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European Heart Journal Advance Access originally published online on March 11, 2008
European Heart Journal 2008 29(7):846-848; doi:10.1093/eurheartj/ehn055
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Evolving concepts of left ventricular hypertrophy

Valérie Tikhonoff and Edoardo Casiglia*

Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy

* Corresponding author. Email: edoardo.casiglia{at}unipd.it

This editorial refers to ‘Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans’{dagger} by U.H. Frey et al., on page 888

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Adaptative left ventricular hypertrophy mainly derives from pressure or volume overload. Nevertheless, in the general population, about one-fifth of normotensives develop left ventricular hypertrophy despite a normal pressure load, while more than one-third of hypertensives do not develop it in response to pressure overload (Table 1). It is unclear why some subjects become hypertrophic while others do not. Hypoxic or ischaemic myocyte loss could account for a limited number of such cases. The natural history of left ventricular hypertrophy is also very different, with some subjects developing heart failure and premature death and others who seem to be free of these prognostic effects1 (Figure 1). Both left ventricular hypertrophy and its consequences are complex integrating multigenic traits acting in the long term.2


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  		Table 1 Prevalence of left ventricular hypertrophy (left ventricular mass index ≥125 g/m2 in men or ≥110 g/m2 in women) in 2368 subjects from the Italian general population (E. Casiglia et al., unpublished data)

 

Figure 1
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  		Figure 1 Cardiovascular and non-cardiovascular mortality rate (mean follow-up 19 ± 7 years) in 5896 subjects from the general population with and without left ventricular hypertrophy (left ventricular mass criteria or Minnesota code 3-1 or 3-3) (E. Casiglia et al., unpublished data). NS, non-significant difference.

 
It has been known since the 1990s that biochemical signalling events and changes in gene expression (including an increase of immediate early genes and re-expression of fetal genes) are important for the hypertrophic response.3,4 These phenomena lead to increased protein synthesis and cell size which are characteristic of a hypertrophic pattern. In recent years, several transcription factors have been identified as determinants modulating gene expression during hypertrophy in differentiated cells.5 The promoter region of specific genes involved in the hypertrophic response is a key point for signal integration. The complete mechanism describing development/decompensation of myocardial hypertrophy has not been fully clarified, but it is known that hypertrophy signalling occurs through multiple parallel pathways, including those linked with activation of the heterotrimeric G-protein Gq, encoded by the GNAQ gene.6,7

It is therefore clear that researchers involved in the field of cardiac hypertrophy have to deal with these complex signalling pathways that are under genetic control, not only to answer some unanswered questions about the pathophysiology of left ventricular hypertrophy but also from a prognostic and therapeutic viewpoint.

Cardiologists are in general sceptical about genetics. Cardiovascular disease is multifactorial, and responds to a mosaic of genes that interact in common pathways to yield a synergistic mechanism of action, adding further experimental uncertainty to the merely probabilistic value of classical risk factors. Futhermore, association studies based on the analysis of several polymorphisms have often been disappointing for cardiologists. However, it must be emphasized that the study of Frey et al.8 discussed here is not a mere study of association, but rather a wide spectrum of research going ‘from genetics, to molecular characterization, to a large clinical study’.

One of the principal candidate signalling pathways for cardiac hypertrophy is stimulation of the G protein Gq through its G-protein-coupled receptors.9 The aim of the study by Frey et al.8 was to investigate in humans the Gq protein overexpression encoded by the GNAQ gene and to identify Gq promoter polymorphism and specific transcription factors that regulate gene expression, as already observed in animal models.9 In a recent study by Clerk et al., 2 they first characterized the GNAQ promoter looking for a possible polymorphism suspected to play a prominent role in disease susceptibility.10 They then identified the transcription factors and their binding sites, and clarified whether the Gq promoter was inducible by circulating stimuli, and whether the novel single polymorphism was really able to increase Gq expression resulting in enhanced activation of the Gq pathway and in enhanced cell growth in a signal-dependent manner.11,12 After identification of the promising GC(–695/–694)TT GNAQ polymorphism and in vitro experiments highlighting its functional expression, they checked in a population survey for its possible association with left ventricular mass. Finally, applying multiple regression models in subjects from the general population, the authors concluded that the GC allele was more common in individuals with than without left ventricular hypertrophy, and—more importantly—that, in contrast, the above-mentioned polymorphism explained a significant part of the variance, really predicting left ventricular hypertrophy.

