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Published online before print July 12, 2005, 10.1148/radiol.2363041165
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(Radiology 2005;236:815-824.)
© RSNA, 2005

Cardiac Imaging

Cine MR Imaging of Myocardial Contractile Impairment in Patients with Hypertrophic Cardiomyopathy Attributable to Asp175Asn Mutation in the {alpha}-Tropomyosin Gene1

Petri Sipola, MD, Kirsi Lauerma, MD, PhD, Pertti Jääskeläinen, MD, PhD, Markku Laakso, MD, PhD, Keijo Peuhkurinen, MD, PhD, Hannu Manninen, MD, PhD, Hannu J. Aronen, MD, PhD and Johanna Kuusisto, MD, PhD

1 From the Departments of Clinical Radiology (P.S., H.M.) and Medicine (P.J., M.L., K.P., J.K.), Kuopio University Hospital, Puijonlaaksontie 2, Kuopio FIN-70210, Finland; Department of Radiology, Helsinki University Central Hospital, Helsinki, Finland (K.L.); and Functional Brain Imaging Unit, Brain Research Center, Helsinki, Finland (H.J.A.). Received July 2, 2004; revision requested September 3; revision received October 19; accepted November 26. P.S. supported by Kuopio University Hospital Research grant 5063502, the Instrumentarium Scientific Foundation, the Aarne and Aili Turunen Foundation, and the Aarne Koskelo Foundation. Address correspondence to J.K. (e-mail: johanna.kuusisto{at}kuh.fi).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To prospectively investigate the relationship between myocardial contractile impairment and left ventricular (LV) hypertrophy measured at cardiac magnetic resonance (MR) imaging in patients with hypertrophic cardiomyopathy (HCM) caused by the substitution of aspartic acid 175 with asparagine (ie, Asp175Asn mutation) in the {alpha}-tropomyosin gene (TPM1).

MATERIALS AND METHODS: The study protocol was approved by the hospital ethics committee, and all subjects gave written informed consent. LV mass, maximal LV wall thickness, and myocardial fractional thickening during systole were measured at cine MR imaging in 24 subjects (11 male, 13 female; mean age, 42 years; age range, 17–68 years) with the Asp175Asn mutation in TPM1 and in 17 healthy volunteers (eight men, nine women; mean age, 38 years; age range, 23–60 years). The proportion of hypokinetic LV segments was calculated as the number of LV segments with fractional thickening of less than 30% divided by the total number of segments measured. Anthropometric and biochemical correlates of LV hypertrophy were determined. Univariate and multiple linear regression analyses were used to investigate the association of the proportion of hypokinetic segments and other correlates of LV hypertrophy with LV mass and maximal wall thickness.

RESULTS: The proportion of hypokinetic segments was higher in patients with HCM than in control subjects (37% ± 20 [standard deviation] vs 12% ± 12, P < .001). In stepwise multiple regression analysis, the proportion of hypokinetic segments accounted for 42% (P < .001); the LV end-diastolic volume, for 24% (P = .003); and male sex, for 10% (P = .014) of the variability in LV mass in patients with HCM. The proportion of hypokinetic LV segments, which accounted for 48% of the variability in LV maximal wall thickness (P < .001), was the only variable significantly associated with maximal wall thickness.

CONCLUSION: The extent of myocardial contractile impairment is strongly and independently related to LV mass and maximal wall thickness in patients with HCM attributable to the Asp175Asn mutation in TPM1.

Supplemental material: radiology.rsnajnls.org/cgi/content/full/2363041165/DC1

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease caused by mutations in genes that encode sarcomeric proteins. In patients with HCM, left ventricular (LV) hypertrophy is variable and explained only in part by the causative mutation; this fact suggests that genetic or environmental modifiers account for the phenotypic differences in HCM (1). The insertion-deletion polymorphism of the angiotensin-converting enzyme (ACE) gene is most consistently reported to be related to LV hypertrophy in patients with HCM who have identical causative mutations, accounting for 10%–15% of the variability in LV hypertrophy (2–4). The other factors that influence LV hypertrophy in HCM caused by the same mutation are largely undefined.

Echocardiography, which has been the standard method of assessing genotype-phenotype correlations in HCM, is limited by a variable acoustic window, inadequate LV wall visualization in more distant areas, and inaccurate evaluation of the LV mass in patients with asymmetric hypertrophy (5,6). In contrast, cardiac magnetic resonance (MR) imaging enables a comprehensive evaluation of LV function, LV wall thickness, and LV mass in patients with HCM (5–8). Previous MR imaging studies (9,10) have revealed impaired regional LV contractility in patients with HCM. To our knowledge, there are no previously published MR imaging studies of the relationships between LV mass, LV maximal wall thickness (MWT), and LV contractility in patients with HCM.

