The number of people with hypertension worldwide in 2021 was estimated to be 1.4 billion [1], and the prevalence of obstructive sleep apnea (OSA) among hypertensive patients is 40% [2]. Hypertensive patients with OSA usually show a high risk of cardiovascular disease (CVD). In comparison with patients showing hypertension or OSA alone, those with both conditions are more susceptible to CVD and frequently experience more severe adverse cardiovascular events [3]. In addition, because OSA often occurs during nighttime sleep and is not easily noticed by patients, its prevalence is heavily underestimated [4]. Therefore, in addition to paying more attention to the population with hypertension and OSA, assessments of CVD prognosis in this population also need to be strengthened.

The pathophysiological mechanisms underlying OSA-induced increments in blood pressure can be summarized as follows: First, intermittent hypoxia caused by OSA leads to systemic oxidative stress, resulting in increased endothelin-1 production and decreased nitric oxide production in endothelial cells and causing increased peripheral arterial resistance [5, 6]. Second, recurrent episodes of hypoxemia and fragmented sleep induce sympathetic excitation, resulting in increased cardiac output and peripheral vasoconstriction [7]. Third, intermittent hypoxia can increase renin production through renal sympathetic excitation and thereby increase the levels of plasma angiotensin-II, which shows vasoconstrictor activity, and aldosterone, which shows sodium- and water-retention effects [8]. Fourth, intermittent hypoxia can result in vascular endothelial dysfunction and aberrant lipid metabolism, both of which are linked to atherosclerosis [9, 10]. All of these factors can contribute to hypertension, and the increased blood pressure can exacerbate these pathophysiological processes [9, 10, 11]. The pathophysiological mechanisms underlying OSA and hypertension overlap and reinforce one another, and the resulting cardiovascular damage is significantly greater than that caused by hypertension or OSA alone. Therefore, patients with both conditions constitute a high-risk CVD group that requires attention.

The assessment of groups showing high cardiovascular risk is currently based on the domestic and international clinical recommendations for CVD. However, in addition to necessitating comprehensive evaluations by professional physicians with extensive clinical experience, this approach also requires a number of tests and assessments of multiple inspection indicators as the basis for evaluation, limiting these evaluations to patients hospitalized in high-level hospitals. In China, however, a majority of the substantial population of patients with hypertension and OSA reside in rural areas with poor medical conditions, so they cannot be tested professionally. In addition, the evaluation group targeted by the clinical recommendations for CVD in China and overseas does not include patients with hypertension and OSA, and evaluations of this population lack specificity. These aspects indicate the urgent need for a practical, inexpensive, noninvasive, measurable, and more relevant methods for predicting and assessing the risk of CVD in hypertensive individuals with OSA.

The hepatic steatosis index (HSI), which is calculated using the formula HSI = 8 (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] ratio) + body mass index (BMI) (+2, if female; +2, if diabetes) was originally used to evaluate hepatic steatosis [12]. While the HSI can effectively evaluate hepatic steatosis (its sensitivity and specificity for diagnosing nonalcoholic fatty liver disease are both above 90%), it has been also shown to be related to the severity of diseases such as type 2 diabetes, CVD, and organ injuries unrelated to hypertension [13, 14, 15, 16]. The aforementioned findings indicate an association between the HSI and other diseases, and suggest that this association is related to a high metabolic risk in the population. Although patients with OSA and hypertension are more likely to develop metabolic disorders [17, 18, 19, 20, 21], to our knowledge, no previous study has evaluated the relevance of the HSI in hypertensive patients with OSA. Thus, the purpose of this study was to use the HSI to assess the risk of major adverse cardiovascular and cerebrovascular events (MACCE) in hypertensive individuals with OSA.

