Independent associations between arterial bicarbonate, apnea severity and hypertension in obstructive sleep apnea

Obstructive sleep apnea (OSA) is associated with intermittent oscillations of oxygen and carbon dioxide (CO₂) during the sleeping period. The severity of these changes is determined not only by altered ventilation during the apneic cycle, but also by the extent of tissue oxidative metabolism and tissue deposition of CO₂ in the body [1]. CO₂ production, transport and elimination are influenced by the activity of the enzyme carbonic anhydrase (CA). CA catalyzes the inter-conversion of CO₂ and water into carbonic acid, protons and bicarbonate (StHCO₃ ^-) [2]. Hence, this enzyme plays an important role for the maintenance of blood gas stability in OSA. We have previously demonstrated an association between whole blood CA activity and the severity of OSA [3]. Further we hypothesized that arterial StHCO₃ ^- concentration (a surrogate for CA activity) was elevated in relation to the degree of disordered breathing in OSA patients.

Hypertension development in OSA has been related to multiple mechanisms including increased sympathetic autonomic activity, endothelial dysfunction and modified activity of the renin-angiotensin aldosterone system [4]. Hypoxic and/or hypercapnic chemoreceptor reflex activation and modified baroreflex sensitivity have also been implied in OSA related hypertension [5]. In fact, hypercapnia may be of greater importance than hypoxia in causing sympathetically induced blood pressure elevation and vascular resistance in OSA [6]. In addition, results from in-vitro and in-vivo protocols suggest an association between CA activity and blood pressure controlling mechanisms [7, 8]. Hypertensive OSA patients reduced blood pressure in response to pharmacological inhibition of CA [9] and acetazolamide partially prevented blood pressure elevation in OSA patients moving from low- to high altitude [10]. Whether the surrogate for CA activity, StHCO₃ ^-, is associated with hypertension in OSA patients independent of sleep apnea severity has never been investigated. In the current study, we aimed to address the association between StHCO₃ ^- and OSA activity as well as to examine a possible link between StHCO₃ ^- and hypertension.

In this large cross sectional study of a predominantly male clinical sleep apnea cohort, we established an independent association between wake arterial StHCO₃ ^- concentration and the intensity of sleep apnea. In addition, there was an independent association between StHCO₃ ^- and hypertension as well as daytime office DBP. Our data suggest that mechanisms related to acid-base balance may link to the expression of OSA and its cardiovascular sequels. Given the strong inter-correlation between StHCO₃ ^- and CA activity we speculate that CA activity is involved in blood pressure regulation in OSA patients.

Elevated StHCO₃ ^- concentration has been used as marker for hypercapnia in patients with respiratory disorders such as obesity-hypoventilation syndrome (OHS) and pre-clinical OHS [16, 17]. The association between StHCO₃ ^- and OSA is less well studied. In this study we excluded patients with chronic obstructive pulmonary disease and OHS based on information of a gold- standard evaluation of respiratory function and a blood gas analysis. Our data unequivocally demonstrated a dose dependent association between OSA and daytime arterial StHCO₃ ^- concentration in this group of patients without a chronic respiratory disorder. Although the magnitude of the StHCO₃ ^- elevation across the spectrum of OSA severity may be considered as rather limited, the association was statistically significant and remained after extensive control of important confounders. To our knowledge this is the first study to demonstrate this association in a well characterized clinical OSA cohort. The exact mechanism behind this finding in OSA remains unknown. Severe OSA may lead to mild nocturnal hypercapnia. The long term effect of OSA on PCO₂ (i.e. StHCO3^-) is determined by the net change of CO₂ over each cycle of apnea/hyperventilation and asymmetry in how the rise and fall of CO₂ affects the kidney. It is likely that changes of CA activity can modulate the transition of obstructive apnea/ventilation cycle and influence the increase in StHCO3^- [18‐20]. We therefore propose that transient hypercapnic episodes during sleep in patients with more severe OSA lead to increased renal reabsorption of StHCO₃ ^- and/or that a chronic increase of StHCO₃ ^- production [18] is induced by high or possibly even up-regulated CA activity.