To exclude the confounding effects of different causative mutations on LV hypertrophy, a study of the relationship between LV contractility and LV hypertrophy should be performed with patients in whom HCM-causing mutations have been identified. Therefore, the purpose of our study was to prospectively investigate the relationship between myocardial contractile impairment and LV hypertrophy measured by using cardiac MR imaging in patients with HCM caused by the substitution of aspartic acid 175 with asparagine (ie, Asp175Asn mutation) in the {alpha}-tropomyosin gene (TPM1).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The study protocol was approved by the Kuopio University Hospital ethics committee, and all subjects gave written informed consent.

Selection of Index Patients with HCM
Kuopio University Hospital serves a region in Eastern Finland that is inhabited by approximately 250 000 individuals. All patients who are suspected of having or confirmed to have HCM in this area are referred to the Kuopio University Hospital Division of Cardiology, Department of Medicine, for diagnosis and treatment. All available unrelated patients from this area who were suspected of having or confirmed to have HCM, according to hospital records, were examined by the same cardiologist (J.K., with 10 years experience in cardiology). A total of 36 unrelated patients older than 16 years who fulfilled the criteria for definitely having HCM were identified (11).

Clinical Diagnosis of HCM in Index Patients and Relatives
In the index patients, the clinical diagnosis of HCM was based on the demonstration of a maximum end-diastolic LV wall thickness of at least 15 mm at two-dimensional echocardiography in the absence of other causes of LV hypertrophy such as arterial hypertension or aortic stenosis. Because the general criteria for the diagnosis of HCM are not sensitive enough for use in diagnosing HCM in the first-degree relatives of patients with established HCM, the clinical diagnosis of HCM in the adult relatives of the index patients was based on the diagnostic criteria suggested by McKenna et al (12). Briefly, relatives who had an LV end-diastolic wall thickness of at least 13 mm at two-dimensional echocardiography or who had pathologic Q waves, LV hypertrophy with repolarization changes, or deep T-wave inversions at electrocardiography were considered to be clinically affected with HCM.

Genetic Analysis
The genetic screening for variants in TPM1 was performed by using the polymerase chain reaction–single-strand conformation polymorphism method and direct sequencing, as previously described (11). Genotypes of the ACE polymorphism were determined by using the polymerase chain reaction and previously described primers and methods (13,14).

Final Study Population
Four of the 36 unrelated patients with HCM were heterozygous carriers of the Asp175Asn mutation in TPM1, which is a well-established HCM-causing mutation (11,15,16). All available relatives of the index patients with the Asp175Asn mutation were examined, and 23 relatives were found to have this substitution. In addition, one family of four HCM-affected individuals from Western Finland who had the identical TPM1 mutation was included in the study. Thus, a total of 31 heterozygous carriers of the Asp175Asn mutation in TPM1 from five families were identified. A conserved haplotype between an intragenic microsatellite marker, HTM{alpha}CA, and two extragenic microsatellite markers, D15S1036 and D15S108, that spanned a region of about 3 cM (on the Marshfield map) and co-segregated with the mutation was observed in all five families (11,17).

One of the 31 subjects was not included in the study because she had undergone coronary bypass surgery, and six subjects were not willing to participate. Thus, the final patient population in the present study consisted of 24 patients (11 male, 13 female; mean age, 42 years ± 13 [standard deviation]; age range, 17–68 years) with the Asp175Asn mutation in TPM1 from five families. Two of these 24 subjects did not fulfill the echocardiographic or electrocardiographic criteria for HCM and thus were regarded as healthy mutation carriers. For practical reasons, however, all subjects with the Asp175Asn mutation in TPM1 are referred to as patients with HCM in the following analyses.

Control Subjects
Seventeen healthy volunteers (eight men, nine women; mean age, 38 years ± 12; age range, 23–60 years) without histories of cardiac disease and with sex and age distributions similar to those of the patients with HCM were recruited for the study. We examined the control subjects by using protocols that, with the exception of the ACE genotype determinations, were identical to the protocols used to examine the patients with HCM.

Clinical and Echocardiographic Evaluations
All patients with HCM and all control subjects were interviewed; underwent height, weight, and at-rest arterial blood pressure measurements; and were examined with echocardiography, as previously described (18). The clinical and echocardiographic examinations of all of the study subjects were performed by the same cardiologist (J.K., with 10 years experience in cardiac echocardiography). Laboratory testing consisted of hematocrit, norepinephrine, epinephrine, somatomedin, renin, aldosterone, fasting glucose, and fasting insulin level measurements (19).

