Determinants of left ventricular mass in hypertensive heart disease: a complex interplay between volume, pressure, systolic function and genes

The adverse prognostic impact exerted by left ventricular (LV) hypertrophy on cardiovascular morbidity and mortality has been repeatedly shown in the setting of arterial hypertension [1,2], chronic renal failure [3], coronary artery disease [4] as well as in the general population [5,6]. However, the relative weight of the factors that trigger the hypertrophic process still remains largely unclear. From a mechanical (and mechanistic) standpoint, there is no doubt that an important factor contributing to LV hypertrophy in hypertensive heart disease is represented by ‘load’. By intuitive definition, arterial hypertension is characterized by an increased pressure load (overload), although volume overload, possibly related to an altered sodium turnover, does play an important role in stimulating cardiac hypertrophy. The latter takes place in a precise, albeit largely unknown, genetic background, as demonstrated in several studies underscoring the role of ethnicity [7,8] and heritability [9,10] in predicting the hypertrophic process. Moreover, environmental factors, such as diet, exercise, psychological stress and social status (that are closely linked to genetic factors in a given family and in a well defined ethnic group), also contribute to determining the effect of mechanical overload in triggering the development of LV hypertrophy. The impact of body size, obesity, diabetes and other metabolic abnormalities cannot be overlooked, as well as the role of sympathetic nerve overactivity and the renin–angiotensin–aldosterone system. Indeed, beyond the well known evidence of neurohumoral activation in hypertension, diabetes and obesity, it has to be recognized that catecholamines, angiotensin II and aldosterone are able to trigger cardiomyocyte growth and extracellular matrix deposition (i.e. two key factors in the development of cardiac hypertrophy). In addition, there are several gender-related differences in cardiac structure and remodelling, as well as in the pattern of the hypertrophic response, as shown both in humans [11] and in animal models of chronic pressure overload [12]. A further level of complexity is related to the interactions between LV mass and the capability of generating systolic force. On the one hand, a hypertrophied muscle is able to face and counteract a higher systolic workload. On the other hand, there is a clear-cut association between stroke volume, stress-corrected midwall systolic shortening and LV mass, which is statistically much stronger than the relationship between mass and resting blood pressure, as elegantly shown by Devereux et al. [13] in the population recruited in the Strong Heart Study. Indeed, several determinants contribute to stroke volume, which results from the interaction between intrinsic myocardial contractility, preload, afterload and heart rate. Left ventricular performance is also affected by chamber geometry, atrioventricular synchronicity, biventricular interaction, and by the effects of phasic and tonic neurohumoral stimuli. Preload and afterload depend on arterial resistance and compliance, dynamics and timing of pulse-wave reflection, venous return, and total blood volume, with the latter being under a very complex regulation involving renal function, salt sensitivity and the many different mechanisms that control fluid and electrolyte balance. It should also be recognized that all these components may have several genetic determinants that are far from being identified and elucidated. These findings, as well as many other points, emphasize the complex interplay between stroke volume and LV mass. In an attempt to define whether stroke volume inheritance might contribute to the genetic heritability of LV mass, de Simone et al. [14] took advantage of the extensive database of the HyperGEN study, by selecting a population of 1792 individuals from 527 families with at least two relatives. According to their analysis presented in the current issue of the Journal, they conclude that ‘most of the heritability of LV mass does not depend directly on variability of volume load’ [14]. The reciprocal influence between LV mass and stroke volume was modestly evident in the African–American subgroup, which accounted for 51% of the entire population, further emphasizing the presence of some degree of ethnic difference in the development and maintenance of the hypertrophic process and/or a condition of high blood pressure values [7,8,15]. Therefore, the observed variability of stroke volume appears to reflect more a physiologic effect of greater LV mass to enhance pump performance than a possible cause contributing to the development of LV hypertrophy. Indeed, this finding is intriguing and emphasizes the complexity of the interaction between hemodynamic load, blood volume regulation, and LV mass. We have to admit that we are still far from fully understanding the basic mechanisms underlying the development of myocardial hypertrophy (i.e. a key mechanism by which the heart is able to adapt its mass and performance to an increased workload). We are only at the beginning of any real integration between the results of basic, clinical and epidemiological studies that will possibly provide some essential clue to help unravel this fascinating and fundamental mechanism of cardiac pathophysiology.