5-MHz transducer, and images were stored on VHS videotape for subsequent analysis. Echos were analyzed independently by three observers without knowledge of the genetic status. End-diastolic left ventricular wall thickness measurements in M-mode were made at the onset of the QRS complex according to the recommendations of the American Society of Echocardiography.²¹ Two-dimensional echo images were obtained in a number of cross-sectional planes in standard transducer positions.²² Hypertrophy was assessed at different locations from the parasternal short-axis view at both the mitral valve and papillary muscle levels and also obtained from the parasternal long-axis view and the apical views. Three consecutive measurements were made and averaged. The MWT from any location was therefore determined.²³ Concordant observations were made in 95% of the subjects. In case of discordance, studies were reviewed and a final agreement was achieved. An MWT >13 mm was considered the major diagnostic criterion for FHC,²⁰ and an MWT of 13 mm was considered a minor diagnostic criterion.

ECG Procedure and Criteria
Standard 12-lead ECGs were performed with patients in the supine position during quiet respiration. The presence of major abnormalities on ECG was defined by (1) Q waves >0.04 second in duration and/or >1/3 of the ensuing R wave in depth and present in at least two leads, or (2) left ventricular hypertrophy assessed by a Romhilt-Estes score 4,²⁴ or (3) repolarization alterations with marked T-wave inversion in at least two leads in the absence of bundle-branch block or hemiblock with or without ST-segment displacement under the isoelectric line. Minor ECG abnormalities were defined by isolated left atrial enlargement assessed by a negative P wave in lead V₁ greater than -0.03 mV-second,²⁵ short PR interval <120 ms, microvoltage assessed by a voltage <5 mV in each limb lead, minor Q waves in at least two leads, or bundle-branch block or hemiblock.²⁶

Statistical Analyses
Sensitivity was defined (in percent) as true-positives/(true-positives+false-negatives)x100; specificity as true-negatives/(true-negatives+false-positives)x100; PPV as true-positives/(true-positives+false-positives)x100; and NPV as true-negatives/(true-negatives+false-negatives)x100.²⁷ Continuous data were expressed as mean±SD and were analyzed with unpaired, two-tailed t tests. Discrete variables were compared by ² tests. For all comparisons, differences were considered to be statistically significant at P<.05.

	Results

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Global Analysis
Among the 155 adults, 77 were genetically affected (age, 38.4±15.5 years; range, 18 to 80 years), and the male/female ratio was 40/37 (52% and 48%). In this group, the mean value of MWT was 17.7±6.6 mm (range, 9 to 35 mm). Seven subjects (9%) had an MWT of 13 mm (age range, 21 to 48 years), and 22 (29%) had an MWT <13 mm (age range, 18 to 77 years). The number of genetically unaffected adults was 78 (age, 35.7±13.6 years; range, 18 to 76), male/female ratio, 40/38 (51% and 49%). In this group, the mean MWT was 10.5±1.5 mm (range, 7 to 13 mm). Four subjects, all without histories of hypertension, had an MWT of 13 mm (5%; age range, 34 to 60 years). MWTs in the two groups are represented in Fig 1.

View larger version (13K): [in this window] [in a new window]   Figure 1. MWTs on echo in group of genetically unaffected adults (n=78) and in group of genetically affected adults (n=77). Dispersion of values is represented by box graphs with median value, quartiles (box), and extreme values (circles). Genotype 1 means genetically affected; 0 means genetically unaffected.

Results of ECG, echo, and genetic analyses in the whole population are presented in Fig 2. All subjects with major ECG or echo criteria were genetically affected except for two individuals with one major ECG criterion. These individuals were 2 women (ages, 30 and 54 years) with marked T-wave inversion in V₃ and V₄ in one case and in V₁V₂V₃V₄ in the other. Neither was taking medication or had any history of hypertension. Among the 21 subjects with minor ECG criteria, 12 (57%) were genetically affected. Six of these 12 individuals had major or minor echo abnormalities. Among the 11 subjects with the minor echo criterion, 7 (63%) were genetically affected. Three of these 7 individuals had major ECG abnormalities, and 1 had minor abnormalities. Therefore, 22 subjects presented only minor criteria (on ECG and/or on echo), of whom 10 (45%) were genetically affected. Finally, healthy carriers of a mutation without any ECG or echo abnormalities represented 17% (13/77) of the genetically affected adults. Only 2 of these healthy carriers were >30 years of age.

