Towards the molecular diagnosis of hypertensive heart disease?

Left ventricular hypertrophy (LVH) represents the heart's response to increased biomechanical stress such as arterial hypertension [i.e. hypertensive heart disease (HHD)]. LVH has been traditionally considered a compensatory mechanism required to normalize wall tension and to maintain cardiac output. However, recent clinical studies as well as several animal models have shown that sustained LVH is rather a maladaptive process, ultimately leading to heart failure, cardiac arrhythmias and alterations of myocardial perfusion [1]. Throughout the past two decades, much effort has thus been spent on deciphering the molecular mechanisms mediating LVH. In response to pressure overload in a setting of arterial hypertension, the heart must work harder than under normal conditions. To counterbalance the chronic increase in wall stress the cardiomyocytes within the left ventricle grow and increase their individual size which, in turn, results in the whole increase in left ventricular mass that characterizes LVH [1]. Growth of cardiomyocytes is critically dependent on changes in gene expression that will increase the rate of protein synthesis and the subsequent organization of contractile proteins into enlarged sarcomeric units [2]. A select group of transcriptional regulators that participate in physiologic growth of the developing myocardium are re-employed in the adult heart in the early response to biomechanical stress [3,4]. Transcriptional regulators of cardiomyocyte growth responses are as follows: Zinc finger transcription factor GATA4. Homeodomain protein Nkx2.5/Csx. T domain containing protein Tbx5. Myocyte enhancer factor 2. Serum response factor (SRF). Nuclear factor of activated T cells. Nuclear factor κB. Basic helix–loop–helix factors Hand1/2. SMAD transcription factors. Chromatin remodeling factors. Therefore, they are thought to mediate the re-expression of the ‘fetal program’ and genes involved in the pathologic growth of the cardiomyocyte [3]. Whereas some of these transcription factors (for instance GATA4 and Nkx2.5) are activated by signal transduction pathways [4], others (for instance serum response factor or SRF) are also activated by a family of related transcriptional coactivators (i.e. myocardin and myocardin-related transcription factors) [5]. GATA4 has been extensively characterized as a regulator of hypertrophic growth of the adult heart [6]. In fact, a number of mechanical and humoral stimuli (i.e. endothelin-1 and angiotensin II) that induce LVH are known to enhance GATA4 transcriptional activity through phosphorylation at serine 105 mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPK [7]. Additionally, in vivo, heart-specific deletion of GATA4 gene reduced the left ventricular hypertrophic response to pressure overload stimulation [8]. On the other hand, Nkx2.5 (also known as Csx) has been hypothesized to participate in the cardiac hypertrophic response given the observation that its expression is upregulated during pressure overload or phenylephrine-mediated and isoproterenol-mediated LVH [9,10]. Recently, STAT3 and ERK1/2 have been identified as specific signaling components involved in Nkx2.5 activation in cardiomyocytes [11]. Finally, cardiac-specific overexpression of SRF in transgenic mice induced cardiac hypertrophy with collagen deposition [12]. SRF is regulated by myocardin that physically associates with this factor to stimulate its transcriptional activity [5]. Interestingly, hypertrophic stimuli induce expression and transcriptional activity of myocardin in the heart [13]. In addition, adenoviral-mediated overexpression of the myocardin gene has been shown to stimulate cardiomyocyte hypertrophy [14]. The current challenge is how to translate to the clinical arena the basic information on these early transcriptional regulators of the cardiac hypertrophic response. In other words, how to use them as means of developing new diagnostic and therapeutic strategies for adult cardiac diseases. In this conceptual framework, Kontaraki et al.