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Cardiovascular Research Advance Access first published online on November 20, 2007
This version [Corrected Proof] published online on February 1, 2008
Cardiovascular Research, doi:10.1093/cvr/cvm075
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Troponin T and β-myosin mutations have distinct cardiac functional effects in hypertrophic cardiomyopathy patients without hypertrophy

Miriam Revera1, van der Merwe Lize2, Marshall Heradien3, Althea Goosen3, Valerie A. Corfield4, Paul A. Brink3 and Johanna C. Moolman-Smook4,5,*

1 Department of Cardiology, IRCCS San Matteo Hospital, Pavia, Italy
2 Biostatistics Unit, Medical Research Council of South Africa, Tygerberg, South Africa
3 Department of Medicine, University of Stellenbosch Health Sciences Faculty, Tygerberg, South Africa
4 MRC/US Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, Room 4036, University of Stellenbosch Health Sciences Faculty, Francie van Zijl Drive, PO Box 19063, Tygerberg 7505, South Africa
5 The Hatter Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa

* Corresponding author. Tel: +27 21 9389693; fax: +27 21 9389476. E-mail address: hm{at}sun.ac.za

Received 17 September 2007; revised 6 November 2007; accepted 16 November 2007

Time for primary review: 20 days


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Funding
 References
 
Aims: The validity of genotype:phenotype correlation studies in human hypertrophic cardiomyopathy (HCM) has recently been questioned, yet animal models and in vitro studies suggest distinct effects for different mutations. The aims of this study were to investigate whether distinct HCM-mutations have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy.

Methods and results: Individuals aged 20–65 belonging to 21 R92WTNNT2, R403WMYH7, or A797TMYH7 mutation-bearing families were investigated with 2D, M-mode, and Doppler echocardiography. Cardiac structural and functional parameters were compared between prehypertrophic mutation-carriers and their non-carrier family members, with concomitant adjustment for appropriate covariates. Findings were evaluated against existing animal and in vitro functional data. The distinct functional effect of the R92WTNNT mutation was a relative increase in systolic functional parameters, that of the A797TMYH7 mutation was reduced diastolic function, while the R403WMYH7 mutation reduced both systolic and diastolic function. The observed early effects of the R92WTNNT2 mutation mechanistically fit with prolonged force-transients precipitated by increased Ca2+ sensitivity of the thin filament, and that of the MYH7 mutations with local ATP depletion.

Conclusion: Evaluation of the impact of the mutations on cardiac structure and function in prehypertrophic mutation-carriers, relative to the baseline norm provided by their non-carrier family members, best recapitulated existing animal and in vitro functional data, while inclusion of mutation-carriers with hypertrophy obscured such findings. The results prompt speculation that timely treatment aimed at ameliorating Ca2+ sensitivity for R92WTNNT2-carriers, and energy depletion for MYH7 mutation-carriers, may offer a plausible approach for preventing progression from a preclinical into a decompensated state.

KEYWORDS Hypertrophic cardiomyopathy; Contractile function; Troponin T; β-myosin; Mutation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Funding
 References
 
Hypertrophic cardiomyopathy (HCM), a primary cardiac muscle disease characterized by thickening of the ventricular wall in the absence of other hypertrophy-predisposing conditions,1 is classically caused by numerous mutations in genes encoding primarily protein components of the cardiac sarcomere, with some evidence for correlations between clinical phenotype and genotype.

In the last few years, the validity of these genotype:phenotype correlations has been questioned.2 Yet, studies of functional consequences of both thick and thin filament protein mutations have indicated that, although most mutations affect the Ca2+-sensitivity of contraction, the effects are variable,3 appear to derive from distinct mechanisms for different defective proteins,3,4 and are intimately linked to alterations in force-transients and/or cellular energetics.5 Similarly, transgenic mouse models suggest that distinct mutations have specific quantitative and temporal effects on hypertrophic gene expression, as well as on structure and function at the myocyte and whole heart level.6 Such distinct effects would be expected to translate into measurable differences at a whole heart level in individuals harbouring specific mutations. The inconsistent detection of such specific effects in human genotype:phenotype studies raises questions about the design of these correlation studies.

