4.1 NORMOTENSION, HYPERTENSION AND RESISTANT HYPERTENSION
Systemic arterial hypertension, both in resistant and non-resistant form, is the principal treatable risk factor for CAD and cerebrovascular disease because of structural and functional changes in cerebral hemodynamics [14]. The multifactorial pathophysiology of hypertension involves the alteration of normal sympathovagal balance [15].
The present study showed that the 24-hour time domain HRV parameters that better represent the total sympathovagal balance (SDANN and SDNN) were reduced in hypertensive patients compared to the non-hypertensive group. A reduced HRV is demonstrated to predict the development of hypertension in normotensive individuals [16] and is associated with a non-dipping pattern in hypertensive individuals [17]. Some studies conducted in patients with RH showed a reduction of HRV secondary to sympathetic overactivity and associated with a blunted nocturnal blood pressure fall [18] and left ventricular hypertrophy [19] Some studies have reported altered sympathovagal balance characterized by increased sympathetic [20, 21] as well as reduced parasympathetic tone but most of all included only patients with borderline and mild essential hypertension. A recent study [7],
demonstrated that the impairment of cardiac autonomic control may be associated with the severity of hypertension. In the cited study the authors distinguish the population in severe and moderate hypertensives according to blood pressure measured values and did not consider RH separately from other hypertensive patients. In our opinion, RH represents a subgroup of patients with particular clinical characteristics and peculiar responses to treatment that can be influenced by sympathovagal balance. Moreover, in our work, the BHI was also reduced in hypertensive patients compared to the non-hypertensive group (Table 2). These data, in agreement with other studies [7, 12, 22], could be indicative of an alteration of the sympathovagal balance due to hyperactivation of the sympathetic nervous system (or a reduction in parasympathetic activity) and an alteration of CVR in response to strongly vasoactive stimuli such as hypercapnia in the BHT. These results, in agreement with previous studies, may testify to an important impairment of hypertensives in adapting the cerebral blood flow in response to CO2 increase in blood circulation. The observed deregulation of CVR in hypertension may be due to impairment of the chemoreflex or alteration in neurovascular coupling regulation that guarantees regional adaptation of arterial/arteriolar diameters and molecular cascade in the perivascular space controlled by astrocytes. From this perspective, it is reasonable that the grade of impairment in cerebrovascular adaptation could be poorer in resistant hypertension because of pressure load, and may expose these patients to major cerebrovascular risk.
4.2 RESISTANT HYPERTENSION AND CVR
We also subdivided the hypertensive group according to the severity of CVR dysfunction (BHI < 0.69 and BHI > 0.69) to compare clinical, anamnestic, and ultrasound features between the two subgroups. We found that hypertensive patients with severe CVR dysfunction (BHI < 0.69) had a more frequent anamnestic ischemic heart disease and ultrasound feature of unstable plaques according to Gray-Weale classification, thus suggesting a higher level of cardio and cerebrovascular risk in these patients. No statistical significance has emerged regarding echocardiographic and pharmacological treatment in the comparison between the two subgroups, though antihypertensive medications do not seem to influence CVR in hypertensive patients.
Some studies suggest that in the setting of hypertension structural and functional changes of the arterial wall appear earlier [23] and found an association between arterial stiffness and lower BHI most pronounced in persons with more severe hypertension.
Both hypertension and age determine structural and functional changes in the cerebral arteriolar wall, such as stiffness, arteriolar caliber reduction, and decreased endothelial nitric oxide synthesis. This pathophysiological process brings augmentation in cerebrovascular resistance and alteration of cerebral vasomotor reactivity [24].
Even in RH patients, SDANN and SDNN parameters were reduced if compared to NRH patients (Table 3) as previous studies have already shown a reduction in HRV parameters in this setting [25, 26] but the impact on CVR has not been considered. Our study showed that BHI values presented a reduction in RH patients compared to NRH ones (Table 3). This result appears particularly significant and may suggest that the hyperactivation of the sympathetic nervous system (or reduction in vagal parasympathetic activity), already partly responsible for cerebral vascular remodeling with consequent concentric hypertrophy of the vessels, may play a role in the dysregulation of cerebral hemodynamics. As expected, in the RH group there was an elevated rate of patients taking beta blockers, calcium challenge blockers, alpha-1 antagonists, and diuretics compared to the NRH group (Table 3b). Recent studies demonstrated that antihypertensive monotherapy or combination therapy, especially beta-blockers, can improve HRV measurements and cardiovascular autonomic treatment [27, 28]. Therefore, in our study, the difference in treatment of patients with RH and NRH could not be considered responsible for the reduction in HRV parameters recorded in the RH group compared to NHR. On the contrary, maybe, in a hypothetical comparison between the two hypertensive groups in a washout from therapy, not performed for ethical reasons, the discrepancy in HRV parameters between RH and NRH patients could be more pronounced. Even in a comparison between NRH patients and normotensive individuals we found a major reduction of BHI and time-domain HRV parameters, SDANN and SDNN, in the former group. Furthermore, within the hypertensive population, we compared time-domain HRV parameters in the two subgroups depending on the presence of severe dysregulation of cerebral hemodynamics (BHI < 0.69) to better understand the role of the hyperactivation of the sympathetic nervous system in those hypertensive patients with severe impairment of cerebral vasoreactivity. Patients with severe dysregulation may be more predisposed to cerebrovascular events to use alternative and targeted therapeutic approaches. However, no statistically significant differences emerged for HRV parameters (SDNN, SDANN, PNN50, and RMSSD) between the two subgroups (Table. 4), probably due to the small sample considered. We also investigate the correlation between HRV parameters and clinical characteristics of patients with NRH and patients with RH. In accordance with the literature [29], we found in the former group, an inverse relationship between SDANN and age (Table 6). The explanation of this phenomenon could be in the alteration of sympathovagal balance linked to a reduction in vagal tone and an increase in sympathetic activity associated with aging. Even in the RH subgroup, there was a tendency to reduce SDANN values with increasing age and in the presence of chronic heart failure (Table 7). Although no evidence takes into account the reduction in HRV parameters proportionally to aging in the population of RH, we can reasonably assume that the explanation for this phenomenon lies in a more marked activation of the sympathetic nervous system, or reduction in vagal parasympathetic activity, in patients with RH compared to NRH and it becomes progressively greater with age, due to factors related to aging per se. An English longitudinal cohort study [30] has shown that HRV parameters (in particular SDNN) tend to decrease regardless of the presence of comorbidities or the use of drugs, due to a gradual reduction of parasympathetic modulation on heart rate correlated to an altered release of acetylcholine by cardiac cells in response to external stimuli, to a reduction in the activity of receptors and a reduction in density of “M” receptors with aging [30]. Furthermore, our study showed another interesting correlation between the reduction of SDANN and the presence of atherosclerosis both in the carotid and aortic arch in RH patients (Table. 7). This data offers food for thought on the role of sympathovagal imbalance on the processes of endothelial dysfunction and atherogenesis.