Patients with obstructive sleep apnea (OSA) are susceptible to developing atherosclerosis. Consequently, such patients are at a high risk of developing cardiovascular diseases, leading to poor prognosis. Many physiological parameters have been previously used to predict the development of atherosclerosis. One such parameter, the cardio-ankle vascular index (CAVI), a measure of arterial stiffness, has garnered much attention as it can also predict the degree of atherosclerosis. The CAVI can be calculated based on noninvasive measurements, and is less susceptible to blood pressure variations at the time of measurement. Therefore, the CAVI can assess changes in arterial stiffness and the risk of developing atherosclerosis independent of blood pressure changes. Continuous positive airway pressure (CPAP) is a standard therapy for OSA and can suppress the issue significantly. Several studies have shown that CPAP treatment for OSA could also reduce the CAVI. In this review, we discuss the relationship between OSA and arterial stiffness, primarily focusing on the CAVI. Furthermore, we propose future perspectives for the CAVI and OSA.
Globally, obstructive sleep apnea (OSA) is a common disease. It is caused by
repetitive obstruction of the upper airway while sleeping. Moreover, during sleep
onset, there is a reduction in the upper airway dilator muscle tone, resulting in
an anatomically narrow upper airway. Physiological release of upper airway
obstruction is usually accompanied by arousal and snoring that facilitate the
resumption of breathing. These repetitive respiratory events lead to frequent
episodes of intermittent hypoxia and fragmented sleep. The frequency of such
repetitive respiratory events, including partial and complete collapse of the
upper airway (i.e., hypopneas and apneas, respectively), generally determines the
severity of OSA, which is quantified by the apnea-hypopnea index (AHI). OSA with
an AHI
Cross-sectional studies have suggested a relationship between the presence of OSA and cardiovascular diseases. Moreover, a direct association between the AHI and cardiovascular diseases was shown, even after adjusting for potential confounding factors. Although the latter implies a causal link between OSA and cardiovascular diseases, evidenced by numerous mechanistic studies, it is still unclear whether OSA really causes cardiovascular diseases. Recently, several longitudinal studies have shown that the presence of OSA, particularly in its severe baseline form, is associated with an increased risk of cardiovascular diseases. It can be argued that the increased risk of cardiovascular diseases in OSA patients is due to coexisting obesity, metabolic syndrome, hypertension, or diabetes mellitus. In some longitudinal studies, adjustments for such confounders resulted in the relationship between OSA and cardiovascular diseases to be no longer significant (Gami et al., 2007; Gottlieb et al., 2010; O’Connor et al., 2009). Still, numerous studies have demonstrated the association between OSA and early signs of arteriosclerosis and/or atherosclerosis as a surrogate of cardiovascular diseases. In addition, results from randomized controlled trials suggest that the elimination of OSA by CPAP also eliminates or ameliorates arteriosclerosis/atherosclerosis (Drager et al., 2007).
In this article, we first review and summarize recently developed noninvasive technologies to detect arteriosclerosis/atherosclerosis, primarily focusing on arterial stiffness parameters. These might indicate systemic atherosclerosis and could, consequently, act as a comprehensive indicator of cardiovascular disease risk. We continue with a specific discussion on the cardio-ankle vascular index (CAVI). This index is a measure of arterial stiffness, generated through noninvasive measurements by simple procedures. We then summarize the relationship between OSA and arteriosclerosis/atherosclerosis while focusing on CAVI data from patients with OSA.
Endothelial dysfunction is one of the first symptoms of atherosclerosis. Noninvasive techniques to detect endothelial dysfunction include measurement of flow-mediated vasodilation (FMD) by ultrasonography and evaluation of forearm blood flow changes during reactive hyperemia using plethysmography. The latter technique is more practical and easier to perform, but is not fully validated (Higashi and Yoshizumi, 2003). In contrast, it is difficult to measure the diameter of vessels using the former technique. Nevertheless, a recent meta-analysis on the use of FMD to assess endothelial function found endothelial dysfunction to be a significant predictor of future cardiovascular events (Matsuzawa et al., 2015).