View larger version (47K): [in this window] [in a new window]   Figure 2. Comparative diagnostic value of ECG and echo in whole adult population (n=155). ECG is considered first, echo second, and genotyping third. A (affected) indicates that a major criterion is present; U (uncertain), that only minor criteria are present; H (healthy), that there is no abnormality; +, genetically affected; and 0, genetically unaffected.

Relations between the ECG and echo in the genetically affected group are shown in Fig 3. When ECG was considered first, 47 of the 77 subjects (61%) had major ECG abnormalities (of whom 3 had no echo abnormalities), and 18 of the 77 subjects (23%) had no ECG abnormalities, although 2 of them had the major and 3 the minor echo criteria. When echo was considered first, 48 of the 77 subjects (62%) had the major criterion and 22 (29%) had no echo abnormalities, although 3 of them had major and 6 minor ECG abnormalities.

View larger version (40K): [in this window] [in a new window]   Figure 3. Comparative diagnostic value of ECG and echo in genetically affected adults (n=77) when ECG is considered first or when echo is considered first. Abbreviations as in Fig 2.

Table 1 indicates the sensitivity and specificity of the ECG and echo for the diagnosis of FHC. The diagnostic values of the major echo and ECG criteria were very similar, with relatively poor sensitivity (62% and 61%, respectively) but excellent specificity (100% and 97%). The combination of (major+minor) ECG criteria increased sensitivity (77%) but also the number of false-positives (specificity, 86%), whereas the combination of (major+minor) echo criteria improved sensitivity (71%), with only a slight decrease of specificity (95%). The PPV was very good for the association (ECG+echo) with major criteria (96%), and the best NPV was given by the association (ECG+echo) with (minor+major) criteria (83%).

View this table: [in this window] [in a new window]   Table 1. Diagnostic Value of ECG and Echo for FHC in Adults (n=155 Subjects)

Diagnostic Value According to Age
Diagnostic value of the ECG and echo according to age is indicated in Table 2. Between 18 and 29 years old (first age group), the diagnostic values of the ECG and echo were very similar for major criteria, with a low sensitivity (46% and 43%, respectively) and a specificity of 100%. The sensitivity of echo was only slightly improved when the minor criterion was added (50%) but was more noticeably improved for ECG (61%). In this age group, healthy carriers represented 39% of genetically affected subjects, and the NPV was therefore very low (70%).

View this table: [in this window] [in a new window]   Table 2. Diagnostic Value of ECG and Echo for FHC According to Age

Between 30 and 49 years old (second age group), the sensitivity of ECG or echo with major criteria increased to 58% and 68% and was improved by the addition of minor criteria, especially for echo (84%). Only 6% of this age group were healthy carriers, and the NPV was therefore high (94%).

At >50 years old (third age group), the sensitivity of the ECG or echo with the major criteria was high (89% and 83%, respectively); it was not improved by the use of the minor echo criterion and increased to a value of 100% with the minor ECG criteria. The diagnostic value of the association (ECG+echo) for the major criteria was very good in this age group (sensitivity, 94%; specificity, 92%), and the NPV of the association was 100% when the minor criteria were taken into account.

Because the sensitivity of echo increased with age (major criterion, 43% in the first age group versus 83% in the third age group, P<.01), regression equations were performed to search for a correlation between MWT and age. There was no correlation in the genetically unaffected group (r=.17, P>.05, n=78) or in the genetically affected group (r=.20, P>.05, n=77).

