Determinants of hypertension-related cardiac organ damage: beyond the haemodynamic overload

Editorials, reviews and original papers published in the past few years have repeatedly shown that the renin–angiotensin–aldosterone axis and the sympathetic nervous system mutually interact with each other in both physiological and pathophysiological states. For example, it has been clearly documented that physiological modulation of vasomotor tone, regulation of circulating blood volume and control of blood pressure closely depend on the two above-mentioned systems, as well as on their mutual interactions [1–4]. In addition, the reciprocal reinforcement that the two systems exert on cardiovascular function also has pathophysiological relevance, as documented by the evidence that in a variety of diseases, such as hypertension, congestive heart failure, myocardial infarction, stroke, cirrhosis and renal failure [4], the renin–angiotensin–sympathetic crosstalks exert unfavourable haemodynamic and metabolic effects, which together adversely affect disease progression as well as the patient's prognosis [5–10]. In this issue of the journal, Schlaich et al. [11] address a question that can be regarded as a further step forward from the previously mentioned investigations (i.e. the interactions between the renin–angiotensin and the sympathetic nervous system). This time, the element of novelty is represented by the investigators’ attempt to assess the relevance of the angiotensin–adrenergic interactions in the development and/or progression of the hypertension-related cardiac organ damage. Left ventricular hypertrophy and hypertension Three sound reasons have made left-ventricular hypertrophy (LVH) a topic of primary relevance for current research in hypertension. First, quantification of LV wall thickness and mass by the echocardiographic approach has demonstrated that, in hypertensive patients, this condition is far more common than it was thought when LVH was detected by the electrocardiographic technique [12,13]. Second, observational studies have documented that LVH is an important predictor of cardiovascular morbidity and all cause mortality [14] not only when diagnosed by electrocardiography, but also when detected by echocardiography, with the cardiovascular risk for a hypertensive patient with marked LVH being three- to four-fold greater than that displayed by a patient in whom the blood pressure elevation is not accompanied by cardiac organ damage. Finally, a large body of evidence indicates that antihypertensive drug treatment can reverse LVH, and therefore that this risk factor is potentially reversible [15–17]. Despite years of intensive investigations, many aspects concerning cardiac hypertrophy are far from being completely clarified. For example, this is the case for the pathophysiology of this hypertension-related complication. Although blood pressure overload appears to be a major trigger of LVH, several other non-haemodynamic factors play a pathogenetic role (Fig. 1). Among them, two neurohumoral determinants (e.g. angiotensin II and catecholamines) have been shown to significantly contribute to the development of the cardiac structural alterations that are frequently detected in the clinical course of the hypertensive disease.Fig. 1Sympathetic-angiotensin II contributions to cardiac hypertrophy The evidence that sympathetic influences exert cardiotrophic effects and thus favour the development of hypertensive heart disease is based on animal and human findings [18]. In almost all experimental animal models of cardiac hypertrophy, the increase of left or right ventricular wall thickness is paralleled by an increase in cardiac sympathetic drive [19]. In addition, chronic infusion of norepinephrine in the systemic circulation, even when devoid of any pressor effect, is capable of increasing LV weight, myocyte cross-sectional area and nucleic acid synthesis from the myocardial tissue [20–22]. In man, both microneurographic nerve traffic recording and norepinephrine spillover technique (i.e. the most sensitive methods available so far for quantifying human regional adrenergic drive) have documented a relevant increase in sympathetic activity when hypertension is linked to cardiac hypertrophy [23,24]. Similar striking evidence has been collected for angiotensin II, which has been shown to be involved in the development of cardiomyocyte hypertrophy and cardiac fibrosis and in the modulation of fibroblast growth and collagen synthesis, both in animal models and in humans [4,18]. Despite these premises, the study by Schlaich et al. [11], although finding a positive significant correlation between cardiac norepinephrine spillover and LV mass index, failed to detect a similar relationship for the coronary sinus difference in angiotensin II. In addition, the authors reported the lack of a correlation between coronary angiotensin I or II levels and any index of systemic or regional norepinephrine spillover. Do these results mean that, at variance from the adrenergic nervous system, the renin–angiotensin axis does not participate in the development of cardiac hypertrophy or do they imply that the cross-talk between angiotensin II and the adrenergic system is a meaningless relationship in vivo? Several hypotheses should be advanced when aiming to correctly interpret their study findings and answer the above-mentioned questions. First, it should be emphasized that circulating levels of angiotensin II are mainly dependent on the systemic (rather than local) renin–angiotensin axis, at variance from the sympathetic nervous system whose activation and/or deactivation often has a predominant regional modulation. Second, it is possible that, although only marginally affecting the process of cardiac hypertrophy, the renin–angiotensin system participates to a greater extent than the sympathetic nervous system in the development and progression of myocardial fibrosis, as recent studies indirectly suggest [25,26]. Finally, it should be recognized that the study by Schlaich et al. [11] has an intrinsic limitation, namely the fact that the possible influence of angiotensin II on myocardial structure and sympathetic function appears to be closely dependent on the degree of renin–angiotensin–aldosterone activation. In other words, and as properly emphasized by the authors, the modest activation of the renin–angiotensin system seen in essential hypertension does not make this disease a valuable model for assessing sympathetic–renin interactions. It is possible that different findings might be found for hypertensive heart disease associated with heart failure or obesity, given the marked renin–angiotensin activation characterizing these conditions [27].