Every effort was made to demonstrate that this polymorphism was important and functional, by reproducing step by step the entire pathway from identification of a novel polymorphism to its phenotypic expression, ‘from genetics, to molecular characterization, to a large clinical study’. The in vitro study was carried out on fresh human atria, as there are no well-established continuous cell lines that can be used to study cardiomyocyte development and growth.13 The investigation showed that this single-nucleotide polymorphism had functional implications, with the GC allele increasing Gq expression (contrasting findings shown by others could be attributable to the different setting14) and enhancing signal transduction via Gq-coupled receptors. In particular, in the GC allele carriers, Gq expression was found to be more inducible by stimulation with angiotensin II, which is of interest as there are higher circulating levels of this hormone in chronic disease, with increased workload leading to heart failure. The greatest merit of the study is to provide confirmation to the hypothesis that cardiomyocyte Gq signalling is both necessary for pressure overload hypertrophy3,4 and sufficient to produce overload-like hypertrophy even in the absence of haemodynamic stress,15 giving support to the pathological and physiological mass increase. In the population study, the effect of being GC allele carriers was more prominent (odds ratio 5.52) in women than in men, possibly explaining at the level of Gq mRNA expression why in population-based studies women have on average higher left ventricular mass and higher prevalence of left ventricular hypertrophy than men (Figure 2).


Figure 2
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  		Figure 2 Prevalence of left ventricular hypertrophy (left ventricular mass index ≥125 g/m2 in men or ≥110 g/m2 in women) among 2368 subjects from the general population. Prevalence is significantly higher in females, a finding that is common in all population-based studies (E. Casiglia et al., unpublished data).

 
Although the study needs to be confirmed in further population cohorts respecting the criteria for internal validity of an association study, Frey et al.8 have opened a way through better knowledge of the onset and natural history of cardiac hypertrophy.

Conflict of interest: none declared.

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

{dagger} doi:10.1093/eurheartj/ehm618 Back

References

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  2. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, Sugden PH. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol (2007) 212:311–322.[CrossRef][Web of Science][Medline]
  3. Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ. Targeting the receptor–Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science (1998) 280:574–577.[Abstract/Free Full Text]
  4. Wettschureck N, Rutten H, Zywtietz A, Gehring D, Wilkie TM, Chen J, Chien KR, Offermanns S. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of G{alpha}q/G{alpha}11 in cardiomyocytes. Nat Med (2001) 7:1236–1240.[CrossRef][Web of Science][Medline]
  5. Pipes GC, Creemers EE, Olson EN. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev (2006) 20:1545–1556.[Abstract/Free Full Text]
  6. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn JW 2nd. Enhanced G{alpha}q signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci USA (1998) 95:10140–10145.[Abstract/Free Full Text]
  7. LaMorte VJ, Thornburn J, Absher D, Spiegel A, Brown JH, Chien KR, Feramisco JR, Knowlton KU. Gq- and Ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following {alpha}1-adrenergic stimulation. J Biol Chem (1994) 269:13490–13496.[Abstract/Free Full Text]
  8. Frey UH, Lieb W, Erdmann J, Savidou D, Heusch G, Leineweber K, Jakob H, Hense HW, Löwel H, Brockmeyer NH, Schunkert H, Siffert W. Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans. Eur Heart J (2008) 29:888–897. First published on March 6, 2008. doi:10.1093/eurheartj/ehm618.[Abstract/Free Full Text]
  9. Howes AL, Miyamoto S, Adams JW, Woodcock EA, Brown JH. G{alpha}q expression activates EGFR and induces Akt mediated cardiomyocyte survival: dissociation from G{alpha}q mediated hypertrophy. J Mol Cell Cardiol (2006) 40:597–604.[CrossRef][Web of Science][Medline]
  10. Hoogendoorn B, Coleman SL, Guy CA, Smith K, Bowen T, Buckland PR, O'Donovan MC. Functional analysis of human promoter polymorphisms. Hum Mol Genet (2003) 12:2249–2254.[Abstract/Free Full Text]
  11. Offermanns S. In vivo functions of heterotrimeric G-proteins: studies in G{alpha}-deficient mice. Oncogene (2001) 20:1635–1642.[CrossRef][Web of Science][Medline]
  12. Wettschureck N, Moers A, Offermanns S. Mouse models to study G-protein-mediated signaling. Pharmacol Ther (2004) 101:75–89.[CrossRef][Web of Science][Medline]
  13. Adams JW, Brown JH. G-proteins in growth and apoptosis: lessons from the heart. Oncogene (2001) 20:1626–1634.[CrossRef][Web of Science][Medline]
  14. Liggett SB, Kelly RJ, Parekh RR, Matkovich SJ, Benner BJ, Hahn HS, Syed FM, Galvez AS, Case KL, McGuire N, Odley AM, Sparks L, Kardia SLR, Dorn GW. A functional polymorphism of the G{alpha}q(GNAQ) gene is associated with accelerated mortality in African-American heart failure. Hum Mol Genet (2007) 16:2740–2750.[Abstract/Free Full Text]
  15. D'Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW 2nd. Transgenic G{alpha}q overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA (1997) 94:8121–8126.[Abstract/Free Full Text]

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Related articles in EHJ:

Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans
Ulrich H. Frey, Wolfgang Lieb, Jeanette Erdmann, Danai Savidou, Gerd Heusch, Kirsten Leineweber, Heinz Jakob, Hans-Werner Hense, Hannelore Löwel, Norbert H. Brockmeyer, Heribert Schunkert, and Winfried Siffert
EHJ 2008 29: 888-897. [Abstract] [FREE Full Text]  




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