Arteries stiffen as atherosclerosis develops. However, the association between endothelial dysfunction and arterial stiffness is controversial and mild at best. Arterial stiffness is dictated by the structural (e.g., elastin/collagen) and functional (e.g., endothelial function or vascular smooth muscle tone, which can be modulated by the autonomic nervous system) components of the arterial wall. Since arterial stiffness affects blood pressure, blood flow, and the arterial diameter, it may not be the simplest indicator of structural and functional changes in the artery, but it can act as a comprehensive marker for developing arteriosclerosis or cardiovascular diseases (Mattace-Raso et al., 2006; Oliver and Webb, 2003). Indeed, increased arterial stiffness was observed in patients with several conditions known to have a pathophysiological link to cardiovascular diseases.
The most common and well-validated technique to assess arterial stiffness is pulse wave velocity (PWV). PWV is based on the concept that the pressure wave propagates faster in a stiffer artery than a softer artery. Increased stiffness results in an earlier reflection of the wave, and a shorter interval between consecutive pressure increases (Fig. 1). These lead to increased augmenting pressure (AP), which can also be a measure of stiffness. AP is often expressed as a ratio with pulse pressure (PP), a ratio termed the augmentation index (AIx). Although at least one meta-analysis suggested that AIx might be an independent predictor of cardiovascular diseases (Vlachopoulos et al., 2010b), the significance of AP and AIx as predictors for cardiovascular events remains controversial.
Arterial pressure waveforms at each point are shown on the same
timeline. Aortic pressure starts rising at the time of the first heart sound and
has two peaks. The first peak is called augmenting pressure (AP), and the second
peak is called pulse pressure (PP). The augmentation index (AIx) is calculated as
AP divided by PP. Since the dicrotic notch in the aorta coincides with the second
heart sound, the time between the dicrotic notch at the brachial artery and the
second heart sound indicates the propagation time from the heart to the brachial
artery. Pulse wave velocity (PWV) can be calculated using the propagation time
between two points if the distance between them is known. Lf is the distance from
the upper margin of the sternum to the navel, and from there to the groin. Lc is
the distance from the upper margin of the sternum to the neck. La is the distance
from the upper margin of the sternum to the navel, and from there to the ankle.
Lb is the distance from the upper margin of the sternum to the elbow. The
cardio-ankle vascular index (CAVI) is calculated using the heart-ankle PWV
(haPWV). Ps and Pd are the systolic and diastolic blood pressure values,
respectively, and
PWV can be measured using several techniques. Devices that use a probe, a
transducer, or a tonometer record the pulse wave, and devices that use cuffs
placed around the limbs record the pulse wave by the oscillometric method. As PWV
can be measured noninvasively, it has been clinically used for several decades.
In particular, the PWV measured between the carotid and femoral arteries
(carotid-femoral [cf] PWV) is well-validated and acts as a surrogate marker of
mortality in various diseases. For instance, in 2,232 participants from the
Framingham cohort, it was found that the higher the cfPWV, the greater was the
risk for a cardiovascular event (Mitchell et al., 2010). In addition, a
meta-analysis of more than 15,000 patients demonstrated that higher cfPWV was
associated with worse clinical outcomes (Vlachopoulos et al., 2010a). When
measuring brachial-ankle [ba] PWV, the cuffs are placed around the limbs so that
an oscillometer can record the arrival of the pulse waves. Generally speaking,
baPWV can be measured more easily than cfPWV. As to the segments of the arteries,
cfPWV represents the stiffness of the aorta, while baPWV represents the
stiffness of the arteries in the extremities and that of the aorta (Yamashina et al., 2002). However, the reproducibility of PWV measurements (cfPWV and
baPWV) is a problem, because cfPWV depends highly on the observer’s skill, and
both cfPWV and baPWV depend on the blood pressure at the time of measurement.