Human genotype:phenotype correlation studies have typically included only individuals with fully developed disease,7 or combined such individuals with their subclinically affected, mutation-carrier relatives.8 The latter approach may be confounded by differences in penetrance between mutations, while interpretation of the consequences of mutations on systolic and diastolic function may be confounded by the degree of underlying hypertrophy-associated cardiac fibrosis and disarray.9 Moreover, genetically or environmentally driven differences between families in demographic and other characteristics which influence cardiac parameters may further confound correlations. This suggests that the effect(s) of mutations could best be studied in mutation-carriers against the ‘family base-line’ characteristics provided by their non-carrier relatives.

Thus, in 21 families in which either one of three previously reported HCM-causing founder mutations [viz. the R92W mutation in the cardiac troponin T gene (TNNT2), the R403W, or the A797T mutations in the β-cardiac myosin heavy chain gene (MYH7)] segregated,10 we compared parameters of left ventricular structure and function between mutation-carriers without left ventricular hypertrophy (mutation+LVH–) and their non-carrier (mutation–LVH–) relatives. We then evaluated our genotype–phenotype correlations against known animal model and functional assay data.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Funding
 References
 
2.1 Subjects and clinical evaluation
The study was approved by the University of Stellenbosch Health Sciences Faculty's Institutional Review Board (N04/03/062). The investigation conforms to the principles outlined in the Declaration of Helsinki. Individuals belonging to seven R92WTNNT2, three R403WMYH7, and 11 A797TMYH7 families were screened for all three of these founder mutations, as previously described.10

Echocardiography was performed on all participating individuals, using a standardized procedure, by a single experienced echocardiographist (M.R.) who was blinded to mutation status. M-mode and 2D echocardiographic investigations were made using a 2.5 Hz transducer to obtain standard parasternal long-axis and short-axis, and apical 6-chamber views with a GE Healthcare Vivid7 cardiovascular ultrasound system. Maximum wall thickness was measured in 2D echocardiography short-axis in the anterior (aIVS) and posterior interventricular septum (pIVS), anterior wall (AW), lateral wall (LW), inferior wall (IW), and posterior wall (PW) segments at left ventricle mitral valve level as well as papillary muscle level, and IVS, AW, LW, and PW segments at the immediate supra-apex level, according to recommendation from the American Society of Echocardiography.11 Left ventricular mass was calculated from 2D-LV linear dimensions:



Formula

where LVIDd, left ventricular internal dimension at end-diastole; SWTd, intraventricular septum thickness at end-diastole, and PWTd, posterior wall thickness at end-diastole. Ejection fraction (EF) and fractional shortening (FS) were calculated using LV diastolic and systolic diameters from 2D-echocardiography images.

LV outflow obstruction was deemed present when a peak instantaneous subaortic gradient ≥30 mmHg was estimated with continuous wave Doppler echocardiography under resting conditions.12 Mitral regurgitation was graded semi-quantitatively (1–4+ scale).13 Blood pressure was taken twice, in the sitting position, after 5 min of bed rest, and the second measurement used. Individuals were considered hypertensive if they had systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 or were on anti-hypertensive medication. Standard electrocardiography was performed on a MAC1200ST after 5 min of rest in the supine position, and resting heart rate and the presence of atrial fibrillation derived. A medical history and demographic data (age, sex, height, and weight) were recorded for each participant.