MR Imaging
MR imaging was performed by one radiologist (P.S., with 6 years experience in cardiac MR imaging) by using a 1.5-T clinical MR imaging unit (Magnetom Vision; Siemens Medical Systems, Erlangen, Germany). A phased-array body coil was used as the receiver. After scout MR images were obtained, 10-mm sections with no intersection gap were acquired in the short-axis plane, from the base to the apex of the heart, by using a turbo fast low-angle shot sequence (20,21). The parameters used to perform cine MR imaging were as follows: 60/4.8 (repetition time msec/echo time msec) with fivefold k-space segmentation, a 20° flip angle, a 110 x 256 data matrix, and a 280–320-mm field of view with a 256 x 256 interpolated matrix. The subjects were imaged during multiple breath holds (one section acquired per breath hold). The average length of time for one breath hold was 20 seconds. The mean number of sections needed to image the entire LV in the short-axis orientation was 9.6 ± 1.3 (standard deviation) (range, 8–14 sections). In addition, we obtained two- and four-chamber long-axis views to evaluate the thickness of the cardiac apex. The time resolution in cine imaging was 30 msec. During image acquisition, a mean of 24 phases ± 5 (range, 13–35) were obtained.

Image Analyses
The same radiologist (P.S.) performed all of the anatomic measurements on MR images by using Numaris software (Siemens, Erlangen, Germany), which was provided with the MR imaging system. LV end-diastolic wall thickness, end-systolic wall thickness, and systolic thickening were evaluated in the short-axis orientation at the basal (ie, tips of the mitral valve leaflets), midcavity (ie, papillary muscles), and apical (ie, beyond the papillary muscles but before the cavity ends) levels. The end-diastolic MR image was the first image acquired after the R wave of the electrocardiographic signal, and the end-systolic MR image was the image showing the smallest LV area at the midventricular level. The short-axis sections were divided into 16 segments according to recent guidelines from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association (22): six segments each at the basal and midcavity levels and four segments at the apical level in the short-axis plane (Fig 1). In addition, the end-diastolic wall thickness of the true apex was measured on long-axis images. However, owing to insufficient endocardial delineation on turbo fast low-angle shot images (21), the end-systolic thickness of the apex was not measured. The maximal end-diastolic wall thickness of the LV at any location was measured and defined as the LV MWT.



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  		Figure 1. Basal (left), midcavity (middle), and apical (right) end-diastolic cine MR images (60/4.8) obtained in a 19-year-old male patient with HCM show locations of segments in the short-axis orientation based on American Heart Association guidelines for standardized myocardial segmentation at tomographic imaging (22). The basal image was obtained at the level of the tips of the mitral valve leaflets; the midcavity image, at the level of the papillary muscles; and the apical image, at the level beyond the papillary muscles.

 
To evaluate LV mass, we manually traced the endocardium and the epicardium, with the papillary muscles and the trabeculations excluded, on end-diastolic MR images. The total myocardial volume of the LV was calculated with the Simpson method by multiplying each traced myocardial area by the section thickness (10 mm) and by summing the volumes of the separate sections combined. The LV end-diastolic and end-systolic volumes were computed in a similar fashion by using short-axis end-diastolic and end-systolic areas, respectively. Stroke volume was calculated by subtracting the LV end-systolic volume from the LV end-diastolic volume. Myocardial mass was calculated by multiplying the myocardial volume by the myocardial density (1.05 g/mL). The LV mass index was calculated by dividing the mass of the LV by the body surface area, which was calculated by using the following equation: [w · h)/3600]0.5 (23), where w is the weight, in kilograms, and h is the height, in centimeters.

Measurement of LV Contractility with MR Imaging
The global ejection fraction was calculated as the stroke volume divided by the end-diastolic volume. Fractional thickening in each of the 16 LV short-axis segments was calculated as follows: [(Tes – Ted)/Ted] · 100, where Tes is the end-systolic wall thickness and Ted is the end-diastolic wall thickness. A segment with fractional thickening of less than 30% was considered to be hypokinetic (24). The proportion of hypokinetic segments was calculated by dividing the number of hypokinetic segments by the total number of LV segments measured. Fractional thickening was not measured in one patient, who had atrial fibrillation. In addition, in 27 (4%) of 640 segments, fractional thickening could not be measured owing to insufficient image quality, masking of the LV wall thickness by the papillary muscles, or the closeness of the outflow tract of the LV.