Diagnostic Value According to Sex
Table 3 shows the diagnostic value of the ECG and echo according to sex. The sensitivity of the ECG and echo appeared significantly higher in men than in women (ECG and echo association with major criteria, 83% versus 57%, P=.01). Specificity appeared similar in the two groups, a little higher for ECG in men (major criteria, 100% versus 95%) and a little higher for echo in women (major+minor criteria, 97% versus 93%).

View this table: [in this window] [in a new window]   Table 3. Diagnostic Value of ECG and Echo for FHC According to Sex

In men, ECG and echo had similar diagnostic value with major criteria. The sensitivity of echo was slightly better than for ECG when the minor criterion was added (major+minor criteria, 88% versus 80%). In women, ECG and echo also had a similar diagnostic value with major criteria. The sensitivity of ECG was better than for echo when minor criteria were added (major+minor criteria, 73% versus 54%).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study describes the diagnostic value of classic ECG and echo criteria for FHC in adults, using the genetic status as the gold standard. Previous studies on relations between the ECG and echo were carried out in the absence of a gold standard, with patients included because of abnormal echo or ECG.^{26 28} Some recent studies included genotyped subjects, but these subjects represented only a minority of the patients included, with a majority selected by echo.²⁹ Other studies were carried out on a small genotyped population and concerned only echo.³⁰

We found that the diagnostic value of the major criteria was similar for ECG and echo. This finding is in contrast to results in other studies of cardiac hypertrophy caused by hypertension,^{31 32} but several ECG criteria were used here for FHC, whereas only one is usually used for hypertension. Specificity was excellent and slightly lower for ECG because of two false-positives. Sensitivity was relatively low but was significantly improved when minor criteria were taken into account, so that the NPV of the ECG and echo association was very good at >30 years of age. Interestingly, our results indicate that sensitivity but not specificity was influenced by age and sex.

The sensitivity of ECG or echo increased with age. This finding is in agreement with some familial studies that found that echo was more often abnormal in parents of index cases than in probands and than in their offspring.^{22 33} The hypothesis is that hypertrophy may appear or progress with age, even in adults. However, regression equations performed between MWT and age to confirm this hypothesis failed to show any correlation. Inconclusive results have been published in adults: no correlation,³³ a negative correlation,^{23 34} and a positive correlation³⁵ have been reported. Because some studies showed the possibility of a decrease of wall thickness with age,³⁶ the absence of correlation found in our study may be the result of two opposite effects: (1) the appearance or progression of the hypertrophy in one subgroup and (2) the decrease of hypertrophy in another subgroup. Prospective follow-up studies are necessary to answer this question.

The sensitivity of criteria used in our study was higher in men than in women, whereas in previous clinical studies the male/female ratio for FHC varied greatly.^{22 33 37 38} For echo, and because a cutoff value was used for the criterion, the difference found in our study could be artificial and partially due to a lower mean MWT in women, because of a lower mean body surface area.³⁹ In our study, however, abnormal ECG was also more frequent in men than in women (although not statistically different), and mean MWT on echo was not significantly different according to sex, as in a recent large clinical study.³⁴ Thus, the difference found between sexes in the sensitivity of the diagnostic criteria is probably not explained by a methodological bias.

The study provides interesting information for the screening of adults in a nongenotyped family with hypertrophic cardiomyopathy. Because it is easy and inexpensive and appeared more sensitive than echo in a preliminary study, the standard ECG has been proposed as the screening test in families with hypertrophic cardiomyopathy.²⁹ Our results indicate that the combination of the two examinations is useful in clinical screening, first because they have similar diagnostic value and second because there is sometimes a dissociation between ECG and echo (5 genetically affected subjects had a wall thickness 13 mm but a normal ECG). The probability of being genetically affected can then be deduced from the results of ECG and echo. (1) When ECG or echo presents one of the major criteria, the diagnosis of FHC is certain (except for negative T wave on precordial leads in women). (2) When ECG and echo are normal without any abnormalities, the diagnosis of FHC is very unlikely after 30 years of age (risk of error, 5%), because healthy carriers were all <30 years old except for 2 subjects. But before this age, regular medical observation (and/or genotyping) is required. (3) When ECG and/or echo present(s) only minor criteria, the risk of being genetically affected is 50%, and clinical diagnosis remains uncertain before genotyping.