Thus, arterial stiffness parameters that are highly reproducible and independent
of blood pressure at the time of measurement were sought for. Blood pressure at
the time of measurement affects all arterial stiffness parameters except
Progression of arteriosclerosis/atherosclerosis leads to the development of visually detectable morphological changes, including arterial wall thickening, plaque formation, and calcification. An intima-media thickening and plaque formation can be detected by ultrasonography. As such, the carotid arteries intima-media complex thickening is often used as an indicator of early-stage arteriosclerosis/atherosclerosis. The carotid intima-media thickness (IMT) has been widely used to predict the risk of future cardiovascular events, independently of other traditional risk factors. In a meta-analysis that included 14 studies, the carotid IMT was a predictor for myocardial infarction and stroke in asymptomatic individuals (Den Ruijter et al., 2012). Computed tomography (CT) can be used to detect and quantify aortic and coronary artery calcification. Coronary artery calcification is known to be a risk factor for cardiovascular events, including myocardial infarction (Taylor et al., 2001). Atherosclerotic plaques in the carotid arteries and the aorta can also be viewed using high-resolution magnetic resonance imaging (MRI). In fact, in an interventional trial, changes in carotid and aortic atherosclerotic plaque burden due to statins were identified by high-resolution MRI (Raggi et al., 2005; Underhill et al., 2008). Viewing coronary plaques by MRI is more challenging. For a review on the various emerging techniques to estimate atherosclerosis severity, see Noguchi et al. (2013).
In summary, the manifestations or consequences of the arteriosclerotic process can be measured in both elastic or muscular arteries in cross-section and longitudinally (Fig. 2).
Using probes or a tonometer, the pulse wave velocity
(PWV) can be measured between the carotid and femoral arteries (cfPWV) or
brachial and ankle arteries (baPWV). The cardio-ankle vascular index (CAVI) can
be obtained from blood pressure and heart-ankle PWV (haPWV) measurements. The
carotid intima-media thickness (IMT) is measured using ultrasonography. The
augmenting pressure (AP) and the augmentation index (AIx) are derived from the
central arterial waveforms. The arterial stiffness parameter
The CAVI is a measure based on a technique similar to that used to measure baPWV. Placing the cuffs around the limbs and recording the pulse wave by an oscillometer is simple and independent of the observer’s skill. More specifically, the heart-ankle PWV (haPWV), rather than the baPWV, is used to measure the values needed to calculate the CAVI. haPWV is calculated by dividing the distance from the aortic origin to the ankle by the time it takes for a pulse wave to propagate over this distance (Fig. 1). Besides, the CAVI is less dependent on blood pressure at the time of measurement because it is calculated using systolic and diastolic blood pressures measured simultaneously. In this section, we will discuss several aspects related to the CAVI.
First, since arterial stiffening is part of the aging process, arterial stiffness and its related parameters are predominantly affected by age. This also applies to arterial stiffness expressed by the CAVI. In healthy subjects, the CAVI is reported to be higher in the elderly than in younger subjects. Moreover, the CAVI was reported to increase linearly with age in individuals aged 20 to 70 years, at an increasing rate of approximately 0.5 units per decade (Shirai et al., 2011a). Besides, the CAVI was reported to be 0.2 units higher in men than in women of the same age groups.
Second, lifestyle habits also have an effect. Smoking is one of the leading causes of arteriosclerosis/atherosclerosis progression. In fact, the CAVI was shown to be higher in smokers than in non-smokers (Kubozono et al., 2007). Furthermore, the CAVI in smokers has improved after complete cessation of smoking (Noike et al., 2010). Warm footbath was reported to reduce systemic arterial stiffness in women, as indicated by the CAVI (Hu et al., 2012). The authors speculated that this reduction was the effect of the increased nitric oxide release on the vascular smooth muscle.
The effect of bodyweight reduction on the CAVI is controversial. A calorie restriction diet and exercise therapy resulted in a CAVI decrease, along with a decrease in the visceral fat area, as viewed on CT images (Nagayama et al., 2013). After a weight decrease, metabolic dysfunctions, including dyslipidemia and hyperglycemia, tend to improve. However, reduction in the visceral fat area, as viewed on CT images, was the only parameter associated with a decrease in the CAVI. Therefore, the authors speculated that the visceral fat area is associated with arterial stiffness, and thus, a decrease in the visceral fat area might contribute to preventing atherosclerosis progression. A three-month weight-loss program improved both metabolic dysfunction and the CAVI in obese patients. These changes might be due to increased adiponectin production, which promotes improvement in endothelial function. Such an improvement leads to a lower CAVI (Satoh et al., 2008). However, in healthy non-obese and obese subjects without metabolic disorders, the CAVI was negatively associated with body mass index (BMI) (Nagayama et al., 2017). The authors suggested that systemic accumulation of adipose tissue per se might lead to a linear decrease of the CAVI.