2.2 Data processing
Only individuals aged from 20 to 65 years without clinical hypertrophy due to any cause, i.e. those with a maximum left ventricular wall thickness (maxLVWT) <12 mm, were targeted for statistical comparisons. Because the distribution of some variables was skewed, they were summarized as median and range. However, percentage changes in the mean were recorded, with a view to subsequent comparisons with functional data previously derived from model systems. Because of skewness, all values were quantile normalized14 prior to statistical comparisons. Quantile normalization transforms values to approximate normality, pulling in outliers, so that skewed data becomes symmetric without altering the distribution of values that are already normal.

2.3 Statistical analyses
The effect of the mutations on parameters of cardiac structure, systolic, and diastolic function was compared between mutation+LVH– subjects and their mutation–LVH– relatives for each of the three mutation groups (R92WTNNT2, R403WMYH7, and A797TMYH7). Mixed-effect modelling in the program package R was used as it enabled us to adjust for covariates as well as to control for familial-relatedness, as a random factor. Comparisons inside a mutation group were done in a single model for all three groups, in order to address multiple testing concerns. We investigated the following parameters: maxLVWT, LVM indexed to body surface area (BSA) (LVMi), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), endocardial fractional shortening (FS), ejection fraction (EF), isovolumic relaxation time (IVRT), the ratio of peak early rapid filling velocity (E) to atrial peak filling (E/A), the ratio of E to deceleration time of the E wave (E/DT), and atrial systolic wave velocity (Ar). In the models, maxLVWT and LVMi were adjusted for age, gender, BSA, systolic blood pressure, diastolic blood pressure, and heart rate, while all other parameters were adjusted for these and also for maxLVWT.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Funding
 References
 
3.1 Clinical evaluation
Thirty individuals from R92WTNNT2 families, 45 individuals from A797TMYH7 families, and 16 individuals from R403WMYH7 families were aged ≥20 and ≤65 years, and had maxLVWT <12 mm in all investigated cardiac segments. Salient echocardiographic measurements, Doppler parameters, symptoms, and additional clinical and demographic information of these mutation-carriers and non-carriers are summarized in Table 1.


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  		Table 1 Summary of demographic data and additional clinical features and symptoms of hypertrophic cardiomyopathy family members

 
3.2 Left ventricular structure
There was no significant difference between mutation-carriers and their non-carrier relatives with regard to wall thickness measurements (Table 2, Figure 1A). Mean LVEDD was smaller in R92+LVH– and A797T+LVH–, and greater in R403W+LVH– individuals, than in their respective non-carrier relatives (Table 2, Figure 1B); however, after adjustment for covariates, viz. age, sex, BSA, systolic and diastolic blood pressure, heart rate, and maxLVWT, these differences were not found to be significant.


Figure 1
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  		Figure 1 Box plots of cardiac hypertrophy parameters in mutation subgroups, means (*) are also shown in the graphs. (A) Maximum end-diastolic left ventricular wall thickness (maxLVWT), (B) left ventricular end-diastolic diameter (LVEDD), and (C) left ventricular mass, indexed to body surface area (LVMi), are shown in subgroups defined by the presence or absence of hypertrophic cardiomyopathy-causing mutations and absence of left ventricular hypertrophy (LVH–).

 


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  		Table 2 Comparison of cardiac structural and functional parameters between mutation-carriers without hypertrophy and their non-carrier relatives

 
Mean unadjusted LVMi was ~15% smaller in R92W+LVH– individuals and ~17% greater in R403W+LVH– individuals than in their non-carrier relatives, while A797TMYH7 subgroups differed by ~6% (Table 2, Figure 1C). However, after normalization and adjustment for covariates, these differences were non-significant.

3.3 Differences in cardiac functional parameters in the absence of hypertrophy
In all mutation groups combined, mutation+LVH– individuals demonstrated mean IVRT values that were increased over that of their non-carrier relatives (Table 2, Figure 2); this difference remained statistically significant after adjustment for covariates (P = 0.003). Within mutation groups, the increase in IVRT in mutation+LVH– individuals remained significant for the A797TMYH7 group (P = 0.031) (Table 2, Figure 2).