The study also allowed us to reevaluate the diagnostic criteria to use in genetic studies to determine the phenotype before linkage analysis. In such studies, diagnosis of FHC should be certain in order to avoid false-positives. The major ECG criteria used here had a good specificity except for negative T waves on pre-cordial leads in women, which should therefore not be considered as a major criterion. Specificity of the major echo criterion was excellent. Specificity of the minor echo criterion was good but should not be considered a diagnostic criterion in genetic studies, because 4 genetically unaffected adults had an MWT of 13 mm in our study. This finding is in agreement with other clinical^{40 41} or genetic studies³⁰ that have found that MWT in a control population (without systemic hypertension) could reach 13 mm.

Study Limitations
Because of the high genetic and phenotypic heterogeneity of FHC, it is possible that our findings would not apply to other mutations or to other morbid genes. Furthermore, in another population, results could be influenced by a modifier gene such as the I/D polymorphism of the ACE gene or by environmental factors. Further studies including larger samples and other mutations are necessary to address these issues. Finally, our results apply to familial forms of hypertrophic cardiomyopathy. Criteria used here and reported results are valid only in this highly selected population and cannot be extended to sporadic forms of hypertrophic cardiomyopathy.

Conclusions
Our study is the first attempt to reassess the diagnostic value of ECG and echo for FHC in a large adult population using the genetic status as the gold standard. We found that ECG and echo have a similar diagnostic value, with an excellent specificity and a lower sensitivity. The addition of minor criteria improved sensitivity, and the combination of ECG and echo provides a very good PPV and NPV, except for young adults, because of the high number of healthy carriers. Therefore, in the subgroup of young adults, it would be useful to search for additional criteria to define more sensitive criteria without altering the specificity too much. This is an important question to address in future studies.

	Selected Abbreviations and Acronyms

 

echo = echocardiography, echocardiographic FHC = familial hypertrophic cardiomyopathy MWT = maximal wall thickness NPV = negative predictive value PPV = positive predictive value

	Acknowledgments

 
This work was supported by INSERM (Reseau de recherche clinique No. 492010), the Association Française contre les Myopathies, the Fédération Française de Cardiologie, and the Délégation à la Recherche Clinique AP-HP (Crédits EMUL et IFR Physiopathologie et Génétique Cardio-Vasculaire). Drs Charron, Isnard, Komajda, Carrier, Bonne, Tesson, Richard, and Schwartz are members of the Institut Fédératif de Recherche "Physiopathologie et Génétique Cardio-vasculaire." We are indebted to the family members and their physicians, without whose participation this work could not have been done.

Received August 27, 1996; revision received November 20, 1996; accepted December 16, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation. 1996;93:841-842.[Free Full Text]
   
2. Maron BJ, Bonow RO, Cannon RO, Leon MB, Epstein SE. Hypertrophic cardiomyopathy: interrelations of clinical manifestations, pathophysiology, and therapy. N Engl J Med. 1987;316:780-789/844-852.[Medline] [Order article via Infotrieve]
   
3. Maron BJ, Spirito P, Wesley Y, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med. 1986;315:610-614.[Abstract]
   
4. Spirito P, Maron BJ. Absence of progression of left ventricular hypertrophy in adult patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1987;9:1013-1017.[Abstract]
   
5. 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.[Abstract/Free Full Text]
   
6. Epstein ND, Lin HJ, Fananapazir L. Genetic evidence of dissociation (generational skips) of electrical from morphologic forms of hypertrophic cardiomyopathy. Am J Cardiol. 1990;66:627-631.[Medline] [Order article via Infotrieve]
   