Third, numerous reports have shown that the CAVI is linked to various diseases that play an essential role in arteriosclerosis/atherosclerosis pathogenesis. It is also linked to other diseases, including cardiovascular diseases (Shirai et al., 2011a). Hypertension, dyslipidemia, diabetes mellitus, and metabolic syndrome were all shown to be associated with a higher CAVI (Shirai et al., 2011a). Furthermore, higher CAVI indicates impaired kidney function, the degree of atherosclerosis/arteriosclerosis, and cardiovascular disease risk in patients with renal insufficiency (Kubozono et al., 2009). Several studies have shown that kidney function markers such as estimated glomerular filtration rate and serum cystatin C level are associated with the CAVI (Kubozono et al., 2009; Nakamura et al., 2009). Moreover, it was shown that the CAVI is higher in hemodialysis patients than in healthy controls (Ueyama et al., 2009). Vascular impairment in chronic kidney disease, which can be caused by chronic inflammation and uremic toxins, plays an important role in the development of cardiac dysfunction (Zanoli et al., 2019). Consequently, high CAVI might also indicate a risk of developing cardiovascular diseases such as angina pectoris, myocardial infarction, and stroke. The severity of coronary artery disease, assessed by the number of stenosed vessels on angiography, was related to a higher CAVI (Nakamura et al., 2008). It was also shown that patients with cerebral infarction have a higher CAVI than healthy controls. Moreover, the CAVI clearly relates to the carotid ultrasonographic plaque score (Suzuki et al., 2013).
Lastly, medical treatment for several diseases, including diabetes mellitus,
hypertension, and hyperlipidemia, can decrease the CAVI. Blood glucose control by
either insulin or oral hypoglycemic agents decreases the CAVI (Nagayama et al., 2010; Ohira et al., 2011). Since CAVI improvement is associated with improved
postprandial hyperglycemia, reduced insulin resistance might contribute to a
reduction in arterial stiffness. Blood pressure control by anti-hypertensive
agents, particularly angiotensin II receptor antagonists, was found to decrease
the CAVI (Kinouchi et al., 2010). Another study, in which the CAVI was
assessed in 12 healthy male volunteers, demonstrated that the systolic blood
pressure and the baPWV value were lowered by both
As discussed above, the CAVI can be used as an indicator of some conditions, including atherosclerotic diseases. However, it is still unclear whether the CAVI is a prognostic indicator in patients with and without atherosclerotic diseases. Analysis of the follow-up data of 194 hemodialysis patients found that neither the CAVI nor baPWV could predict mortality (Kato et al., 2010). In a recent study (Kim et al., 2019), the association between several arterial stiffness parameters and cardiovascular disease incidence and all-cause mortality was examined in older adults aged 66-90 years. The study found no association between the CAVI and cardiovascular events or all-cause mortality. The prognostic value of the CAVI seems to be limited in older adults. In a meta-analysis (Matsushita et al., 2019) of nine prospective and 17 cross-sectional studies, a modest association between the CAVI and the risk of cardiovascular diseases was found. The author mentioned as a limitation the fact that most of the included studies were conducted in Asia and that relatively high-risk patients for cardiovascular diseases were included. Although many studies have shown that cfPWV has a prognostic value (Vlachopoulos et al., 2010a), blood pressure at the time of measurement acts as a confounder. Thus, studies that assess whether the CAVI per se is associated with clinical outcomes are warranted.
In the general population, obesity is a significant risk factor for OSA, probably because of the associated neck thickening and narrowing of the pharynx lumen by fat pads adjacent to it. In fact, the pharynx is generally narrowed in patients with OSA (Nichols et al., 1988). The loss of pharyngeal dilator muscle tone at sleep onset causes the pharynx to completely or partially collapse, leading to obstructive apnea and hypopnea, respectively.