Figure 2
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  		Figure 2 Box plots of cardiac functional parameters in mutation subgroups, means (*) are also shown in the graphs. (A) Left ventricular end-systolic diameter (LVESD), (B) % fractional shortening (%FS), (C) isovolumic relaxation time (IVRT) and (D) atrial regurgitation wave velocity (Ar) are shown in subgroups defined by the presence or absence of hypertrophic cardiomyopathy-causing mutations and the presence or absence of left ventricular hypertrophy. {dagger}{dagger}P < 0.05 for difference between mutation+LVH– individuals and their mutation–LVH– relatives; {dagger}P < 0.06 for difference between mutation+LVH– individuals and their mutation–LVH– relatives. For isovolumic relaxation time, the difference between mutation-carriers and non-carriers as a whole was significant (P = 0.003).

 
Despite similar LV wall structure (Table 2, Figure 1), the mean LVESD was smaller (Figure 2), and mean FS and EF greater (Table 2, Figure 2), in R92W+LVH– individuals than in their non-carrier relatives. After adjusting for covariates, the R92WTNNT2 mutation was shown to independently contribute significantly to the decreased LVESD (P = 0.020) and increased FS (P = 0.011) and EF (P = 0.014) in R92W+LVH– individuals compared with their R92W–LVH– relatives. On the other hand, besides IVRT, measures of diastolic function (E/A, E/DT, Ar) were not significantly different between R92WTNNT2 mutation-carriers and non-carriers in the absence of hypertrophy (Table 2, Figure 2).

R403WMYH7-carriers demonstrated an increase in mean unadjusted LVESD, which was reflected in similar decrease in mean FS, but, due to a slightly increased LVEDD, only a ~9% decrease in mean EF, compared with their non-carrier relatives (Figure 2, Table 2). The differences in FS and EF were significant (P = 0.013 and 0.014, respectively), and the difference in LVESD was marginally significant (P = 0.056) after adjustment for covariates. Furthermore, mean unadjusted Ar was over a third greater in R403WMYH7-carriers than in their non-carrier relatives; this difference was highly significant after adjustment for covariates (P = 0.003) (Table 2, Figure 2).

Differences in systolic functional parameters were non-significant between the A797TMYH7 subgroups (Table 2, Figure 2). However, aside from significantly increased IVRT (P = 0.031), A797T+LVH– individuals also demonstrated an increase in mean Ar over their non-carriers relatives, which was weakly significant (P = 0.056) after adjustment for covariates (Figure 2).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Funding
 References
 
In order to ensure that any observed statistical differences in cardiac structure or function were attributable to the effects of the particular mutation, the confounding effects of puberty and ageing on these parameters were avoided by the age-delineation of subjects, while adjustments for their covariates, as well as family-relatedness, were made. Besides calculation from LV dimensions, EF was also determined by the method of discs;11 the quantitatively smaller values indicated changes in the same direction (results not shown). Further, although diagnosis of relatives of HCM index-cases typically involves a cut-off parameter of maxLVWT≥13 mm, we excluded all individuals with maxLVWT≥12 mm to provide a margin that would ensure that hypertrophy, due to any cause, and its sequelae did not confound correlations. The differences generated were robust even when the exclusion stringency was increased to maxLVWT≥11 mm (results not shown). Conversely, comparisons of all mutation-carriers, including those with clinical hypertrophy, revealed no statistically significant differences between mutation groups (results not shown). To evaluate our novel stratification-by-hypertrophy approach to genotype:phenotype correlation studies, we then compared our findings to relevant animal models and in vitro functional data.

The 15% reduction in mean LVMi seen in the R92W+LVH- individuals compared with their non-carrier relatives (Figure 1C) was similar to the 14% lower mean heart weight/body weight ratio of R92WTNNT2 transgenic mice compared with their non-transgenic litter mates.6 In these mice, and in the phenotypically and functionally related R92QTNNT2 and I79 NTNNT2 mice,15,16 this observation has been ascribed to an equivalent reduction in cardiomyocyte size that accompanies higher basal levels of myocyte activation.6 The observation was statistically significant in analyses of only male mice, or mixed-gender samples, suggesting an influence of gender.15,17 In our sample, the R92W+LVH– group consisted predominantly of females, perhaps accounting for the lack of statistical significance.

