2 [11–13]. Increased free leptin is at least partly associated with increased central and peripheral sympathetic ﬁring in experimental animal models [14, 15], while nonapneic and nonobese subjects with out-of-oﬃce hypertension are characterized by hyperleptinemia with respect to their normotensive counterparts [16]. Therefore, it is plausible that leptin could represent an accelerator of sympathetic activation in both obesity and hypertension alone. Obesity itself is frequently observed in OSA patients in whom sympa- thetic activation is further augmented by episodic nocturnal hypoxia and hypercapnia due to the repetitive collapse of the upper vulnerable airway, yet whether leptin levels are raised in normotensive nonobese patients with OSA is still debated [17]. Additionally, sympathetic overactivity per se is accompanied by BP and heart rate increases, as well as by enhanced sodium retention. The above operating mechanisms in obese hypertensive patients with OSA are at least partly responsible for the increased hemodynamic load, and frequently three or more drugs in the maximum tolerated doses are insuﬃcient to eﬀectively reduce BP levels. 2.2. Kidney Function. Focusing on the kidney in obese sub- jects, “pressure natriuresis” is impaired, and higher BP levels are required to achieve sodium balance [18]. Additionally, urinary albumin excretion is increased in obese OSA patients with hypertension compared to hypertensive nonOSA con- trols [19]. A further hypothetical mechanism by which OSA aﬀects renal hemodynamics is that the continuous nocturnal intrathoracic pressure swings are accompanied by changes in systemic and renal venous pressure, as it has been shown that renal venous congestion is accompanied by a decline in kidney function in patients with both preserved and impaired cardiac function undergoing right heart catheter- ization [20]. Considering the above, kidney impairment in OSA subjects may contribute to the development of drug- resistant hypertension, and diuretics implementation may be accompanied by better antihypertensive results by promoting both sodium excretion and venous decongestion. 2.3. Aldosterone. Plasma aldosterone levels are increased in both obese hypertensive patients and those with OSA [6]. Renin-angiotensin-aldosterone axis activation is implicated in most hypertensive states, and apart from sympathetic overdrive, visceral adiposity could also participate in that phenomenon by mechanisms that have not yet been fully elucidated [21]. In patients with resistant hypertension who were referred to an outpatient hypertensive unit, those with a high clinical suspicion for OSA exhibited increased plasma aldosterone levels with respect to those with no symptoms of OSA. In those with a ﬁnal positive diagnosis of OSA as well as in obese hypertensive subjects, renin activity was suppressed, a ﬁnding that suggests that aldosterone secretion is at least partly plasma renin independent; thus, in resistant hypertensive patients with OSA targeting of renin inhibition seems pathophysiologically a less justiﬁed therapeutic strat- egy compared to blockers of subsequent steps of the renin- angiotensin-aldosterone cascade. Such a concept is further supported by the ﬁnding that hyperaldosteronism prevalence in resistant hypertension is as high as 20%, with obesity and International Journal of Hypertension suspected OSA being the two extremely common clinical features in this setting [21, 22]. 2.4. Arterial Stiﬀening. Arterial stiﬀening constitutes a pathophysiological substrate that promotes acceleration of vascular aging observed in both hypertension and OSA [23]. Increased levels of circulating vasoconstrictors [24], enhanced subclinical inﬂammation [25], endothelial dys- function [25], and repetitive increases of left ventricle afterload may separately or in combination contribute to the increasing magnitude of arterial stiﬀening. Even though it is known that resistant hypertension is more prevalent in the elderly, increased arterial stiﬀness observed in OSA may also precipitate the development of the drug-resistance phenomenon in younger ages. 3. Epidemiological Issues 3.1. Noninterventional Studies. In the beginning of the present millennium Logan et al. [26] demonstrated for the ﬁrst time in the literature the striking prevalence (82.9%) of OSA in 41 middle-aged obese patients with “true drug- resistant hypertension” recruited from a hospital university hypertension clinic. Although most men with resistant hypertension suﬀered from OSA (95.8%), among women those not aﬀected by the syndrome (35.3%) were younger, received less drugs, presented with a longer sleep time by 30% and less arousal movements per hour of sleep by 80%, and ﬁnally demonstrated a higher 24-hour pulse pressure, compared to those not aﬀected by OSA. Another surprising ﬁnding in the same study was that almost one third of OSA patients with resistant hypertension had a normal dipping proﬁle, suggesting that the nondipping phenomenon in resistant hypertension may be driven by OSA-independent pathophysiological mechanisms. In another cross-sectional case-control study from the same investigational group [27], patients with drug-resistant hypertension were compared with a group of patients with controlled hypertension matched for age, sex, and body mass index. Accordingly, Ruttanaumpawan et al. [27] reported that those with controlled hypertension—as expected— received fewer antihypertensive medications and the use of diuretics was 60% less frequent with respect to those with resistant hypertension. Moreover, the prevalence of OSA was almost 50% more frequent in those with resistant hypertension. Total time asleep, sleep eﬃciency, and time of rapid-eye movement sleep were signiﬁcantly higher in those with controlled hypertension compared to their resistant hypertension counterparts; interestingly, only the two latter parameters in tandem with the presence of OSA were unadjusted determinants of resistant hypertension in the total study population. After adjusting for confounders, OSA and reduced time of rapid-eye movement sleep qualiﬁed as independent signiﬁcant determinants of resistant hyperten- sion. Among antihypertensive medications, calcium blockers implementation was associated with a lower amount of rapid-eye movement sleep, suggesting that disruption of sleep architecture might be associated in some degree with the selection of antihypertensive drugs.