Nondipping status and impaired nitroglycerin-mediated vasodilation in resistant hypertension

The clinical significance of resistant hypertension as an epidemiologic phenomenon has grown in recent years due to better understanding of its pathophysiologic background and new possible treatment options. Several pathways have been implicated for the development of resistant hypertension, including sympathetic overactivity, altered sodium handling, activation of the renin–angiotensin–aldosterone system, obesity, obstructive sleep apnea, endothelial dysfunction, and arterial stiffness [1–3]. An important consequence of this condition is a selective increase in nocturnal blood pressure, with a reduced blood pressure fall from day to night. This nondipping pattern has been found to be associated with an increased rate of cardiovascular events [4,5]. The study by Fontes-Guerra et al.[6], published in this issue of the Journal, confirms the association of resistant hypertension with a blunted blood pressure fall at night. In a cross-sectional study of 280 resistant hypertensive patients who performed 24-h ambulatory blood pressure monitoring, polysomnography, and brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) by high-resolution ultrasonography, the authors found that a nondipping pattern was present in approximately 50% of the individuals in the various subgroups. The pathogenetic mechanisms of the nondipping condition are still poorly understood, and it is not known how much the overall variance in the sleep–wake blood pressure difference can be accounted for simply by changes in physical activity or by other confounders [7]. Sleep disturbances that might lead to arousals have been suggested as a possible causative mechanism for the higher levels of nocturnal blood pressure in nondippers [8]. Several studies have shown that patients with frequent episodes of sleep apnea are more likely to have a nondipping blood pressure profile than patients with a normal sleep pattern [9,10]. The nocturnal increase in blood pressure in these patients has been attributed to a heightened sympathetic activity during sleep – a condition which often accompanies sleep-disordered breathing syndromes. It should be underlined, however, that the adrenergic overdrive does not seem to be confined to the night-time sleeping hours only. Indeed, in a study carried out some years ago by the Milan/Monza group, it was found that even in the daytime hours, nondipper as well as reverse dipper hypertensive patients display a sympathetic activation much greater in magnitude than that detectable in the age-matched dipper hypertensive patients [11]. An intriguing new finding of the study by Fontes-Guerra et al.[6] was that the nondipping profile in resistant hypertension was more common in patients with impaired endothelial/vascular function, nondippers being 61.2 and 64.3% in people with low FMD and low NMD, respectively. In a multiple regression analysis, only NMD remained independently associated with the nocturnal blood pressure decline. This relationship remained significant also after adjustment for sleep apnea, suggesting that mechanisms other than those related to sleep disturbances are operative in patients with resistant hypertension. There is general agreement that the nocturnal fall in blood pressure is mostly due to a decline in cardiac output, mainly driven by the well known decrease in heart rate that occurs during sleep [6]. Whether a variation of total peripheral resistance contributes to the diurnal rhythm of blood pressure is more controversial as peripheral resistance has been found to be lower during sleep in some studies [12], but not all [13]. The study by Fontes-Guerra et al. suggests that impaired modulation of peripheral resistance is an important mechanism of nondipping in resistant hypertension [6]. Inclusion of aortic stiffness or plasma aldosterone concentration into the models did not attenuate the association of NMD with the nocturnal blood pressure fall. In addition, this relationship was not affected by exclusion of patients with diabetes. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis – a process that, in the long run, may lead to cardiovascular complications [14]. In the present study, Fontes-Guerra et al.[6] used two different markers of vascular dysfunction – FMD and NMD. FMD is an index of endothelium-dependent vasodilation and has been widely used as a method for assessing endothelial function in humans [15,16]. Nitric oxide – the main mediator of FMD [17] – leads to relaxation of smooth muscle cells and subsequent vasodilation. Thus, assessment of endothelial function by FMD implies a normal structural vascular condition. At variance, NMD is an index of endothelium-independent vasodilation [18], and is currently used to differentiate endothelium-dependent from endothelium-independent effects on vascular smooth muscle cells. Although both FMD and NMD are impaired in patients with cardiovascular risk factors and coronary heart disease, impaired NMD is thought to be associated with structural vascular alterations involving the smooth muscle cells as a result of atherosclerotic lesions and thus be the expression of more advanced disease [19,20]. However, differences between FMD and NMD in association with severity of atherosclerosis remain unclear, especially in patients with hypertension. The data from Fontes-Guerra et al.'s study shed new light on this controversial issue. Only NMD remained independently associated with night-time blood pressure and the nondipping pattern, and thus seemed a better marker of risk in resistant hypertension than the widely used FMD [6]. However, it should be noted that in Fontes-Guerra et al.'s study, FMD, but not NMD, was associated with the presence of clinical cardiovascular diseases. According to a recent Japanese study in a general population, NMD should be considered as a marker of the grade of atherosclerosis, whereas FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in patients with impaired NMD [20]. It is possible that the association of FMD and NMD with established cardiovascular diseases may vary in different clinical settings. To clarify this controversial issue, future prospective studies in different settings are needed. A limitation of the study by Fontes-Guerra et al. is that FMD and NMD were evaluated only during a morning session, and this may not capture diurnal changes in endothelial/vascular function. Several authors who measured brachial artery FMD on two or more different occasions during the day reported a decrease in early morning endothelial function [21,22]. Controversial results were reported for NMD, because some authors [22,23] did not find any diurnal change in NMD in healthy individuals, whereas others [24] reported that NMD was significantly higher in early morning compared with late evening hours. It has been reported that intrinsic differences in the endothelial nitric oxide vasodilator system contribute to the diurnal variation in FMD [21,22]. These intrinsic differences could be explained by cyclical changes in nitric oxide bioavailability or nitric oxide synthase phosphorylation, which are thought to influence endothelial function [25,26]. Alternatively, cyclical variation in components opposing vasodilation, such as endothelin-1 or sympathetic nerve activity, which were not measured in the present study, could contribute to diurnal variation in endothelial/vascular function [27,28]. In a study by Cavelaars et al.[7], systemic vascular resistance calculated from the intra-arterial blood pressure waveforms showed a different diurnal variation in dippers and nondippers. In dippers, peripheral resistance did not change significantly from day to night, whereas it significantly increased in nondippers. In a study by Narkiewicz et al.[29], patients with higher daytime resting measurements of sympathetic traffic had a greater day–night blood pressure difference than patients with lower sympathetic activity. The smaller difference between daytime and night-time blood pressure in nondippers may also be due to a blunted cardiovascular response to daily activities, as shown by Raikkonen et al.[30]. The above data point to a role of higher sympathetic tone or higher reactivity during wakefulness in dippers rather than to a reduced night-time vasodilatory activity in nondippers. Thus, the impaired night-to-day modulation of peripheral resistance can be attributed both to an abnormal diurnal variation in autonomic nervous system activity and to a compromised endothelial/vascular function. Clearly, the cross-sectional nature of Fuentes-Guerra et al.'s study [6] makes it more difficult to provide a correct interpretation of the results. It is possible that the endothelial/vascular dysfunction is the causative factor that affects the circadian blood pressure variability pattern. On the contrary, a high nocturnal blood pressure (and the consequent reduction in the day–night blood pressure difference) may be the cause of the impaired vascular function. A better understanding of the mechanisms underlying the altered diurnal blood pressure rhythm in nondipper patients with resistant hypertension would help to establish whether and how a nondipping pattern should be treated with appropriate modulation of antihypertensive therapy with the purpose of restoring a normal rhythm. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.