To an extent, both hypertension and cardiac hypertrophy are genetically determined, and the two phenomena are related. They also have a common series of predisposing factors. Blood pressure, by general consensus, has a genetic component of approximately 30%; the remaining variability is due to aspects of lifestyle or environment. Left ventricular mass (LVM) heritability is of a similar order. However, variation of blood pressure may only explain 25% of the variation in LVM, whereas a massive 60%, in animal models at least, appears to be independent of blood pressure . Some factors affecting these two complex traits may be common to both, and others specific to one or the other. Some may therefore affect cardiac growth directly, blood pressure directly or cardiac growth indirectly through blood pressure. There are examples of hormones (e.g. angiotensin II or aldosterone) which act in all these ways [2,3]. To add to their interest, there is also some evidence of their production in the heart itself [4–8]. Unravelling these interacting processes from gene differences to final outcome has taken several decades; any advancement has inevitably been governed by technical ingenuity, and progress in experimental animals has been more satisfactory than in human subjects, either normal or abnormal. The question that remains is how to distinguish between the direct and indirect effects on left ventricular mass and what might be the useful intermediate phenotypes? Furthermore, is it possible to monitor phenotype and intermediate phenotypes during the early, preclinical development of LVH, in particular, in a clinically useful, but also scientifically informative way?
The basic sequence of events to be analysed is obvious: genetic variation leading, via a series of intermediate phenotypes, to the ultimate phenotype which, in the case of blood pressure and left ventricular mass, comprise continuous variables with no delineation between normal and abnormal other than by definition. The inherited component of both phenotypes is polygenic. Many genes and/or quantitative trait loci have been implicated, each making a small albeit significant contribution [1,9–13]. The recent publication of the rat, mouse and human genome will certainly lead to an increase in their number. These genotype/phenotype relationships are much more easily established in animal models for several reasons. First, by selective breeding, particular chromosome regions can be studied in isolation. Similarly, specific study of single genes can be achieved by over-expression, mutation or knockout technology. Second, the time sequence of intermediate phenotypic differences can be assessed invasively or even post mortem or in vitro. Third, importantly, the ultimate phenotypes can be measured directly and therefore with a high level of precision. Blood pressures by telemetry  and heart or left ventricular weights provide simple, high calibre data. Although information from animal experiments provides invaluable clues to the situation in man, these associations still need to be confirmed directly.
Do particular gene alleles have differential or independent effects on blood pressure and LVM in man? Does the difference in blood pressure between genotypes precede, accompany or follow those in LVM? To distinguish between these alternatives, it is essential to monitor phenotypes early in the disease process (i.e. prospectively) and to repeat this as frequently as possible thereafter. Identification of informative intermediate phenotypes is also necessary. ‘Cardiac hypertrophy must be understood at the most basic level as a growth process …’ . Genotyping in man is no more difficult than in the animal but assessing phenotype with high precision is a problem. However, because the contribution of individual gene variability may be small, identifying related differences in phenotype requires high precision. Both phenotypes present problems in this respect. Blood pressure data from human studies are relatively ‘soft', especially in large-scale, multicentre population surveys although their large numbers aid statistical selectivity. Method performance criteria are rarely available. Ambulatory monitoring may provide better precision but is more expensive. Myerson et al.  recently compared methods of measuring cardiac and/or LVM and reviewed the relevant literature. They concluded that magnetic resonance imaging is the current gold standard but that more generally available methods, such as three-dimensional echo, can achieve reasonable levels of accuracy and precision.
Finally, it is the many stages of response between gene expression and ultimate phenotype (i.e. the intermediate phenotypes) that might provide clues both to onset and to mechanism. Association of many genes with LVH has been shown, although ‘cause and effect’ is difficult to establish in vivo in man. A proportion of these relate to cardiac-active hormones and their receptor mechanisms (e.g. angiotensin II, atrial natriuretic peptide, catecholamines and mineralocorticoids), and can be monitored by peripheral blood hormone levels. Their receptor concentrations can be followed in readily available cells such as the leucocyte. Monitoring early changes in cardiac growth and remodelling biochemically is more difficult. Two types of cell are involved: the cardiomyocyte and the cardiac fibrocyte. For the cardiomyocyte, genes identified as important in growth and hypertrophy are those for the myosin chains, heat shock proteins and growth factors, none of which is accessible to study in normal man . The fibrocyte synthesizes collagen. During the process of aldosterone-induced cardiac fibrosis in rats, Robert et al.  noted that the accumulation of procollagen preceded collagen deposition in both ventricles. In this context, the study by Takahashi et al.  reported in this issue of the journal is of interest. In their study of the contribution of angiotensin-converting enzyme (ACE) genotype to cardiac function, they used a propeptide of collagen type I (PICP), released into the circulation during synthesis, as a monitor of fibrosis and presumably of ‘remodelling'. They cite earlier work  showing that plasma PICP concentration correlates with myocardial fibrosis better than do some cardiographic variables and, in their own study, they demonstrate significant effects of ACE genotype on PICP concentration. However, they studied hypertensive patients, and direct and indirect effects cannot be distinguished. How sensitive is this test? It would be interesting to compare PICP concentration in the DD and II genotypes, or indeed other genotypes such as the –344 TT and CC genotypes of CYP11B2, in normotensive subjects to establish whether changes precede rises in blood pressure and LVM. At the same time, a method to assess cardiomyocyte activity non-invasively would be welcome.
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