Statistical Analyses
Because the LV mass and the plasma renin, serum aldosterone, and fasting plasma insulin levels were not normally distributed, these variables were log 10 transformed in all statistical analyses. The independent samples t test was used to study the differences in continuous variables between the patient and control study groups. Because segmental wall thickness and segmental fractional thickening were measured in multiple segments per patient, the differences in segments between groups were analyzed by using appropriate least-square mean differences (and the corresponding P values) estimated from the mixed model that accounted for the possible dependencies of the measurements within subjects (25). The Kruskal-Wallis test was used to study differences in ACE genotypes between the patients with HCM and the control subjects. The Levene test for equality of variances was used to study the difference in LV MWT variability between the patients with HCM and the control subjects. Univariate linear regression analysis was used to investigate the association of the proportion of hypokinetic segments and other correlates of LV hypertrophy with LV mass and LV MWT, as well as the association of LV segmental end-diastolic wall thickness with fractional thickening. Correlates that were significant (P < .05) in univariate analysis were included in the multiple regression analysis.

The multicolinearity of variables in multivariate analysis was investigated by using colinearity statistics tolerance. A tolerance limit of greater than 0.7 was used to indicate non-multicolinearity. By using the stepwise method, we entered or removed variables from the model if the probability of the F value was less than .05 or greater than .10, respectively, and the change in R2 value was used to assess the contribution of each variable to LV mass. Mixed-model analysis was performed by using SAS for Windows, version 8.02 (SAS Institute, Cary, NC), and all other statistical analyses were performed by using SPSS for Windows, version 11.5.1 (SPSS, Chicago, Ill). Data are presented as means ± standard deviations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Clinical and Echocardiographic Findings
The clinical and echocardiographic findings in the patients with the Asp175Asn mutation in TPM1 are summarized in Table 1. There was no significant difference in systolic or diastolic blood pressure between the patients with HCM and the control subjects. At two-dimensional echocardiography, the mean maximal end-diastolic thickness of the septum was 19 mm ± 6 (range, 8–29 mm). At echocardiography, the LV end-diastolic and end-systolic diameters and the LV ejection fraction were within the normal limits in all of the patients with HCM. None of the patients with HCM had a significant (>25 mm Hg) obstruction of the LV outflow tract. One of the patients with HCM had undergone myotomy-myectomy surgery. One-third of the patients with HCM were taking cardiac medication—most often ß-blocking agents.


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  		TABLE 1. Clinical Characteristics of Patients with HCM Attributable to the Asp175Asn Mutation in TPM1 and of Control Subjects

 
The clinical and echocardiographic findings in the control subjects also are shown in Table 1. All control subjects had normal physical examination, electrocardiographic, and echocardiographic findings, as well as normal blood pressure.

ACE Polymorphisms and Biochemical Markers
Four (17%) of the patients with HCM had the DD genotype, 15 (62%) had the ID genotype, and five (21%) had the II genotype of the ACE gene. The respective numbers in a previously examined group of 110 control subjects were 34 (31%), 61 (56%), and 15 (14%) subjects (P = .137) (14). Plasma epinephrine and plasma insulin levels were significantly higher in the patients with HCM than in the control subjects (330 pmol/L ± 220 vs 130 pmol/L ± 90 [P < .001] and 62.4 pmol/L ± 25.8 vs 45.0 pmol/L ± 10.8 [P < .019], respectively). No significant differences in the levels of the other biochemical markers were observed between the patients with HCM and the control subjects (data not shown).

LV Mass and Volume in MR Imaging
No significant differences in LV mass (151 g ± 57 vs 123 g ± 32, P = .064) or LV mass index (77 g/m2 ± 24 vs 66 g/m2 ± 12, P = .099) were observed between the patients with HCM and the control subjects, although there was a trend toward increased LV mass in the HCM group (Fig 2a, Table 2). The patients with HCM had smaller LV end-diastolic volumes (Table 2). Accordingly, the volume-adjusted LV mass was greater in the patients with HCM than in the control subjects (1.27 g/mL ± 0.33 vs 0.86 g/mL ± 0.22, P < .001). The LV end-systolic volume was similar between the two groups (Table 2), but the stroke volume was smaller in the patients with HCM (70 mL ± 24 vs 90 mL ± 18, P = .008).



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  		Figure 2a. (a, b) Graphs illustrate LV mass (a) and LV MWT (b) in MR imaging in 24 patients with HCM and in 17 healthy control subjects. A significant difference in LV MWT between the patients with HCM and the control subjects is demonstrated.

