Role of neuroendocrine activation for left ventricular hypertrophy in hypertension

The development of left ventricular hypertrophy (LVH) imparts an adverse prognosis in patients with arterial hypertension [1,2]. A major goal of antihypertensive therapy is, therefore, to achieve reversal of LVH, which has repeatedly been demonstrated to improve prognosis [3–6]. The lowering of blood pressure (BP) is widely viewed as the dominant factor for achieving reduction of an elevated LV mass in hypertension. On the basis of currently available evidence, the European Society of Hypertension Practice Guidelines recommend a target BP value of less than 140/90 mmHg, regardless of whether LVH is present or not [7]. Interestingly, in an open-label randomized study in 1111 hypertensive patients, electrocardiographic evidence of LVH after 2 years was less frequent in patients with tight BP control (<130 mmHg compared with those with usual BP control of less than 140 mmHg systolic) [8]. In accordance, there is recent evidence that targeting such a lower BP value of less than 130/80 mmHg has beneficial effects on diastolic function in patients with arterial hypertension [9]. As diastolic dysfunction is associated with adverse outcomes independently of LVH [10], target BP may need to be revised in the future for hypertensive patients with hypertensive heart disease. In addition to the role of BP, a positive relationship between level of sodium intake and LV mass was demonstrated decades ago [11]. Although only few data are available, there is some evidence from older studies that sodium restriction causes regression of LVH after several weeks of sodium restriction [12]. More recently, sodium restriction has also been shown to reduce ECG criteria of LVH. However, the fact that this appears to occur very rapidly, within 7 days, is puzzling, and may have more to do with alterations in the conduction of electrical signals through the chest wall than with true changes of cardiac structure after such a short period of intervention [13]. Benefits of specific targeting of neuroendocrine pathways are spare in humans [14]. Nevertheless, at least animal studies provide strong evidence that increased levels of angiotensin II (Ang II) and aldosterone, as the primary effector molecules of the renin–angiotensin–aldosterone system (RAAS), as well as activation of the sympathetic nervous system (SNS) [15] can directly cause LVH. In humans, except perhaps for the role of aldosterone in the special case of primary hyperaldosteronism [16], the involvement of these factors in the genesis of LVH in patients with arterial hypertension is more difficult to demonstrate and has relied on cross-sectional data. Using a radioactive tracer spillover- technique, Schlaich et al.[17] have shown that sympathetic activation to the heart is increased in patients with hypertension who have LVH as compared with hypertensives without LVH. Interestingly, using this methodology, local cardiac Ang II levels were not found to correlate with LVH [18]. Only when the activity of the RAAS was related to sodium excretion, an inadequate high concentration of circulating Ang II was related with the degree of LVH in hypertensive patients [19]. The results of individual clinical trials on the effect of specific drugs on the regression of LVH have been very heterogeneous. Our previous meta-analysis of 80 trials suggests that Ang II receptor antagonists, calcium antagonists, and angiotensin-converting enzyme inhibitors are more effective at reducing LV mass than β-blockers [20]. Others, using a similar approach, have recently confirmed the inferiority of β-blockers [21]. However, the use of echocardiography for the assessment of LV structure, with its inherent limitations in accuracy, is a caveat of these studies that needs to be acknowledged. MRI is a far superior method in the detection and quantification of LVH, and therefore considered the new scientific gold standard for this purpose. In routine clinical work, cardiac MRI is more expensive and access more limited compared with widely available echocardiography. So far only few studies on regression of LVH have been performed with MRI [22–27]. In the current issue of the Journal of Hypertension, the study by Burns et al.[28] presents the results of their open-label, randomized clinical trial that examined the hypothesis that a drug combination specifically selected to interfere with neuroendocrine pathways achieves more pronouced regression of LVH than a drug combination without these effects. LV structure was assessed by MRI before and after the treatment period of 6 months with valsartan/moxonidine versus 6 months with bendroflumethiazide/amlodipine. In addition, microneurography was performed to assess the effect of these drug combinations on sympathetic outflow, and aldosterone levels were measured as an effector of the renin–angiotensin–aldosterone system. After 6 months treatment, office BP was lowered to a similar extent with the two combination treatments. Data on 24-h ambulatory BP that represents a better tool to assess the afterload on the LV in hypertensives [29] are unfortunately not provided. LV mass was similar at baseline, but the valsartan/moxonidine combination led to a significantly greater reduction of mass compared with bendroflumethiazide/amlodipine treatment (−25.9 g versus −18.4 g, P < 0.05). Furthermore, the reduction of LV mass was correlated with the reduction of peripheral sympathetic nerve activity, whereas no correlation was seen between changes in mass and changes in aldosterone levels. By using state-of-the-art technology for cardiac assessment, this study therefore adds to the evidence that inhibition of neuroendocrine pathways has beneficial effects on the LV beyond BP lowering. Unfortunately, the use of combination treatment does not permit allocation of the cardiac effects specifically to one neuroendocrine pathway or the other, that is, effects mediated by inhibition of the SNS versus effects mediated by inhibition of the RAAS. More treatment groups, requiring much higher overall sample size, were certainly prohibitive of such an approach. The fact that reduction in peripheral nerve firing, but not changes in aldosterone level, was related with the cardiac effects is also noteworthy and would be in line with the aforementioned studies using the cardiac spillover technique, which demonstrated a relationship between LVH and local SNS activations but not Ang II levels. An assessment of Ang II and aldosterone concentration related to the 24-h urine sodium excretion was not possible and an analysis of the relation of ‘inadequate’ suppression of RAAS under high salt condition (i.e. under exposure to our current western diet) could not be performed due to the lack of such measurements. The study by Burns et al.[28] should also encourage conduction of more interventional clinical trials into the role of neuroendocrine pathways for LVH in conditions that are commonly associated with arterial hypertension. As an example, elevated circulating levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23) were found to mediate LVH in animal models of chronic kidney disease (CKD) [30]. Cross-sectional studies suggest that FGF23 may indeed contribute to LVH in human patients with CKD [30]. Another example is patients with insulin resistance/diabetes mellitus. Various factors, including increased glucose and insulin levels and reduced adiponectin levels have been associated with LVH in these conditions [31]. These data strongly suggest that the pathogenesis of LVH in patients is not entirely understood and the nonhemodynamic factors underestimated. In that light, the current study by Burns et al. deserves our special interest [28]. We call, therefore, for conclusive clinical trials targeting the various nonhemodynamic factors that ultimately will allow us to achieve the best possible reversal of LVH in our hypertensive patients. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.