Essential hypertension and left ventricular hypertrophy in cardiovascular disease

`The extensive financial support given to the study of hypertension from the point of view of its mechanisms and management is based on its high incidence (approximately 25% of the population has blood pressure > 140/90 mmHg); the markedly decreased life expectancy, because of severe complications, if it is not treated; and the fact that it is one of the largest healthcare expenditures', opens senior scientist and clinician Dr Genest in his recent review on progress in hypertension research during the last century [1] regarding the social impact of hypertension. One of the first ideas as the review commences on the mechanisms of essential hypertension is that blood pressure may be corrected by a low-sodium diet to levels < 140/90 mmHg in 35 to 50% of patients with essential hypertension, thereby importantly linking sodium (intake and handling) to hypertension. Subsequently, evidence is summarized that integrates (overactivity of) the renin–angiotensin system and its effector molecule angiotensin II with (a lesser suppression of) adrenal secretion of aldosterone and the renal (dys-)regulation of sodium, expressed as the renin–angiotensin– aldosterone–sodium (RAAS) system, and its fundamental involvement in human essential hypertension. The author suggests that it is now more widely accepted that the hypertensive process expresses itself through the common final pathway of the RAAS system, inducing functional changes (increased myogenic tone and contractile responses) in precapillary arterioles leading to increased peripheral resistance and structural arteriolar changes. Accordingly, if we propose overactivity of the RAAS as an important potential determinant for the development of hypertension and associated complications, then identification of individuals prone to RAAS overactivity (by feasible methods such as genotyping) obviously appears to be warranted. This recognition some decades ago initiated the search for human polymorphisms in genes coding for the RAAS that may be associated with overactivity of RAAS components and cardiovascular disorders. Amongst other findings, it was shown that the antiotensin II type 1 (AT1) receptor (A1166C) polymorphism is associated with essential hypertension [2] and increased contractile responses to angiotensin II in human arteries [3,4]. Another example is the angiotensin-converting enzyme (ACE) I/D polymorphism in which the DD-genotype is associated with a higher incidence of left ventricular hypertrophy (LVH) [5], increased plasma ACE-activity and increased tissue conversion of angiotensin I [6]. Nevertheless, transgenic rats that selectively overexpress the human AT1 receptor or ACE do not display phenotypical changes, except in the presence of other factors, in which case enhanced deterioration in cardiovascular function may be observed [7–9]. Such findings suggest that the above RAAS polymorphisms per se may not cause hypertension and associated cardiovascular disorders but may lead to further deterioration in a process that is started by other risk factors. Additionally, these polymorphisms may modify the response to treatment [10,11]. Some of these aspects are covered together in a recent study by van der Kleij et al. [12]. The authors determined blood pressure responses to infused angiotensin I and II in healthy subjects during sodium restriction and liberal sodium intake, as is more or less normal for a Western industrialized society, studied in randomized order. DD-subjects demonstrated an increased response of blood pressure, glomerular filtration rate and aldosterone secretion to infusion of angiotensin I. Because angiotensin II sensitivity was similar in the three genotypes, it appears that the enhanced angiotensin I responses may be the result of increased angiotensin II formation in DD-subjects. Most remarkably, the increased response to angiotensin I in DD-subjects was only demonstrated during liberal sodium intake, and sodium restriction completely abolished the differences between the genotypes, for blood pressure, renal function and as aldosterone, thus suggesting that elevated ACE levels in the DD genotype could have a functional significance under specific conditions (i.e. liberal sodium intake). The same authors in another study showed that, in DD genotype patients with proteinuria, the response to ACE inhibition was significantly more modified by variable sodium intake compared to patients with ID and II genotype [13]. The above findings indicate the importance of sodium per se, but also the use of sodium balances as a therapeutic and experimental study tool. This may be further underlined by the study of Sànchez et al. [14] in this issue of the journal, where they report on their findings in essential hypertensives (HT) and normotensive offspring of hypertensive parents (HTO) compared to normotensive controls (NT) during three different sodium loads. They found that when moving from high to regular and low sodium diets, blood pressure values showed a tendency to decrease, which was only significant in the HT group for systolic blood pressure. Normotensive controls showed a progressive increase in plasma renin activity, apparently related to reduction in sodium intake while, in HT and HTO, plasma renin activity was increased during low sodium only. Serum aldosterone showed a progressive and significant increase only in HT and HTO, while failing to further increase