 

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  		TABLE 2. LV Characteristics in Patients with HCM and in Control Subjects at Cine MR Imaging

 
LV MWT in MR Imaging
In the patients with HCM, the LV MWT was increased (19.5 mm ± 4.9) compared with that in the control subjects (9.7 mm ± 1.7, P < .001) (Table 2). In Levene test analysis, LV MWT values were more variable among the patients with HCM than among the control subjects (P = .014) (Figs 2b, 3). Three of the 24 patients with the Asp175Asn mutation in TPM1 had an LV MWT of less than 13 mm in MR imaging: 11 mm in two patients and 10 mm in one patient. The highest LV MWT among the patients with HCM was 31 mm.



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  		Figure 2b. (a, b) Graphs illustrate LV mass (a) and LV MWT (b) in MR imaging in 24 patients with HCM and in 17 healthy control subjects. A significant difference in LV MWT between the patients with HCM and the control subjects is demonstrated.

 


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  		Figure 3a. End-diastolic cine MR images (60/4.8, 20° flip angle) show great variability in LV hypertrophy between two cousins with the Asp175Asn mutation in TPM1: (a) a 19-year-old man with the Asp175Asn mutation in TPM1 and extensive LV hypertrophy (arrows) and (b) a 17-year-old girl with the same mutation but no hypertrophy (LV MWT, 10 mm).

 


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  		Figure 3b. End-diastolic cine MR images (60/4.8, 20° flip angle) show great variability in LV hypertrophy between two cousins with the Asp175Asn mutation in TPM1: (a) a 19-year-old man with the Asp175Asn mutation in TPM1 and extensive LV hypertrophy (arrows) and (b) a 17-year-old girl with the same mutation but no hypertrophy (LV MWT, 10 mm).

 
Segmental Wall Thickness in MR Imaging
The end-diastolic wall thickness values in 17 LV segments in the patients with HCM and in the control subjects are summarized in Table 3. The anterior segment at the basal level was the thickest in the patients with HCM (16.8 mm ± 6.3). The anterior septum at the basal level and the inferoseptal wall at the midcavity level were hypertrophied (≥13 mm in 18 [75%] patients with HCM) the most often. The anterolateral segment at the midcavity level was not hypertrophied in any of the patients with HCM, and the apex was hypertrophied (≥13 mm) in only one of these patients.


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  		TABLE 3. LV Segmental End-Diastolic Wall Thicknesses and Fractional Thickening Values in Patients with HCM and in Control Subjects

 
LV Contractility in MR Imaging
The global LV ejection fraction measured in MR imaging was similar between the patients with HCM (58% ± 7) and the control subjects (61% ± 7, P = .227) (Table 2). However, the segmental fractional thickening values were lower in the HCM group (44% ± 32) than in the control group (62% ± 31, P < .001) (Table 3). Also, in three patients who had the Asp175Asn mutation in TPM1 but normal LV wall thickness in MR imaging, the mean fractional thickening was decreased compared with that in the control subjects (52% ± 26 vs 63% ± 31, P = .045). The proportion of hypokinetic segments was higher in the patients with HCM (37% ± 20; range, 6%–81%) than in the control subjects (12% ± 12; range, 0%–31%) (P < .001).

In the patients with HCM, most (11 of 16) of the segments had decreased fractional thickening compared with the fractional thickening of segments in the control subjects. Some segments, particularly those in anterolateral and apical areas, had fractional thickening values similar to those in the control subjects (Table 3).

Association of LV Contractility with LV Mass and MWT in Patients with HCM
At the segmental level, LV end-diastolic wall thickness correlated negatively with fractional thickening of the segment (r = –0.741, P < .001 [Fig 4]). Mean fractional thickening did not correlate significantly with LV mass (r = –0.406, P = .055) or LV MWT (r = .236, P = .278). However, the proportion of hypokinetic LV segments was strongly associated with LV mass (r = 0.647, P < .001 [Fig 5a]) and LV MWT (r = 0.691, P < .001 [Fig 5b]). When the data for three patients who had the Asp175Asn mutation in TPM1 but no LV hypertrophy and for one patient who had undergone myectomy previously were excluded from the analyses, the associations between proportion of hypokinetic segments and both LV mass (r = 0.638, P = .003) and LV MWT (r = 0.613, P = .005) remained significant. When the proportion of hypokinetic segments was calculated by assessing the midcavity segments only, the associations between proportion of hypokinetic segments and both LV mass and LV MWT also remained significant (r = 0.605 and P = .002 for both analyses).



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  		Figure 4. Scatterplot shows negative correlation between LV wall thickness and fractional thickening at the segmental level in patients with HCM.

 


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  		Figure 5a. (a, b) Scatterplots show associations of log 10 (Lg10) transformed LV mass (a) and LV MWT (b) with proportion of hypokinetic LV segments in patients with HCM. The proportion of hypokinetic segments is significantly associated with LV mass and LV MWT.