China has a large population of hypertensive patients with OSA, and this population often shows multiple risk factors that promote each other and further increase the risk of CVD and serious cardiovascular adverse events [28, 29]. However, the current clinical guidelines do not include assessments of serious cardiovascular adverse events in hypertensive patients with OSA. Therefore, this study used a retrospective cohort to characterize the relationship between the HSI and MACCE in a hypertensive population with OSA. Our results showed that an increase in the HSI value was independently associated with an increased risk of MACCE. The risk of MACCE in the highest HSI quartile was 2.95 times that in the lowest quartile. We observed similar results and trends when the study endpoints were subdivided into cardiac and cerebrovascular events and observed a linear relationship between the HSI and the risk of MACCE. More importantly, in comparison with the traditional model composed of risk factors, addition of the HSI was shown to increase the predictive power for MACCE.

Our results showed that patients with higher HSI values had a greater likelihood of MACCE. This outcome remained unchanged irrespective of whether the HSI was considered a categorical or continuous variable. In a cross-sectional study of healthy individuals, Kweon et al. [14] reported that participants with HSI $>$36 had a 2.43-fold higher risk of being in a cardiovascular high-risk group than those with HSI 30. This is consistent with the results of our study, in which patients with HSI $>$35.5 indicated a higher risk of MACCE. Hepatic steatosis is thought to be the component most closely associated with these results. Fatty liver has been previously shown to be an independent risk factor for CVD, and nonalcoholic fatty liver is the most common form of fatty liver [30, 31, 32, 33]. According to a meta-analysis conducted by Targher et al. [34], nonalcoholic fatty liver disease (NAFLD) is related to a 64% increased risk of cardiovascular disease. To further investigate the relationship between the HSI and cardiovascular and cerebrovascular disorders, the researchers developed a generalized additive model; their results revealed a linear relationship between the HSI and the risk of MACCE events. The HSI value has also been demonstrated to be linearly connected to the occurrence of cardiovascular and cerebrovascular events in the general population, and the risk of cardiovascular and cerebrovascular events increases by 4% for each 1-SD increase in the HIS [35]. Nevertheless, these findings were derived from investigations of broader populations. Our findings imply that the HSI value is associated with an increased risk of cardiovascular and cerebrovascular illnesses in patients with hypertension and OSA, which were attributable to the following reasons: First, the HSI formula includes numerous classic cardiovascular disease risk variables that have a synergistic effect on the HSI score; therefore, the association between the HSI and CVD is stronger than those of individual risk factors. Second, the higher the HSI value, the more severe the degree of hepatic steatosis. Numerous studies have indicated that OSA shows a high comorbidity rate with hypertension and that this population has a greater risk of developing lipid metabolism disorders and NAFLD than patients with simple hypertension or OSA [18, 19, 20, 21, 23]. In addition, patients with hypertension alone or those with OSA alone have a high risk of developing NAFLD [18, 33, 36], which are all independent risk factors for CVD [2, 30, 37, 38]. Third, hypertension, OSA, and NAFLD are independently associated risk factors for each other. In addition to the pathophysiological mechanisms described in the introduction by which hypertension and OSA contribute to each other, interactions between OSA and NAFLD have also been demonstrated. Bahr et al. [39] found a high prevalence of NAFLD in patients with moderate-to-severe OSA in a Caucasian population, while similar findings have been reported in Asian populations [40, 41]. Chung et al. [42] also observed a high risk of OSA in patients with NAFLD, and similar findings showed significance in special populations such as women and children, wherein NAFLD was a risk factor independent of OSA [43, 44]. Fourth, inflammatory responses and oxidative stress and structural changes in blood vessels are pathophysiological mechanisms shared by hypertension, OSA, and fatty liver, all of which can cause the vascular endothelial cell deterioration that, in combination with inflammatory factors and lipid molecules, ultimately results in adverse cardiovascular events [38, 45, 46].