7. Geisterfer-Lowrance AAT, Kass S, Tanigawa G, Vosberg H-P, McKenna W, Seidman CE, Seidman JG. A molecular basis for familial hypertrophic cardiomyopathy: a ß-cardiac myosin heavy chain gene missense mutation. Cell. 1990;62:999-1006.[Medline] [Order article via Infotrieve]
   
8. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman C. -Tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77:701-712.[Medline] [Order article via Infotrieve]
   
9. Bonne G, Carrier L, Bercovici J, Cruaud C, Richard P, Hainque B, Gautel M, Labeit S, James M, Weissenbach J, Vosberg HP, Fiszman M, Komajda M, Schwartz K. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. Nat Genet. 1995;11:438-440.[Medline] [Order article via Infotrieve]
   
10. Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna W, Maron BJ, Seidman JG, Seidman CE. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet. 1995;11:434-437.[Medline] [Order article via Infotrieve]
    
11. Poetter K, Jiang He, Hassenzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet. 1996;13:63-69.[Medline] [Order article via Infotrieve]
    
12. Dausse E, Komajda M, Fetler L, Dubourg O, Dufour C, Carrier L, Winesnewsky C, Bercovici J, Hengstenberg C, Al-Mahdawi S, Isnard R, Hagège A, Bouhour JB, Desnos M, Beckmann JS, Weissenbach J, Schwartz K, Guicheney P. Familial hypertrophic cardiomyopathy: microsatellite haplotyping and identification of a hot spot for mutations in the ß myosin heavy chain gene. J Clin Invest. 1993;92:2807-2813.
    
13. Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy: insights provided by comparisons of kindreds with distinct and identical ß-myosin heavy chain gene mutations. Circulation. 1994;89:22-32.[Abstract/Free Full Text]
    
14. Watkins H, McKenna W, Thierfelder L, Suk HJ, Anan R, O'Donoghue A, Spirito P, Matsumori A, Moravec CS, Seidman JG, Seidman CE. Mutations in the genes for cardiac troponin T and -tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995;332:1058-1064.[Abstract/Free Full Text]
    
15. Al-Mahdawi S, Chamberlain S, Chojnowska L, Michalak E, Nihoyannopoulos P, Ryan M, Kusnierczyk B, French J, Gilligan D, Cleland J, Williamson R, Ruzyllo W, Oakley C. The electrocardiogram is a more sensitive indicator than echocardiography of hypertrophic cardiomyopathy in families with a mutation in the MYH7 gene. Br Heart J. 1994;72:105-111.[Abstract/Free Full Text]
    
16. Posen B, Moolman JC, Corfield VA, Brink PA. Clinical and prognostic evaluation of familial hypertrophic cardiomyopathy in two South African families with different cardiac ß-myosin heavy chain gene mutations. Br Heart J. 1995;74:40-46.[Abstract/Free Full Text]
    
17. Dufour C, Dausse E, Fetler L, Dubourg O, Bouhour JB, Vosberg H-P, Guicheney P, Komajda M, Schwartz K. Identification of a mutation near a functional site of the ß cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy. J Mol Cell Cardiol. 1994;26:1241-1247.[Medline] [Order article via Infotrieve]
    
18. Richard P, Tesson F, Hainque B, Mathieu B, Carrier L, Komajda M, Schwartz K, Guicheney P. ß-Myosin heavy chain gene mutations screening in 18 unrelated families with familial hypertrophic cardiomyopathy. J Mol Cell Cardiol. 1996;28:A65. Abstract.
    
19. Farza H, Townsend PJ, Carrier L, Forrissier JF, Komajda M, Yacoub MH, Schwartz K. Genomic organisation of human cardiac troponin T gene: relevance in mutation analysis in familial hypertrophic cardiomyopathy. J Mol Cell Cardiol. 1996;28:A35. Abstract.
    