Apnea is defined as an absence of tidal volume for
Repetitive intermittent hypoxia and post-apneic reoxygenation, in association with OSA, lead to increased oxidative stress and the production of reactive oxygen species (ROS) (Lavie, 2003). ROS decrease the bioavailability of nitric oxide, which has antiatherogenic properties, including inhibition of platelet aggregation and adhesion, smooth muscle cell proliferation, leucocyte adhesion, and vascular permeability. In addition, decreased bioavailability of nitric oxide results in impairment of the vascular endothelium vasodilatory effects (Moncada and Higgs, 1993). Hypoxia and production of ROS increase the release of inflammatory mediators such as serum amyloid A and C-reactive protein (Punjabi and Beamer, 2007; Svatikova et al., 2003) by activated transcription factors, leading to exacerbated endothelial dysfunction (Garvey et al., 2009). Endothelial dysfunction leads to the production of various factors that regulate cellular adhesion, smooth muscle cell migration and proliferation, and focal inflammation (Libby et al., 2002; Ross, 1999). Endothelial cells prevent thrombosis by numerous mechanisms, including inhibition of platelet aggregation and the release of fibrinolytic mediators. Fibrinogen concentration and plasminogen activator inhibitor type-1 level were shown to be elevated in patients with OSA (von Känel et al., 2006). Thus, patients with OSA have a higher risk for thrombosis, which can, however, be reversed by treating the OSA (Chin et al., 1996; von Känel et al., 2006). Endothelial dysfunction also triggers the recruitment of proinflammatory circulating cells, which results in increased vascular permeability for plasma lipids, and, consequently, promotes plaque formation.
In patients with OSA, these processes cause FMD impairment, increased arterial
stiffness, and IMT (Monneret et al., 2010). These effects are reversible by
OSA treatment (i.e., CPAP) (Drager et al., 2007; Hui et al., 2012). In a
meta-analysis (Ning et al., 2019) of 15 randomized controlled trials that
assessed the efficacy of several biomarkers, subgroup analysis showed that CPAP
was particularly effective in improving FMD in severe OSA patients and patients
with effective CPAP use for
Nevertheless, the indirect impact of OSA on arteriosclerosis/atherosclerosis should also be considered. It is well-recognized that OSA causes daytime and nighttime hypertension and insulin resistance. Hypertension and insulin resistance are risk factors for the development and progression of arteriosclerosis/atherosclerosis and cardiovascular diseases. In fact, randomized controlled trials and meta-analyses have found that CPAP treatment reduces systemic blood pressure in patients with OSA. In a meta-analysis of 15 studies that evaluated the effect of CPAP treatment on insulin resistance, CPAP did not induce glycemic control changes but improved insulin resistance in 12 of the studies with non-diabetic patients (Yang et al., 2013). In another meta-analysis of six diabetic studies, CPAP treatment significantly improved insulin resistance (Chen et al., 2014). Further large-scale randomized controlled trials are needed to evaluate the effect of CPAP on diabetes because the aforementioned meta-analyses included only a few randomized controlled trials. CPAP was shown to have a favorable effect on cardiovascular diseases in a non-randomized clinical trial. A prospective cohort study, which followed 449 patients with OSA for a median of six years (Buchner et al., 2007), showed that, compared with no treatment, CPAP therapy was associated with a reduction in the likelihood of developing cardiovascular events such as myocardial infarction, stroke, or acute coronary syndrome that required a revascularization procedure. An observational study (Marin et al., 2005) that followed 1,651 men recruited from a sleep clinic, and a population-based sample of healthy men, demonstrated that severe OSA significantly increased the risk of fatal and non-fatal cardiovascular events and that CPAP treatment reduced this risk.
According to a recent meta-analysis (Wang et al., 2015) that included five
cross-sectional studies, arterial stiffness, determined by cfPWV or AIx, was
significantly higher in patients with OSA than in healthy controls. Another
meta-analysis of 15 articles (
Some studies have suggested an association between OSA and white coat hypertension (García-Río et al., 2004; Li et al., 2015). Therefore, the CAVI is considered superior to other arterial stiffness parameters because it is highly reproducible and does not vary with blood pressure changes at the time of measurement.