The HSI was originally a noninvasive index used to assess nonalcoholic fatty liver disease, and higher HSI values indicated more pronounced hepatic steatosis [12]. In addition to being directly associated with a nonalcoholic fatty liver, the HSI is also intimately associated with the development and occurrence of other disorders. Cai et al. [13] discovered that a 1-SD increase in the HSI in a healthy group was related to a 62% greater chance of developing diabetes. In addition, Han et al. [47] found that dynamic monitoring of the HSI can more accurately predict the onset of diabetes. The HSI is also independently linked to decreased bone mineral density, dementia, asthma, and sarcopenia [48, 49, 50, 51]. These studies have shown that the HSI can not only be used as a predictor of adverse diseases, but its ability to predict adverse events is not disease-specific. Therefore, we utilized the HSI reliably to assess CVD risk. In addition, we assessed the discriminative performance of the model after incorporating the HSI by evaluating the C-statistic, NRI, and IDI, and using other approaches, and the assessments yielded ideal outcomes.

This study had the following strengths. First, it was a retrospective cohort study with a large sample size of a special population with hypertension and OSA, and the results were relatively stable and reliable after statistical adjustments for confounding variables. Second, after adjusting for multiple confounding variables, HSI was independently associated with MACCE in the hypertensive OSA population. Third, using the C-statistic, IDI, and NRI, our findings validated the superior discriminatory ability of the model including the HSI in comparison with the conventional model, lending credence to the notion that the HSI is a better predictor for patients with hypertension and OSA. However, this study also had the following limitations: First, this was a retrospective single-center cohort study that was subject to the limitations of nonrandomized trials; therefore, the results should be interpreted with caution. However, every effort was made to ensure the reliability of the findings by adjusting for confounding factors using statistical methods. Second, we only investigated the association between the HSI and MACCE at baseline; however, factors such as medication, lifestyle, weight changes, and the presence or absence of CPAP treatment during patient follow-up could contribute to reverse causality. Consequently, our next line of inquiry will focus on time-dependent HSI variations and the associated influencing factors. Third, the study population consisted of patients with hypertension and OSA from western China, and the prevalence of hypertension, OSA, and CVD can be affected by local diet, lifestyle, and ethnicity, which can strengthen or weaken the association between the HSI and MACCE. Therefore, the findings of this study are not applicable to other populations, but they indicate the need for long-term clinical evaluation of specific patient populations, such as those with hypertension with OSA. Fourth, the paucity of liver-related imaging data in this study precluded further imaging-based evaluation of the severity of hepatic steatosis in patients. Fifth, genetic background can also influence hypertension, OSA, metabolic diseases, and CVD; however, our study did not evaluate genetic factors; therefore, the use of methods such as Mendelian randomization may provide new genetic-level insights into the observed results.

Among patients showing a combination of hypertension and OSA, those with high HSI were at an increased risk of CVD, and HSI showed a linear relationship with the risk of MACCE. Therefore, patients showing hypertension combined with OSA should undergo HSI evaluations as early as possible, and early intervention on the basis of the HSI levels should be provided to prevent adverse cardiovascular events.

The data of this study are available from the corresponding author upon reasonable request.

Conceptualization (NL, WW and XC). Methodology (XC and QZ). Initials formal analysis and investigation (WW). Writing—original draft preparation (WW). Writing—review and editing (WW and XC). Funding acquisition (JHu). Resources (JHong). Supervision (NL and XZ). All authors contributed to the study conception and design, revised the draft critically for important in intellectual content, and approved the final manuscript. All authors have participated sufficiently the work and agreed to be accountable for all aspects of the work.

The study obtained the consent of all participants and was approved by the Medical Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region (ethical approval number: 2019030662). The study strictly adhered to the ethical standards of the Declaration of Helsinki.

We appreciate all those who contributed and assisted with the UROSAH. We thank Dr. Kainan Zhang for statistical assistance with the preliminary data for this article.

This research was funded by the Natural Science Foundation of Xinjiang Uygur Autonomous Region, grant number 2021D01C173.

The authors declare no conflict of interest.