 


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  		Figure 5b. (a, b) Scatterplots show associations of log 10 (Lg10) transformed LV mass (a) and LV MWT (b) with proportion of hypokinetic LV segments in patients with HCM. The proportion of hypokinetic segments is significantly associated with LV mass and LV MWT.

 
Figure 6 and Movies 1 and 2 (radiology.rsnajnls.org/cgi/content/full/2363041165/DC1) show the cine MR images obtained in two patients with the Asp175Asn mutation in TPM1. The first patient (Fig 6a, 6b; Movie 1 [radiology.rsnajnls.org/cgi/content/full/2363041165/DC1]) had mild LV hypertrophy and only one hypokinetic segment, whereas the second patient (Fig 6c, 6d; Movie 2 [radiology.rsnajnls.org/cgi/content/full/2363041165/DC1]) had marked LV hypertrophy and numerous hypokinetic segments.



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  		Figure 6a. (a, b) Short-axis end-diastolic (a) and end-systolic (b) LV cine MR images (60/4.8, 20° flip angle) obtained in 23-year-old man with the Asp175Asn mutation in TPM1 and mild LV hypertrophy, showing only one hypokinetic segment (anteroseptal segment at basal level, arrow). (c, d) Corresponding short-axis end-diastolic (c) and end-systolic (d) LV cine MR images (60/4.8, 20° flip angle) obtained in 22-year-old man with the Asp175Asn mutation in TPM1, showing marked LV hypertrophy, and several hypokinetic segments (arrows).

 


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  		Figure 6b. (a, b) Short-axis end-diastolic (a) and end-systolic (b) LV cine MR images (60/4.8, 20° flip angle) obtained in 23-year-old man with the Asp175Asn mutation in TPM1 and mild LV hypertrophy, showing only one hypokinetic segment (anteroseptal segment at basal level, arrow). (c, d) Corresponding short-axis end-diastolic (c) and end-systolic (d) LV cine MR images (60/4.8, 20° flip angle) obtained in 22-year-old man with the Asp175Asn mutation in TPM1, showing marked LV hypertrophy, and several hypokinetic segments (arrows).

 


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  		Figure 6c. (a, b) Short-axis end-diastolic (a) and end-systolic (b) LV cine MR images (60/4.8, 20° flip angle) obtained in 23-year-old man with the Asp175Asn mutation in TPM1 and mild LV hypertrophy, showing only one hypokinetic segment (anteroseptal segment at basal level, arrow). (c, d) Corresponding short-axis end-diastolic (c) and end-systolic (d) LV cine MR images (60/4.8, 20° flip angle) obtained in 22-year-old man with the Asp175Asn mutation in TPM1, showing marked LV hypertrophy, and several hypokinetic segments (arrows).

 


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  		Figure 6d. (a, b) Short-axis end-diastolic (a) and end-systolic (b) LV cine MR images (60/4.8, 20° flip angle) obtained in 23-year-old man with the Asp175Asn mutation in TPM1 and mild LV hypertrophy, showing only one hypokinetic segment (anteroseptal segment at basal level, arrow). (c, d) Corresponding short-axis end-diastolic (c) and end-systolic (d) LV cine MR images (60/4.8, 20° flip angle) obtained in 22-year-old man with the Asp175Asn mutation in TPM1, showing marked LV hypertrophy, and several hypokinetic segments (arrows).

 
Correlates of LV Mass and MWT in Linear Regression Analysis in Patients with HCM
The correlates of LV mass and LV MWT in linear regression analyses in the patients with HCM are shown in Tables 4 and 5. In univariate analyses (Table 4), sex, body surface area, systolic blood pressure, LV end-diastolic and end-systolic volumes, stroke volume, proportion of hypokinetic segments, and fasting plasma glucose level were significantly associated with LV mass. Only the proportion of hypokinetic segments was significantly associated with the LV MWT; this variable accounted for 48% of the variability in LV MWT (P < .001).


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  		TABLE 4. Correlation Coefficients for Relationships between LV Mass, MWT, and Various Demographic and Clinical Variables in Univariate Linear Regression Analysis in Patients with HCM

 

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  		TABLE 5. Correlates of LV Mass in Patients with HCM at Stepwise Multiple Linear Regression Analysis

 
To investigate which variables were independently associated with LV mass, stepwise linear regression analysis was performed. No significant multicolinearity between the proportion of hypokinetic segments and the other variables assessed in multiple linear regression analyses was observed. The best stepwise multivariate model, which accounted for 75% of the variability in LV mass, included proportion of hypokinetic segments, LV end-diastolic volume, and male sex. The proportion of hypokinetic segments accounted for 42% (P < .001); the LV end-diastolic volume, for 24% (P = .003); and male sex, for 10% (P = .014) of the variability in LV mass.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In the present study, we used cine cardiac MR imaging to investigate the relationship between contractile function and LV hypertrophy in patients with an identical HCM-causing mutation. The proportion of hypokinetic segments was increased in the patients with HCM, compared with that in the control subjects, and was both the only variable that correlated with LV MWT and the most important correlate of LV mass; this variable accounted for 48% of the variability in LV MWT and for 42% of the variability in LV mass.