StHCO₃ ^- concentration is known to be influenced by CA enzyme activity. One major function of this enzyme includes the catalysis of the interconversion of bicarbonate and protons into CO₂ and water for subsequent removal of CO₂ via the respiratory apparatus [2]. In OSA, repetitive changes in pCO₂ may induce CA enzyme activity and increase arterial StHCO₃ ^- concentration. Alternatively, anaerobic metabolism and respiratory acidosis following intermittent hypoxia may induce an increased activity of enzymes and transporters involved in cellular pH regulation and erythrocyte acid-base handling [21]. In this manner both hypercapnia and hypoxia may contribute to increased CA activity in patients with OSA. Along these lines it is worth mentioning that CA enzyme inhibition has been shown to reduce StHCO₃ ^- concentration in patients with sleep disordered breathing [9, 22, 23] and that we previously have demonstrated an association between CA activity and the severity of OSA [3].

A particularly interesting finding in the current study was the strong association between StHCO₃ ^- and hypertension status or diastolic blood pressure. It may be argued that this association could be explained by the well-established link between OSA and hypertension [5]. However, our data suggest that StHCO₃ ^- was linked to hypertension independently of the AHI. Only few studies have addressed the possible association between StHCO₃ ^- and hypertension. In a population based study of middle-aged non-obese females, lower plasma StHCO₃ ^- was associated with an elevated incidence of hypertension [24]. A small experimental study of oral sodium bicarbonate induced approximately 5 mmHg reduction of systolic blood pressure [25] whereas other studies did not [26, 27]. However, these studies did not address subjects with the acute blood gas changes that characterize the OSA condition. In fact, our data suggest that the association between hypertension and StHCO3^- is mainly confined to subjects with severe OSA. As previously stated several different mechanisms, including increased renal re-absorption of StHCO₃ ^-, extended CO₂ loading and/or increased CA activity, could all have increased of StHCO₃ ^- in OSA [3, 18, 28]. In fact, a positive association between whole blood CA activity and blood pressure has been reported [3]. In addition, CA inhibition by zonisamide in OSA patients reduced both the AHI and the systolic blood pressure [9]. The CA inhibitor acetazolamide and hydrochlorothiazide induced vasodilation by an activation of calcium activated potassium channels [7, 29] or via a modulation of nitric oxide metabolism activity [30]. It cannot be excluded that the increase of StHCO3^- in our study might have resulted from the effect of hypertension on renal StHCO3^- reabsorption. However, this is less likely the explanation considering that StHCO3^- was elevated only in the severe OSA group with hypertension. We therefore propose that increased CA activity in OSA may provide a novel intermediary mechanism for hypertension development in OSA.

Our study has both strengths and limitations. First, this large predominently male clinical OSA cohort applied a rigorous and unique control of important confounders of StHCO₃ ^- like arterial blood gas samples and pulmonary function tests. Second, blood pressure and hypertension status were carefully assessed during daytime as part of the study protocol. Sleep disordered breathing was assessed with a contemporary polygraphy recording device on two consecutive nights in order to exclude inaccuracy of the AHI value due to a first night effect [31]. Weaknesses include a lack of quantitative data on overnight hypoxic events like oxygen desaturation in the multivariate analyses. However, nocturnal hypoxic exposure was captured as 4% oxygen desaturation events that were used for compution of AHI. Another weakness in this study is the lack of detailed information on the type of antihypertensive medication. It cannot be excluded that prescribed antihypertensive medication, e.g. diuretics such as hydrochlorothiazide, might have influenced the association between StHCO₃ ^- and blood pressure although the influence of thiazides on StHCO₃ ^- is likely to be very limited [32]. Information on CA was not available in this retrospective study. Finally, the cross sectional design of our study does not allow conclusions about the causality of the demonstrated associations.

It is concluded that StHCO₃ ^- concentration was independently associated with AHI, a hypertension diagnosis and office diastolic blood pressure in OSA patients. The potential causal relationship (s) behind these associations remain unclear. Higher StHCO₃ ^- was linked to more intense OSA indicating that high or upregulated CA activity is associated with OSA. In addition, StHCO₃ ^- was associated with hypertension independent of sleep apnea suggesting a novel CA–related mechanism for blood pressure regulation in hypertensive OSA patients.