Ioana Madalina Zota1,2, Radu Sascau1,2, Cristian Statescu1,2 *, Mihai Roca1,3, Daniela Boisteanu1,4, Maria Magdalena Leon Constantin1,3, Alexandra Mastaleru1,3, Teodor Vasilcu1,2, Radu Gavril1,3, Florin Mitu1,3
1 „Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
2 „George I.M. Georgescu” Institute of Cardiovascular Disease, Iasi, Romania
3 Clinic of Cardiovascular Rehabilitation, Iasi, Romania
4 IIIrd Clinic of Pneumology, Iasi, Romania
Abstract: Objectives – Obstructive sleep apnea (OSA) has been linked to arterial stiffness and increased cardiovascular risk. The aim of this study was to analyse the relationship between OSA severity, arterial stiffness and clinico-biological pa-rameters in moderate-severe OSA subjects. Methods – We assessed arterial stiffness using the Arteriograph (Tensiomed, Hungary) in 41 patients with newly diagnosed moderate-severe OSA prior to the initiation of positive pressure therapy. Results – Our study included 18 and 23 patients with moderate and severe OSA, respectively. Mean apnea hypopnea index (AHI) 40.69 events/h. Desaturation index, minimum nocturnal O2 saturation, erythrocyte sedimentation rate (ESR), ejection duration and return time were significantly different between the two subgroups. AHI was correlated with the other OSA severity parameters but also with pulse wave velocity (PWV), C reactive protein and ESR. PWV was negatively correlated with magnesium. Mean nocturnal oxygen saturation, age, body mass index and abdominal circumference did not signifi cantly differ between the moderate and severe OSA subgroups. Conclusions – PWV and inflammation markers are correlated with OSA severity. We also found a negative correlation between serum magnesium and PWV in moderate-severe OSA patients.
Keywords: arterial stiffness, obstructive sleep apnea, subclinical inflammation.
INTRODUCTION
Intermittent upper airway collapse leads to obstruc-tive sleep apnea (OSA) and thus to recurrent oxygen desaturations, micro awakenings, oxidative stress and overactivation of the RAAS (renin angiotensin aldoste-rone) and sympathetic systems1,2. Through its frequent association with hypertension and obesity, vascular remodelling (endothelial dysfunction, increased arte-rial stiffness with elevated aortic pulse wave velocity and augmentation index) is common among OSA pa-tients2. The pulse wave is formed by the summation of both the forward traveling and the reflected waves. While the forward pulse wave is produced by the left ventricular systole, the returning wave is its reflection
by the aortic bifurcation and the peripheral arteries3. Aging promotes the replacement of the elastin fibres from the medial layer of arteries with fibrous tissue, leading to arterial stiffness. This leads to the prema-ture fusion of the two pulse waves, and thus to an increased amplitude of the systolic pulse wave, in the detriment of the diastolic wave amplitude4. The modi-fied pulse wave pattern is thus associated with isolated systolic hypertension (HBP) (the most common form of HBP among the elderly) and a reduced BP value during diastole. Reduced diastolic perfusion of the co-ronary arteries along with the growing oxygen neces-sities of the hypertrophied heart muscle favours myo-cardial ischemia4. Diabetes, obesity, smoking, hyper-tension, infl ammation (high C reactive protein levels), moderate chronic kidney disease, menopausal status and a sedentary lifestyle are also associated with in-creased arterial stiffness5, which is also associated with a higher stroke risk, due to elevated central PP (pulse pressure) and subsequent arterial remodelling4,5.
Pulse wave velocity (PWV) reflects the speed at which the pressure waves travel along the arteries, re-flecting their elasticity, distensibility and compliance6. Carotid-femoral PWV is considered the gold stan-dard method for non-invasive arterial stiffness assess-ment3,5. The Arteriograph (Tensiomed, Budapest, Hungary) is an oscillometric method which records the early and the late systolic peaks (the wave reflec-ted from the aortic bifurcation) using a blood pressure cuff placed in the upper arm region. The algorithm has been validated for the assessment of AoPWV (aor-tic pulse wave velocity), aortic and brachial Aix (aug-mentation indexes), return time (RT) and central SBP (which correlates well with the central SBP measured through invasive methods)3,7.
Ao PWV is correlated with serum cholesterol and with mean carotid IMT (intima-media thickness) (p<0.001). PWV is a marker of arterial rigidity in the analysed segment, while Aix is a composite vascular function parameter, providing information regarding the wave refl ection site and velocity, endothelial func-tion but also a measure of the peripheral resistance against which the heart has to pump. Early atheroscle-rosis can be recognized by Aix values greater than 33%. PWV becomes elevated in more advanced sta-ges of atherosclerosis, after the vessels have become narrower and thus stiffer3. Although the previous cut-off point for arterial stiffness was set to 12 ms-1, cur-rent guidelines consider a threshold of 10 ms-1 in the risk stratification of hypertensive patients, stating that aortic stiffness is independent risk factor for cardio-vascular events in these patients8,9. RT measures the period of time in which the pulse wave travels from the aortic root to the aortic bifurcation and then re-turns to the initial emergence point. Smaller RT values (<124ms) are associated with aortic stiffness5,10.