[15,16] have developed in the recent years an approach based on the assessment of myocardial gene expression in peripheral blood cells (PBC) from patients with chronic cardiomyopathies. From their findings, it seems that alterations in transcript levels of early cardiac response genes associated with altered indices of left ventricular mass and function [15,16]. In particular, increased expression of GATA4 and myocardin was positively correlated with increased left ventricular mass in patients with hypertrophic cardiomyopathy [15]. In this issue of the Journal, the same authors report the results of their investigation on the assessment of GATA4, Nkx2.5 and myocardin transcripts in PBC from 62 patients with untreated essential hypertension and 38 healthy controls [17]. The expression of the three early cardiac genes was increased in patients compared with controls. Although the authors did not analyze differences in the expression of GATA4, Nkx2.5 and myocardin between patients with and without LVH, the three transcripts were positively correlated with the left ventricular mass index in hypertensive patients. Of interest, the magnitude of these correlations did not change significantly when partial correlation was applied using 24-h ambulatory blood pressure monitoring (ABPM) parameters. Collectively, these findings point to the possibility that PBC could be used for analysis of the expression of early regulators of cardiac hypertrophic response in hypertensive patients. Additional questions arise, as should be the case for such a provocative study. One question is how representative are PBC in terms of cardiac gene expression? A recent study using both an expressed sequence tag and a microarray hybridization approach to compare PBC transcriptome with genes expressed in different human tissue types revealed that expression of over 84% of the detected genes was shared with cardiac tissue [18]. The authors also sought to determine whether those gene transcripts undetected by these methods were also expressed in peripheral blood cells. Using reverse-transcriptase-polymerase chain reaction, they detected additional tissue-specific gene transcripts including the heart specific β-myosin heavy chain [18]. It thus can be hypothesized that PBC can act as sentinels of cardiac disease and that we could capitalize on this property of blood for the diagnosis/prognosis of disease (the ‘Sentinel Principle’). Another question is how alterations in the levels of gene transcripts may reflect PBC responses to changes in the macro-environments and micro-environments? Recent blood gene expression studies have shown that the expression profiles of PBC do contain specific expression signatures in response to various pathological changes including arterial hypertension [19,20]. In this regard, it is interesting to remark that in the study by Kontaraki et al.[17] GATA4 and myocardin were positively correlated with 24-h ABPM parameters and negatively with the dipping status in hypertensive patients. As recently proposed [21], time has come to revisit current management of HHD simply focused on detecting LVH and reducing left ventricular mass. It is now necessary to develop new molecular approaches before LVH is clinically detectable (Fig. 1). These approaches should be aimed at early identification of hypertensive patients highly prone to develop LVH (e.g. patients carrying specific polymorphisms in genes encoding components of the renin–angiotensin–aldosterone system [22]), patients having initiated the cellular and molecular responses of the myocardium to biomechanical stress imposed by systemic hypertension (e.g. patients exhibiting a transcriptional profiling that reflects the hypertrophic response of the cardiomyocyte [23]), and patients developing structural changes of the myocardium that lead to its remodeling (e.g. patients with increased circulating levels of biomarkers of the histopathological lesions present in the hypertensive heart [24]). In this context, the possibility exists also to select those patients who may benefit from new strategies aimed to prevent the future development of HHD through the blockade of the early molecular and tissue cardiac responses that initiate the process of LVH [25]. In so doing, the adverse risk associated with HHD should be reduced more effectively.Fig. 1In summary, Kontaraki et al.[17] deserve to be congratulated for shedding new light on the potential usefulness of the molecular diagnosis of HHD focused on transcriptional profiling of PBC. Nevertheless, further research is required for a better knowledge on the nature of the regulation of myocardial gene expression in PBC from hypertensive patients, as well as on the evolution of GATA4, Nkx2.5 and myocardin transcript levels during the progression of HHD. In addition, clinical studies are necessary to evaluate the true usefulness of myocardial gene transcripts determined in PBC to detect HHD in its preclinical phase, as well as to evaluate the molecular efficacy of already available and forthcoming therapies provided to regress LVH in hypertensive patients. Acknowledgements This work was partially funded through the UTE-FIMA cooperative project, the Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (RECAVA) (grant RD06/0014/0008) and FIS project (PS09/02234) from the Instituto de Salud Carlos III, Ministry of Science and Innovation, Spain, and the European Union (InGenious HyperCare, grant LSHM-CT-2006-037093).