during low sodium intake in NT. Under low sodium-intake, plasma renin activity and serum aldosterone levels were always higher in HT and HTO than in normotensive controls. Furthermore, effective renal plasma flow was reduced in HT and HTO, while glomerular filtration rate was similar in the three groups. These findings clearly reveal the presence of RAAS overactivity in HT and normotensive subjects with a positive family history of hypertension, who are known to have increased risk for developing essential hypertension. What makes the study of Sànchez et al. [14] of particular interest is the fact that they concomitantly studied parameters of the kallikrein–kinin system, an important counterplayer of the RAAS, with which it shares common enzymes such as ACE [15]. They found that total urinary kallikrein and urinary kallikrein activity was lower in HT and HTO compared with NT during the three diet conditions. Their results suggest the presence of a hormonal imbalance in the RAAS and the kallikrein–kinin system, both in essential hypertensives and hypertensive offspring, probably affecting the kidney circulation and sodium homeostasis in these subjects as it was associated with reduced effective renal plasma flow in both populations. However, they showed that a reduced activity of the kallikrein–kinin system predominated over RAAS overactivity in all conditions of sodium balance in HT and HTO individuals. Interestingly, in this context, Slim et al. [16] recently reported the existence of a loss-of-function polymorphism in the human kallikrein gene with reduced urinary kallikrein activity. In addition, a potentially functionally significant polymorphism in the core promotor of the kinin B2 receptor was recently identified, which could represent a susceptibility marker for essential hypertension in African Americans [17]. Such findings remind us that although, on the one hand, interest has focused on the RAAS, leading to the important recognition of RAAS overactivity in hypertension and cardiovascular disease in general and thereby also explaining the seemingly superior effects of ACE inhibitors and AT1 receptor blockers (ARBs) as RAAS inhibitors, on the other hand, RAAS is still but one of the systems involved in cardiovascular homeostasis and RAAS overactivity may express its deleterious effects by insufficient (reactive) counteraction of opposing systems, such as the kallikrein–kalikrein system. Keeping this in mind, it is interesting to consider the findings of the recent Losartan for Intervention for Endpoint Reduction in Hypertenion (LIFE) study, a randomized trial comparing an atenolol-based treatment strategy with a losartan-based therapy in > 9000 hypertensive patients with left ventricular hypertrophy (LVH) over a period of ≥ 4 years [18], as discussed by Messerli and Mehra [19]. The occurrence of LVH in hypertension is a strong and independent marker for cardiovascular morbidity and mortality, and has been demonstrated to be an even more reliable and powerful surrogate end point for cardiovascular fatal and non-fatal events than blood pressure by itself. Losartan-based therapy in LIFE reduced LVH better than atenolol-based antihypertensive therapy for a similar decrease in systolic and diastolic pressure [18]. However, as pointed out by Messerli and Mehra [19], despite the difference in LVH in the two treatments arms, the incidence of fatal and non-fatal myocardial infarction was similar and cardiovascular mortality only non-significantly decreased in the losartan arm, while fatal and non-fatal strokes were significantly reduced by > 20% in the whole study population. They further note that, although LVH has also been identified as a risk factor for cerebrovascular disease, the absence of any cardiovascular benefit in the presence of a well-documented LVH reduction with losartan-based therapy remains baffling and unexplained, indicating the need for LVH as a surrogate end point for hypertension to be revisited. The findings may be in line with experimental evidence that ARBs have specific stroke-protective effects, but appear to question the alleged role of RAAS overactivity only in hypertension and LVH. Is this possibly where RAAS inhibition using ARBs versus ACE inhibitors dissociate and differentiate? Note that by inhibiting ACE, ACE inhibitors simultaneously inhibit the RAAS and increase the activity of the kallikrein–kinin system, and that increased kallikrein activity [20], as well as ACE inhibitor inhibition through bradykinin accumulation and B2 receptor stimulation, has been assigned important beneficial cardiovascular actions [21]. To end this commentary as it started, a further reference to the notions of Dr Genest in his review on the progression of hypertension research seems appropriate. As he concludes his part on the mechanisms of hypertension, it is stated that despite the great advances made in the past 50–60 years, fundamental questions remain. Amongst these are the question of how RAAS exerts its effects on arteriolar levels, and the need to elucidate the fine-tuning of the final sodium excretion in essential hypertension. Importantly, this requires the integration of the key factors involved. This includes the major hormonal factor comprising the interplay of the RAAS system with others such as atrial natriuretic factor, endothelin, nitric oxide, local prostaglandins and kinins, thus requiring studies such as that performed by Sànchez et al. [14] which go beyond RAAS overactivity.