Assessing Cardiac Anatomy and Systolic Function with Cardiac MR imaging
Cardiac MR imaging is considered the standard of reference for measuring LV end-diastolic and end-systolic volumes, mass, and ejection fraction (5,6,26–28). Cine MR imaging performed by using a segmented k-space turbo gradient-echo technique facilitates accurate and reproducible wall thickness and thickening measurements (29,30). Systolic wall thickening has been shown to reflect myocardial function in a single region during normal and abnormal cardiac states and to be more precise than wall motion analysis (31,32). In patients with myocardial infarction, wall thickening analysis has been shown to have high specificity and moderate sensitivity for the detection of myocardial dysfunction (24).

In patients with HCM, MR imaging has been used to study LV hypertrophy (5–8), myocardial perfusion (18,33), and myocardial scarring (34,35), but there have been only a few MR imaging studies of regional contractile function associated with HCM (9,10), and these investigations have involved the use of myocardial tagging. In the present study, we found that cine MR imaging can be used to investigate not only LV hypertrophy but also the extent of contractile impairment in HCM. We used fractional thickening of less than 30% to define hypokinetic LV segments. In patients who have had myocardial infarctions, the mean fractional thickening in the affected region of the myocardium has been shown to be 31% (24). Consequently, fractional thickening of less than 30% in LV segments probably represents physiologically substantial hypokinesia.

Myocardial Contractility and Its Relationship with LV Hypertrophy in HCM
In the present study involving patients who had HCM with the Asp175Asn mutation in TPM1, global ejection fractions were normal but stroke volumes were decreased. In HCM, the global systolic contractility measured by using the ejection fraction is usually preserved and could even be hyperkinetic (9). However, with concentric LV hypertrophy caused by arterial hypertension, the global systolic function measured by endocardial shortening represents an overestimated indicator of myocardial function (36,37). Also, two MR imaging studies (9,10) have revealed that in patients with HCM, although the global ejection fraction is preserved, the regional systolic function of LV is impaired. Accordingly, in the present study, the regional LV contractile function measured by mean fractional thickening or the proportion of hypokinetic segments was impaired. Some LV segments in the patients with HCM, however, had normal systolic contractility. This variable regional systolic function is consistent with findings in previous studies (10,38,39) and appears to be a characteristic feature in patients with HCM.

In the present study, in each LV segment, the fractional thickening was related to the end-diastolic thickness of the segment; this finding is in accordance with the findings of Dong et al (9). Moreover, the extent of impaired contractility measured as the proportion of hypokinetic LV segments in MR imaging was an independent and the strongest correlate of both LV mass and LV MWT. Although all of the patients with HCM in the present study had the same causative mutation, they had marked differences in contractility and LV hypertrophy. In a transgenic animal model, the cardiac-specific expression of the mutant TPM1 protein was shown to have a dose-dependent association with the extent of cardiac dysfunction (40,41). It is possible that also in human HCM, the variable expressions of mutant protein may influence myocardial contractility. The extent of cardiac systolic impairment, in turn, may activate the expression of stress-responsive trophic factors, such as adrenergic mediators that trigger LV hypertrophy (42). In our previous study (43), cardiac adrenergic tone was increased and related to LV hypertrophy in patients who had HCM with the Asp175Asn mutation.

What evidence do we have that impaired contractility precedes LV hypertrophy in HCM? Both in transgenic animal models of HCM and in human studies, reduced myocardial contraction has been detected in disease-causing mutation carriers without LV hypertrophy (44–46) and to predict the later development of LV hypertrophy (46). Accordingly, in the current study, the LV fractional thickening in MR imaging was decreased in patients who had the Asp175Asn mutation in TPM1 but normal wall thickness and normal LV mass; this finding supports the notion that impaired contractility precedes LV hypertrophy. However, because systolic impairment was more severe in the patients who had HCM with marked LV hypertrophy, we cannot rule out the possibility that severe or moderate LV hypertrophy further impairs contractile function by causing mechanical interference between myocardial cells or an increase in connective tissue (9).