20. Dubourg O, Isnard R, Hagège A, Jondeau G, Desnos M, Sacrez A, Bouhour JB, Messmer Pellenc P, Millaire A, Fetler L, Guicheney P, Schwartz K, Komajda M. Doppler echocardiography in familial hypertrophic cardiomyopathy: the French Cooperative Study. Echocardiography. 1995;12:235-240.[Medline] [Order article via Infotrieve]
    
21. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083.[Abstract/Free Full Text]
    
22. Maron BJ, Nichols PF III, Pickle LW, Wesley YE, Mulvihill JJ. Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am J Cardiol. 1984;53:1087-1094.[Medline] [Order article via Infotrieve]
    
23. Spirito P, Maron BJ. Relation between extent of left ventricular hypertrophy and age in hypertrophic cardiomyopathy. J Am Coll Cardiol. 1989;13:820-823.[Abstract]
    
24. Romhilt DW, Estes EH. Point score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J. 1968;75:752-758.[Medline] [Order article via Infotrieve]
    
25. Morris JJ, Estes EH, Whalen RE, Thompson HK, McIntosh HD. P-wave analysis in valvular heart disease. Circulation. 1964;29:242-252.[Abstract/Free Full Text]
    
26. Savage DD, Seides SF, Clark CE, Henry WL, Maron BJ, Robinson FC, Epstein SE. Electrocardiographic findings in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation. 1978;58:402-408.[Abstract/Free Full Text]
    
27. Hurst JW. The Heart. 5th ed. New York, NY: McGraw-Hill Inc; 1982.
    
28. Maron BJ, Wolfson JK, Ciro E, Spirito P. Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by 2-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol. 1982;51:189-194.
    
29. Ryan MK, Cleland JGF, 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.[Medline] [Order article via Infotrieve]
    
30. Solomon ST, Wolff S, Watkins H, Ridker PM, Come P, McKenna WJ, Seidman CE, Lee RT. Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene. J Am Coll Cardiol. 1993;22:498-505.[Abstract]
    
31. Levy D, Labib SB, Anderson KM, Christiansen JC, Kannel WB, Castelli WP. Determinants of sensitivity and specificity of electrocardiographic criteria for left ventricular hypertrophy. Circulation. 1990;81:815-820.[Abstract/Free Full Text]
    
32. Devereux RB. Is the electrocardiogram still useful for detection of left ventricular hypertrophy? Circulation. 1990;81:1144-1146.[Free Full Text]
    
33. Greaves SC, Roche AHG, Neutze JM, Whitlock RML, Veale AMO. Inheritance of hypertrophic cardiomyopathy: a cross sectional and M mode echocardiographic study of 50 families. Br Heart J. 1987;58:259-266.[Abstract/Free Full Text]
    
34. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphological observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol. 1995;26:1699-1708.[Abstract]
    
35. Bjarnason I, Jonsson S, Hardarson T. Mode of inheritance of hypertrophic cardiomyopathy in Iceland: echographic study. Br Heart J. 1982,47:122-129.
    
36. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of progressive left ventricular thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol. 1987;59:123-129.
    
37. Clark CE, Henry WL, Epstein SE. Familial prevalence and genetic transmission of idiopathic subaortic stenosis. N Engl J Med. 1973;289:709-714.
    
38. Shapiro LM, McKenna WJ. Distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a two dimensional echocardiographic study. J Am Coll Cardiol. 1983;2:437-444.[Abstract]
    
39. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation. 1980;62:1054-1066.[Abstract/Free Full Text]
    
40. Gardin JM, Henry WL, Savage DD, Ware JH, Burn C, Borer JS.Echocardiographic measurements in normal subjects: evaluation in an adult population without clinically apparent heart disease. J Clin Ultrasound. 1979;7:439-447.[Medline] [Order article via Infotrieve]
    
41. Doi YL, McKenna WJ, Gerhrke J, Oakley CM, Goodwin JF. M mode echocardiography in hypertrophic cardiomyopathy: diagnostic criteria and prediction of obstruction. Am J Cardiol. 1980;45:6-14.[Medline] [Order article via Infotrieve]
    

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