The Arteriograph report includes a series of other parameters, such as mean arterial pressure (MAP), pulse pressure (PP), ejection duration (ED), diastolic refl ection area (DRA), systolic and diastolic area in-dex (SAI and DAI). A PP value greater than 60 mmHg (representing the difference between the systolic and diastolic BP values) is associated with increased cardi-ovascular risk. SAI and DAI represent the areas from beneath the pulse wave curve that correspond to the systole and diastole, respectively. Thus, higher DRA (>40) and DAI (>50%) values are associated with su-perior coronary perfusion. SAI should not exceed 50% in healthy individuals10. Heart failure is associated with a reduced ejection duration (ED), measuring the time between the opening of closure of the aortic sigmo-id valves5,10. While aortic PWV reflects only arterial stiffness, the other 3 markers are influenced by the refl ectance point, the amplitude of the reflected pulse wave, ventricular systolic function and heart rate. It seems that aging has a greater infl uence on Aix in sub-jects younger than 50, and a more important impact on aortic PWV in patients older than 50 years old5.
Several drugs (beta-blockers, renin-angiotensin-al-dosterone system inhibitors, aldosterone antagonists), as well as non-pharmacological measures (exercise training, weight loss, moderate alcohol consumption) are able to reduce arterial stiffness5. Renin-angioten-sin-aldosterone system (RAAS) inhibitors have proven effective in reducing PWV, independent from their BP reduction effect. However, further studies are requi-red in order to assess their superiority in reducing arterial stiffness, compared to other antihypertensive agents8.
METHODS
Our research included 41 patients with newly diagno-sed moderate-severe OSA, referred to our Cardio-vascular Rehabilitation Clinic prior to the initiation of CPAP (continuous positive airway pressure) therapy. The obstructive sleep apnea syndrome diagnosis was made by ambulatory or in-hospital six-channel cardio-respiratory polygraphy, using either a Porti 7 device (from DeVilbiss) or an Alice Night One (from Phi-lips Respironics). The cardiorespiratory polygraphy was manually scored by a trained doctor, according to the American Academy of Sleep Medicine (AASM) standards. The CPAP effective pressure was autotitra-ted in the sleep lab using either a DreamStation Auto CPAP (from Philips Respironics) or an Airsense 10 Autoset (from Resmed).
We performed clinical examination – resting heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), along with anthropometric evaluation – weight, height, body mass index (BMI) and abdominal circumference (AC). Our subjects under-went arterial stiffness examination using the Tensio-med Arteriograph (Tensiomed, Budapest, Hungary)3. Statistical analysis was performed in Microsoft Excel and Statistical Package for the Social Sciences (SPSS) 20.0. Chi square and student’s t test were used for comparisons between groups. A potential relationship between variables was evaluated using Pearson cor-relation coefficient. A p value <0.05 was considered statistically signifi cant.
RESULTS
Our study group included 18 and 23 patients with mo-derate and severe OSA, respectively (Table 1). The only significant differences between the moderate and severe OSA groups were regarding desaturation index, minimum nocturnal O2 saturation, CPAP pressu-re requirements, ejection duration and erythrocyte sedimentation rate (ESR) (Tables 1-3).
Both ED and RT were significantly lower in the se-vere OSA group, with an average value for RT below the known 124ms cut-off point for arterial stiffness (Table 2). Although PWV, Aortic SBP and PP were higher in the severe OSA group, the differences did not reach statistical significance.
AHI was significantly correlated with other OSA severity parameters, including CPAP pressure requi-rements (Table 4). AHI was positively correlated with aortic PWV and infl ammation markers (ESR, CRP) but negatively correlated with ED and RT (the latter with borderline statistical significance p=0.05) (Table 4). We found a negative correlation between apnea severity and Aortic Aix (r=-0.31, p=0.04). PWV was significantly correlated with both AHI and desaturati-on index, but not with average or minimum nocturnal O2 saturation. No significant correlation was found between BMI, age, ESR, CRP, lipid profi le, renal func-tion, glycemic control and PWV. PWV was negatively correlated with serum magnesium in moderate-seve-re OSA patients (Table 4). Aortic Aix was correlated with resting HR, BP values but also with uric acid, CRP and age.