Although R92W+LVH– individuals tended to have non-significantly smaller ventricles than their non-carrier relatives, they demonstrated disproportionate enhancement in systolic indices (Figure 2, Table 2). The differences in FS noted in the R92WTNNT2 group are not likely to be accounted for by differences in load, as R92WTNNT2-carriers and their non-carrier relatives did not differ statistically in systolic or diastolic pressure, heart rate or wall thickness, and none of these individuals were hypertensive or on medication (Tables 1 and 2). Additionally, comparisons were made with adjustment for a number of covariates that may influence load. The clinical significance of a change in FS is uncertain, but it has been shown to correlate with LV peak +dP/dt in mice and rats without overt hypertrophy18,19 and is determined in part by the force of the contraction of the sarcomeres.20 Thus, these findings strongly suggest that inotropy increases as a direct result of the R92WTNNT2 mutation.

We found the correspondence in increased FS and EF between human and transgenic mouse models interesting. Although not reported for R92WTNNT2 mice with established disease, switch-on–switch-off R92QTNNT2 mice in which transgene expression had been induced with mifepristone for 16 days demonstrated a ~20% increase in FS and EF, termed ‘hypersystolic function’, compared with those receiving placebo induction.21 Both these R92 mutations increase Ca2+-binding to the thin filament,6 facilitating myosin head attachment at lower cytosolic Ca2+-concentration. This results in a slower decay of the Ca2+-transient, a broader force transient and faster force development,22 which may result in increased systolic function. This mechanism of action is also reminiscent of the inotropic yet oxygen-sparing effects of the Ca2+-sensitizer EMD-57033.23

R92WTNNT2 transgenic mice do not develop cardiac hypertrophy, despite activation of the hypertrophic gene program.6 Although, we previously reported minimal to mild hypertrophy occurring in R92WTNNT2 individuals,a recent follow-up study noted that more than a third of R92WTNNT2-carriers developed clinically recognized hypertrophy after the age of 35yrs, a correlation that was not seen in the R403WMYH7-carriers.24 This finding may indicate that additional environmental or genetic factors influence the clinical phenotype observed in human R92WTNNT2-carriers.

The MYH7 mutation+LVH– groups did not show improvement in systolic function; no effect on contractility was noted in the A797TMYH7 subgroups, but results suggested ‘relative systolic impairment’ in R403W+LVH– individuals compared with their non-carrier family members. However, the apparent mean FS in the R403WMYH7 non-carrier group may have been influenced by three individuals, one on an ACE-inhibitor, one on a beta-blocker, and another with untreated hypertension, factors not adjusted for in analyses.

Individuals carrying either of the MYH7 mutations also demonstrated ‘relative diastolic impairment’ as reflected not only by increased mean IVRT, but also increased Ar, compared with their non-carrier relatives. This effect on late diastole was extant before the manifestation of clinical cardiac hypertrophy, and was not apparent in R92W+LVH– individuals (Table 2, Figure 2).

Although no transgenic animal models of these MYH7 mutations have been reported, in vitro functional data on the R403WMYH7 mutation and mutations occurring in the vicinity of the A797TMYH7 mutation within the myosin lever arm may be relevant to their pathophysiological mechanisms. Under in vitro conditions, D778GMYH7 myofilaments demonstrate extremely fast actin sliding velocity (~30–50% higher than wild-type), and a shorter Ton for the myosin head resulting in a shorter duty cycle, but no more than wild-type unitary force production.25 Similarly, functional assays of recombinant and patient R403WMYH7 myosin26 demonstrated increased actin sliding velocity (~18–30% higher than wild-type) and affinity of myosin for actin, and a disproportionate increase in myosin ATPase activity (>100% higher than wild-type).25