Other Correlates of LV Hypertrophy in Patients with HCM
We observed a positive relationship between the number of *D alleles of the ACE gene and both LV mass and LV MWT in patients with the Asp175Asn mutation in TPM1, but the association was not significant. Although the possibility of a statistical type II error cannot be excluded, our results are in accordance with those in previous studies indicating that the influence of ACE gene polymorphism on LV hypertrophy in patients with HCM is relatively minor (1,2). In our study, LV size and male sex influenced the LV mass but not the LV MWT. Other anthropometric, hemodynamic, and biochemical factors had no independent effect on LV hypertrophy in the patients with HCM; this finding suggests that such factors have a limited role in LV hypertrophy associated with HCM. However, owing to the relatively small number of subjects examined in the current study, the possibility of a statistical type II error cannot be excluded.

Heart Morphologic Features in Patients Who Have HCM Attributable to the Asp175Asn Mutation in TPM1
All previous genotype-phenotype characterizations of HCM have been based on echocardiographic studies, and, to our knowledge, our study is the first to involve the use of cardiac MR imaging and recently standardized LV segmentation guidelines (22). HCM caused by the Asp175Asn mutation in TPM1 is characterized by highly variable LV hypertrophy, as shown by the findings in both the present study and previous investigations (15,16,47,48). The penetrance of this mutation in adult patients has been estimated to be 100% (15,16,47,48), but in our study there were three patients aged at least 17 years who had an LV MWT of less than 13 mm. Only one patient with HCM had an LV MWT greater than 3 cm. The septum and the LV anterior free wall were hypertrophied the most often. The patients with HCM had smaller end-diastolic LV volumes than the control subjects.

Study Limitations
Study subjects.—In the present study, a limited number of patients who had HCM attributable to a single causative mutation were examined. Although most sarcomeric mutations are considered to be hypocontractile (49), the findings in the present study cannot necessarily be extrapolated to all HCM-causing mutations. On the other hand, as demonstrated by the present study findings, an adequate number of patients who have HCM attributable to an identical disease-causing mutation are needed to investigate the relationship between contractility and LV hypertrophy, because different causal mutations induce both contractile deficit and LV hypertrophy in variable degrees (1,49).

Methodological limitations at cine MR imaging.—First, when one measures the LV wall thickness at end systole by using cine MR imaging, the endocardial surface can be obliterated by papillary muscles and trabeculations. However, by observing the moving structures image-by-image in a cine series, it is usually possible to detect the location of the endocardium at end systole. Only a few segments had to be excluded from the image analyses because of endocardial surface obliteration in the present study. Second, the motion of the heart can cause the myocardium to move out of the imaging plane at end systole with respect to end diastole, and this movement might disturb the investigation of the relationship between contractility and LV hypertrophy. To avoid this error, we investigated the relationship between LV contractility and LV hypertrophy also by using segments at the midventricular level only, where the longitudinal movement of the LV is relatively minor (4 mm) (9,10), and use of this approach did not influence the results. With the MR imaging myocardial tissue tagging method, it is possible to assess regional myocardial shortening three dimensionally (10,38,50–52). Although tissue-tagging images are easy to obtain, the analysis of these images is complicated and no commercial software packages for this assessment are available. Fractional thickening analysis, in contrast, is simple and can be performed with any software used to measure distance.

Our conclusions based on the present study findings are as follows: (a) Cine MR imaging is a feasible method of detecting not only LV hypertrophy but also the extent of contractile impairment associated with HCM. (b) In patients with HCM attributable to the Asp175Asn mutation in TPM1, LV hypertrophy and segmental contractility are highly variable. (c) The extent of myocardial contractile impairment in cine MR imaging is a strong correlate of LV hypertrophy; this finding supports the concept that contractile deficit is an essential factor in the pathogenesis of LV hypertrophy in HCM.


   ACKNOWLEDGMENTS
 
The authors thank Marja-Liisa Sutinen, RN, for technical assistance and Jyrki T. Kuikka, PhD, for valuable comments.


   FOOTNOTES
 

Abbreviations: ACE = angiotensin-converting enzyme • HCM = hypertrophic cardiomyopathy • LV = left ventricle • MWT = maximal wall thickness

Authors stated no financial relationship to disclose

Author contributions: Guarantors of integrity of entire study, P.S., K.L., J.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, P.S., K.L., P.J., H.M., H.J.A., J.K.; clinical studies, K.L., P.J., J.K.; experimental studies, K.L., M.L.; statistical analysis, P.S., K.L., M.L., H.J.A.; manuscript editing, K.L., P.J., M.L., K.P., H.M., H.J.A., J.K.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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