DISCUSSION
RT was significantly lower in the severe OSA group, reaching an average value below the 124ms cut-off point for arterial stiffness (Table 2). We also found a significant difference regarding ED between the mode-rate and severe OSA groups, but not regarding PWV, Aortic SBP and PP (although average PWV was higher in the severe OSA group). A recent report did not find a correlation between PWV and OSA severity pa-rameters (AHI, desaturation index, minimal nocturnal O2 saturation) in 101 elderly patients with OSA and a mean age of 75.3 years11. However, we should note that the subjects presented a milder form of OSA (mean AHI 17.8 events/h) and that obesity was less prevalent among the study group (mean BMI 25.7 kg/ m2). The authors did report that patients with AHI greater than 30 (severe OSA) presented higher PWV despite having a similar BMI11. Although we did not find a statistically significant correlation between average or minimum nocturnal O2 saturation and AHI, previous reports showed that intermittent noctur-nal desaturations induce sympathetic nervous system hyperactivation, promote infl ammation and endotheli-al dysfunction, thus playing a pivotal role in OSA-rela-ted cardiovascular consequences12. The magnitude of nocturnal hypoxemia in Sforza’s study was low, thus explaining the lack of association between PWV and OSA severity11.
Another study found a mild but statistically signi-ficant correlation between AHI and PWV (r=0.350, p=0.000) in OSA patients who developed an ische-mic stroke13. A stronger correlation between the 2 parameters was reported by Cortuk et al (r=0.521, p<0.001) in 90 patients with OSA14. We also found a mild but statistically significant correlation between PWV and AHI (r=0.315, p=0.004) and a similar corre-lation between PWV and desaturation index (r=0.351 and p=0.047). A recently published meta-analysis
found that PWV in OSA patients is not significantly correlated with OSA severity parameters and is in-stead influenced by age, BMI and SBP15. However, our results show quite the opposite – we found that PWV is significantly correlated with both AHI and desatura-tion index, but not with age, BMI or BP values.
Although other authors have cited a correlation between hypomagnesemia and arterial stiffness16,17, to our knowledge, this is the fi rst study to report a nega-tive correlation between PWV and serum magnesium in moderate-severe OSA patients. Further studies are required in order to assess a potential influence of magnesium supplementation on overall cardiovascular risk in OSA.
We found that aortic Aix is significantly correlated with SBP, DBP and age (r=0.324, p=0.039; r=0.359, p=0.021 and r=0.385, p=0.013, respectively). A pre-vious report showed that augmentation index is sig-nifi cantly higher in morbidly obese OSA patients than in controls with similar BMI (24.5% versus 10.5%, p<0.001)2. Although we obtained a similar aortic Aix value (24.41%), we found a paradoxical negative asso-ciation between AHI and aortic Aix (r=-0.31, p=0.04) and between Aortic Aix and resting HR (r=-0.426, p=0.006). Given fact that AHI was positively corre-lated with PWV could suggest that PWV is a more reliable arterial stiffness parameter in moderate-seve-re OSA patients, that probably have a more advanced stage of subclinical atherosclerosis. This paradoxical association could also be explained by a more impor-tant infl uence of the applied treatment regimen appli-ed to those with more severe OSA, due to associated comorbidities. The fact that CPAP therapy seems to improve aortic stiffness parameters in OSA patients is an indirect argument that sleep apnea induces arterial stiffness1,2.
ESR was significantly higher in the severe OSA group and we found a positive correlation between OSA severity and ESR, CRP (r=0.371, p=0.0017 and r=0.353 p=0.02, respectively). This is in line with cur-rent evidence that supports an association between OSA and subclinical infl ammation18. However, our analysed inflammation markers were not signifi cantly correlated with PWV, although current literature re-ports have linked subclinical inflammation with both OSA and arterial stiffness18. Our study’s limitations include the small number of patients but also the use of brachial artery stiffness parameters, known to be inferior to carotid-femoral PWV according to the Framingham study9. Our re-sults are also infl uenced by the fact that although all patients were under antihypertensive drugs, not all of them were using RAAS blockers, which could be the most effective agent in reducing arterial stiffness and PWV8. Further studies on CPAP naïve OSA patients who do not follow any therapeutic regimen should be performed in order to accurately assess the impact on arterial stiffness of OSA alone.
CONCLUSIONS
Mean nocturnal O2 saturation, age, BMI and AC did not significantly differ between the moderate and severe OSA subgroups. Multiple arterial stiffness parameters (PWV, ED, RT), but also inflammation markers (ESR and CRP) are correlated with OSA severity. PWV co-uld be a more appropriate arterial stiffness evaluation parameter in OSA patients. Further studies are requi-red in order to determine whether arterial stiffness is correlated with a poorer prognosis in OSA patients and the role of pharmacological and non-pharmacolo-gical interventions in reducing arterial stiffness in OSA. We found a negative correlation between serum mag-nesium and PWV in moderate-severe OSA patients which should be confirmed by larger studies.
Conflict of interest: none declared.
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