Such faster, but less energy cost-efficient, crossbridge cycling by a constant number of myosin heads at a given Ca2+-concentration could be expected to outstrip the rate of ATP production in the myocyte. The resultant high concentrations of free Pi and ADP could slow cardiac relaxation rates by means of both myofilament- and intracellular Ca2+-based mechanisms.27,28 However, recent reports suggest that factors relating to crossbridge mechanics and kinetics, rather than Ca2+-based thin filament deactivation, appear to be primarily responsible for load-dependent changes in relaxation rates (reviewed in Poggesi et al.29). Thus, it could be speculated that the Doppler data observed in this study for both MYH7 mutations, which reflect both early and late diastolic effects, are indicative of impaired crossbridge release, which most likely derives from a local increase in ADP concentration, caused by an increased inherent myosin ATPase rate.

The mechanism underlying the apparent ‘relative systolic impairment’ seen in R403WMYH7 individuals is not immediately clear. Interestingly, an unrelated patient homozygous for the R403WMYH7 mutation was reported to suffer early cardiac dilation and required heart transplantation.26 It could be speculated that a mutation at this position, adjacent to the actin-binding cleft, could destabilize strong myosin–actin interaction after the powerstroke, or alternatively may perturb interaction between myosin heads, thus disturbing the coordination between heads needed for effective mechanical work.30 Such effects would be less likely for the A797TMYH7 mutation in the lever arm region. On the other hand, systolic indices were higher in the R403W–LVH– control group than in the other non-carrier groups (Table 2, Figure 2), and were not significantly different between R403W+LVH– individuals and a combined control group consisting of all mutation–LVH– individuals (results not shown). Thus, it is possible that the observed apparent decrease in systolic function relates to unusually high systolic indices in the R403W–LVH– group.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Funding
 References
 
The exploratory analyses, focused on comparison of structural and functional differences in mutation-carriers without clinical hypertrophy, relative to the base-line norm provided by their non-carrier relatives, illustrate that distinct mutations do have different effects in humans, as they do in animal and in vitro studies. This approach distinguishes between mutations in a manner that fits known functional mechanisms; in contrast, combining individuals with and those without hypertrophy may cloud interpretation of genotype–phenotype correlations.

Further, this study illustrates that, given a sufficiently large family setting, comparison of cardiac function between non-carriers and prehypertrophic mutation-carriers may shed light on the predominant functional consequences of HCM-mutations. However, it remains possible that prehypertrophic adults may reflect a subset of the population in which modifying genetic and/or environmental factors, and not solely the causal mutation, influence the clinical phenotype, and thus conceivable that overall disease mechanisms in individuals with and without hypertrophy may differ.

Although further studies are required to validate these deduced mechanisms in other sample sets, it is tantalizing to speculate whether mechanistic insights might in future be useful in management of the disease. The HCM phenotype can be prevented, and even reversed, in animal models,21,31 while early treatment with high-dose beta-blockers has been reported to alter the course of the disease in humans.32,33 It is interesting to contemplate whether early intervention aimed particularly at ameliorating the predominant effect of a particular disease-causing mutation, perhaps beta-blockers or Ca2+-channel blockers for R92WTNNT2-carriers, and metabolic modulation for carriers of these MYH7 mutations, may facilitate prevention of hypertrophy development and ameliorate cardiac dysfunction.


   Funding
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Funding
References
 
Wellcome Trust (International senior research fellowship GR073610MA to J.C.M.-S.) and South African National Research Foundation (FA2006040300007 to J.C.M.-S.).


   Acknowledgements
 
GE Healthcare (Germany) is thanked for providing the Vivid 7 cardiovascular ultrasound system pro Deo for the duration of the study.

Conflict of interest: none declared.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Funding
 References
 

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