Several studies measuring the CAVI in patients with OSA concluded that the CAVI
increases with OSA severity. Kumagai and colleagues (2009) investigated the
clinical utility of the CAVI in 543 consecutive patients with OSA (AHI
Although data from elderly patients is limited, a cross-sectional study (Kim et al., 2015) on elderly patients (
Our retrospective study included 574 OSA patients who underwent assessment for
the CAVI and overnight polysomnography. The mean age was 53
Patients were divided based on a cardio-ankle
vascular index (CAVI) cut-off value of 7. In men, the apnea-hypopnea index (AHI)
was similar in both groups (37.1 vs. 35.6, P = 0.483). In women, the AHI was
higher in the CAVI
The CAVI can measure changes in arterial stiffness that are less dependent on
changes in blood pressure. Non-hypertensive patients with OSA and matched
controls without either hypertension or OSA were compared for overnight change in
the CAVI based on measurements performed before and after sleep (Lü et al., 2008). After sleep, the CAVI was significantly higher than before in patients
with OSA (8.3
Author, year | Participants | n | Intervention | Duration | Results |
Lü et al., 2008 | Hypertensive patients with OSA | 22 (of 60) | CPAP | 1 day 3 days | CAVI |
Kato et al., 2011 | Moderate to severe OSA | 30 | CPAP | 1 month 1 year | CAVI |
Kasai et al., 2011 | Moderate to severe OSA | 27 (of 50) | CPAP | 1 month | CAVI |
Iguchi et al., 2013 | Overweight or obese patients | 60 | Weight reduction | 3 months | CAVI |
Yoshihisa et al., 2013 | HFpEF with moderate to severe SDB | 18 (of 36) | ASV | 6 months | CAVI |
AHI, apnea-hypopnea index; ASV, adoptive servo-ventilation; BNP, brain natriuretic peptide; BP, blood pressure; CAVI, cardio-ankle vascular index; CPAP, continuous positive airway pressure; HFpEF, heart failure with preserved ejection fraction; NYHA, New York Heart Association functional classification; OSA, obstructive sleep apnea; SDB, sleep disordered breathing. |
Weight reduction as an intervention for OSA was assessed in overweight or obese
subjects (Iguchi et al., 2013). Although the study included a small number of
OSA patients (average AHI, 18), subjects who successfully reduced their weight
during the three months of the study, defined as
It should be noted that the aforementioned studies included patients with no
cardiovascular disease other than hypertension, and therefore whether the CAVI
can act as an indicator of disease condition or prognosis for the secondary
prevention of cardiovascular diseases remains to be investigated. There is only
one study (Yoshihisa et al., 2013) that included heart failure patients with
moderate to severe sleep apnea. All patients had preserved left ventricular
function of
OSA can promote arteriosclerosis/atherosclerosis and lead to cardiovascular events. Various physiological parameters have been used to predict the onset of cardiovascular events and mortality (Den Ruijter et al., 2012; Kato et al., 2010; Matsuzawa et al., 2015; Mattace-Raso et al., 2006; Mitchell et al., 2010; Oliver and Webb, 2003; Shirai et al., 2011a; Taylor et al., 2001; Vlachopoulos et al., 2010a, b). Arterial stiffness is one such parameter. Compared with other parameters such as FMD, IMT, and inflammatory markers, arterial stiffness can reveal systemic arteriosclerosis/atherosclerosis and provide hints to the functional properties of the arteries. Although cfPWV is the gold-standard parameter for arterial stiffness evaluation, the CAVI is a promising emerging parameter that is easy to measure, highly reproducible, and represents changes in the central arteries and resistance in the peripheral arteries. In patients with OSA, who are more likely to have blood pressure variations at the time of measurement (Shiina et al., 2016), the CAVI might be a useful parameter of arterial stiffness assessment because it is less affected by blood pressure variations at the time of measurement. To evaluate changes in arterial stiffness following interventions that might change blood pressure, the CAVI appears superior to other parameters. In studies evaluating changes in the CAVI before and after CPAP treatment initiation (Drager et al., 2007; Hoyos et al., 2015; Jones et al., 2013; Kohler et al., 2008, 2013; Litvin et al., 2013), longer nightly CPAP usage was associated with improvement of the CAVI. Therefore, the CAVI can be used as a parameter of compliance or adherence to CPAP usage in patients with OSA. Further epidemiological studies are needed to elucidate the CAVI prognostic value in OSA patients by comparing it to cfPWV.
Yasuhiro Tomita and Takatoshi Kasai drafted the article; Takatoshi Kasai revised it critically.
This was partly supported by a JSPS KAKENHI Grant Number JP17K09527. The funding source has no other roles in this study.
Drs. Kasai and Tomita are affiliated to a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi.