Obesity and Non-Obesity Obstructive Sleep Apnoea Hypertension Syndromes (OOHS & NOOHS): New Clinical Discoveries

Obesity, obstructive sleep apnoea (OSA) and hypertension are common clinical risk factors. Their coexistence is termed Obesity and Non-Obesity OSA Hypertension Syndromes (OOHS & NOOHS) due to high linkage. This study reported the clinical characteristics of OOHS and NOOHS. A total of 163 patients, aged 23–74 years, were randomly enrolled at the outpatients department who were either obese or non-obese, suffered OSA and hypertension. Subjects with a Body Mass Index (BMI) of ≥ 25 (Chinese criteria), of ≥ 27 (criteria of this study), and of ≥ 30 (WHO criteria) were dened as obese or non-obese, respectively. Cases with snoring were classied as mild, moderate and severe OSA by using the Apnoea-Hypopnoea Index where mild is 5–15, moderate is 15–30, and severe is > 30. Daytime blood pressure (BP) was measured to assess any correlation. Data from those with isolated obesity, OSA, hypertension, and metabolic syndrome were compared. Long-term follow-up was carried out. 7 typical cases with OOHS and NOOHS were assessed and included general patient information, initial diagnosis, medical history, related risk factors, BMI, and BP. 163 cases with OOHS and NOOHS often have similar or different clinical characteristics. Both potentially suffer from Major Adverse Cardiovascular Events (MACE) which are associated with increased BMI, OSA, and increased BP. Long-term follow-up showed the outcomes consistently linked to their lifestyle and adherence to treatment. Our new clinical discoveries suggest that both OOHS and NOOHS are high risk factors in MACE. There is an urgent need for early lifestyle interventions and related treatments.


Introduction
Obesity, OSA and hypertension are common internationally and present major challenges in the eld of public health. According to the Report on the Nutrition and Chronic Disease Status of Chinese Residents, more than 50.0% of Chinese residents aged ³18 years were obese, there were only 30.1% obese residents in 2012 1 . OSA is a common condition among patients with cardiovascular disease (CVD) affecting at least 9 to 15% of middle-aged adults in 2000 2 , 17% of women and 34% of men in the US 3 and 40% to 60% of CVD patients in 2015 4 . There are almost 1.0 billion individuals affected globally and with prevalence exceeding 50% in some countries in 2019 5 . OSA is associated with a 2-to 3-fold increased risk of CVD. 3 In fact, OSA is an important and independent risk factor of CVD 6 and contributes to the increased incidence of MACE, stroke, cardiometabolic risk, cardiovascular morbidity and mortality [7][8][9] . In addition, the Survey on the Status of Nutrition and Health of the Chinese People in 2012 showed that ³25.2% of adults in China aged 18 years had hypertension 1 .
Epidemiologic data support the link to obesity, OSA, and hypertension. Data also shows that each of obesity, OSA and hypertension is an independent risk factor of both CVD and cerebrovascular diseases. If undiagnosed and untreated, both obesity and OSA may lead to hypertension and other CVD [10][11][12] . There was an obvious correlation of of obesity, OSA and hypertension. Nevertheless, it is currently unclear of the incidence of their correlation and little is known how about the exact risk of their correlation to the cardiovascular and cerebrovascular system. This is a preliminary report on the clinical characteristics of the correlation of obesity, OSA, and hypertension. As new clinical discoveries, this correlation for obesity has been termed as OOHS and that of non-obesity as NOOHS 13 . Data relating to OOHS and NOOHS by different criteria of obesity according to the World Health Organization (WHO) (BMI³30), China (BMI³25), and this study (BMI³27) were also compared.

Results
Clinical characteristics of 7 typical cases with OOHS and NOOHS syndromes were assessed including general information, primary diagnosis, past and family history, "environment-sleep-emotion-exercise-diet" [E(e)SEED] related risk factors, BMI, BP, and others (Tables 1 & 2   in the males and females respectively. Cardiovascular and cerebrovascular events including CHF, IHD (AP, MI), arrhythmia (APC,VPC, AT, AF) and cerebrovascular accident (CVA) were also found in both male and female patients (Tables 4 & 5). Fewer cases were associated with dis-lipidaemia and no fatty livers were found. Some had signi cant family history, especially in females, but none of the patients smoked and drank excess alcohol, and there was no sudden cardiac death in female patients.
In the group of BMI 25 (Chinese criteria of obesity), there were 93 cases with OOHS syndrome, 71 were male and 22 were female. This indicates that OOHS cases increase greatly in this group. However, according to WHO criteria of BMI 30, only 12 cases were male and 3 cases were female, OOHS syndrome cases decrease in this group (Table 6).
Both OOHS and NOOHS are very high risks for the cardiovascular and cerebrovascular system. There were high rates in related MACE which include CHF, IHD (AP, MI), arrhythmia (APC,VPC, AT, AF, AVB, LBBB), and CVA, and similar spectrums as showed in this study ( Fig. 1. A, B, C). However, no cases with impaired glucose tolerance (IGT) or type 2 diabetes (T2D) were found in the group of OOHS, but these were found in the NOOHS group. No fatty liver cases were found in the group of NOOHS, but were seen in OOHS syndrome. Both IGT or T2D and fatty liver are related to BMI. It was found that there were often MACE in both OOHS and NOOHS. This infers that increased BMI and also OSA will result in high risk to the cardiovascular and cerebrovascular systems.
The clinical features of OOHS and NOOHS were compared with isolated obesity, OSA, hypertension (iHTN), and MS.
Obesity or non-obesity and the severity of OSA strongly link to increased and high risk in both OOH and NOOH syndromes when compared with isolated groups. After 12 years of long-term follow-up, the clinical outcomes of patients with OOHS and NOOHS have been assessed and are shown in Table 7.

Discussion
Obesity, OSA, and hypertension are independent risk factors of for the cardiovascular and cerebrovascular systems.
There have been previous studies of obesity, OSA, and hypertension respectively 14 . However, none of these studies increased the understanding of the association of obesity or non-obesity, OSA, and hypertension in relation to OOHS and NOOHS. In fact, the co-clinical spectrum of OOHS and NOOHS relating to the cardiovascular and cerebrovascular systems includes arterial hypertension (40-60%), pulmonary hypertension (20-30%), CHD (20-30%), CHF (5-10%), arrhythmia (AVB, sinus arrests, and AF), and CVA (5-10%) 15 . These are the wide range of vascular diseases related to OOHS or NOOHS.
Several mechanisms related to obesity, OSA, and hypertension such as sympathetic activation, hyper-leptinaemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and in ammatory stress, endothelial dysfunction, impaired barore ex function, and perhaps effects on renal function have been reported [16][17][18] . These mechanisms could result in the cardiovascular and cerebrovascular complications resulting from OOHS or NOOHS, but the exact relationship is still unclear. Further work may include using animal models of OOHS and NOOHS to further assess the relationship to obesity and OSA 19,20 . The genetic basis of OOHS and NOOHS also requires further analysis, one possible candidate is FTO 21,22 . Factors such as endothelial dsynfunction 23 , the TASK-1 gene and the gut microbiome may be important 17,24 .
The clinical signs and symptoms of OOHS or NOOHS are obesity, OSA (including poor sleep quality), apnoea and excessive daytime somnolence. There are also associated Major Adverse Cardiovascular Events (MACE) such as hypertension, arrhythmias, and CHF especially in older patients with untreated OSA. The known risk factors are oxidative stress, age, obesity, smoking, OSA, hyper-lipidemia, hypertension, and T2D and these represent the co-founding factors in OOHS or NOOHS. The risk of CVD (including CHD, insulin resistance, stroke, and T2D) increases with BMI. Hence, OOHS and NOOHS should be considered as new high risk factors which increase the risk of MACE.
OSA-related OOHS or NOOHS may contribute to Metabolic Syndrome (MS) which in turn is associated with obesity, hypertension, dyslipidemia, sex hormone abnormalities, in ammation, vascular dysfunction, insulin resistance, and sleep deprivation. Both OOHS and NOOHS are common, especially among individuals such as truck drivers and African Americans 25,26 . There are known gender differences in obesity and OSA [27][28][29] and this study con rmed that OOHS or NOOHS is more common in men than in women, the ratio being about 2 to 3:1.
The treatment of OOHS or NOOHS includes to remove the confounding factors and anti-hypertensive treatment. Patients suffering from OOHS are advised to decrease their BMI by lifestyle interventions such as E (e)nvironment sleep, emotion, exercise and diet intervention (E(e)SEEDi) 30,31 . Medication is necessary to control hypertension which may otherwise result in MACE. Treating OSA by continuous positive airway pressure (CPAP) or surgery is potentially useful in patients suffering from OOHS and NOOHS 9 . Nevertheless, one study found that CPAP treatment does not prevent MACE resulting from OSA 4 .
It has previously been shown that BP decreases in some of patients after the surgical treatment of OSA. Most of the patients with OOHS or NOOHS need medication to lower BP and to control CHF, arrhythmia, CHD, and CVA. There are a number of patients suffering from OOHS or NOOHS with high levels of obesity and OSA who show a decrease in their BP following control of the BMI and OSA. There is evidence that untreated OSA is associated with left ventricular diastolic and systolic failure and in these cases treatment with CPAP improves systolic function 6,32,33 .
Weight management is clearly very important for patients with OOHS. Weight loss based low calorie diets with behavioural modi cations and sometimes bariatric surgery is helpful either as a primary therapy or combination with surgical treatment of OSA. Liraglutide, a glucagon-like peptide-1 analogue, may be bene cial for weight loss in some patients 34 , especially when combined with lifestyle modi cation. In addition the safety and e cacy of Lorcaserin, a selective serotonin 2C receptor agonist, has been con rmed by a clinical trial for sustained weight loss in obese patients 35 .
The diagnosis and treatment of OOHS and NOOHS may help to achieve better clinical control and improve long-term prognosis. The cardioprotective effects of aggressive treatment, and a reduction in important clinical endpoints such as the rates of myocardial infarction and CVA may be bene cial to patients 36-38 . When assessing obesity, OSA, hypertension (iHTN) and MS, we found that each of them is a risk factor of CVD. Despite this OOHS or NOOHS is a higher risk to both the cardiovascular and cerebrovascular system. It was also found that the diagnosis of patients suffering from OOHS or NOOHS is more likely in those patients with a high prevalence of obesity and OSA. It is recommended that more attention should be paid to these cases due to the higher risk to the patients and higher incidence of MACE.
The coexistence of obesity and OSA may result in a series of dysfunctions in patients with OOHS and easily contribute to MS. Nevertheless, we cannot just de ne OOHS or NOOHS syndrome as a Pre-MS status. Since all these patients have OSA, it is still unclear whether the threat to the cardiovascular and cerebrovascular is via MS or not. In this study, it seems that the risk of OOHS or NOOHS in some patients is associated with MS, but in others it seems to be not associated with MS. It may be dependent on patients other factors such as race, gender, genetic history, BMI (obesity or non-obesity), and the severity of OSA. The positive treatment of OSA by lifestyle interventions, medication, surgery or CPAP is clearly very important.
Further understanding and investigation of the mechanisms of OOHS and NOOHS are needed possibly by using animal models and related studies. Previous studies found that activation of IκB kinase-β (IKK-β) and the proin ammatory protein nuclear factor κB (NF-κB) is a primary pathogenic link between obesity and hypertension 39 . There are pathogenic genetic variants in melanocortin 2 receptor accessory protein 2 (MRAP2) among individuals with severe obesity 40 , and loss-of-function MRAP2 variants are pathogenic for monogenic obesity and hypertension 41 . Hence, these genetic variants and related risk factors (obesity, OSA, and hypertension) could be potential targets to improve human health due to the causal effect of blood pressure and obesity on lifespan 42 . It may be time to renew the criteria of obesity from BMI ≥25 to BMI ≥27 in China, but BMI ≥30 in the WHO. The mortality resulting from OOHS and NOOHS is still unknown. As special types of C-type hypertension 13,43 , the prognosis of OOHS and NOOHS depends on the data from long-term follow-up and large-scale clinical trials 44 . However, this study is just a preliminary report on OOHS and NOOHS, there is a need to nd and understand more clinical data on the subject. Second, the patient numbers are still small, and long-term follow-up is needed to observe further the clinical outcomes, e.g. MACE, other endpoint events and overall prognosis. Finally an understanding is needed about whether or not patients suffering from OOHS and NOOHS will develop cardiovascular disease, diabetes, and cancer (CDC) strips 13,45 . Animal models of OOHS and NOOHS are need to better understand the mechanisms and vital pathogenic genes involved in the syndromes.
All in all, our results indicate that obesity, OSA, and hypertension are not only independent risk factors but also common and major challenges in clinical practice. In this preliminary study on the clinical characteristics, our new clinical discoveries suggest that both OOHS and NOOHS are high risk and may result in MACE. They both need early lifestyle intervention and treatment.

Data Collection
A total of 163 patients aged 23-74 years were randomly enrolled at the outpatients department with obesity or nonobesity, prevalence of self-reported chronic snoring or OSA, and hypertension from October, 2003 to December, 2017.
Individuals with a BMI ≥25 (China), ≥27 (this study) and ≥30 (WHO) were de ned as obese or non-obese (BMI 18-23), respectively. Subjects were divided into two groups (obese and non-obese) by BMI. Patients with snoring were determined mild, moderate, and severe OSA, respectively, by apnoea-hypopnea index (AHI) i.e. the number of apnoeic and hyponoeic events per hour in the range of 5-15, 15-30, and > 30. Daytime blood pressure (BP) was measured for determination of the correlation between obese or non-obese, OSA, and hypertension. Data from patients with OOHS and NOOHS (according to different criteria of BMI) and from those with isolated obesity, OSA, hypertension, and metabolic syndrome (MS) were compared.

IINFORMED CONSENT
Written informed consent was given by all patients included in this study. The study protocol was approved by the Institutional Review Board for Human Subjects Research at Nanchang University. The research study was performed in accordance with the principles of the Declaration of Helsinki. There were no potential sources of bias.

Investigations
All of the patients underwent physical and biochemical examinations including routine U&E, liver function, fasting blood glucose, blood lipids, blood viscosity, uric acid, myocardial enzymes, troponin I, oral administration glucose tolerance test or post-prandial 2-hour blood sugar, hepatitis B, prostatic antigen. Other related auxiliary examinations included chest X-ray, routine electrocardiogram, exercise test and 24-hour ambulatory electrocardiogram, ambulatory blood pressure monitoring, colour Doppler ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI), coronary angiography, mammography where relevant).

Statistical analysis
The results of original records were used. Data were statistically analyzed using the Statistical Package for the Social Sciences (SPSS version 17.0, SPSS Inc., Chicago, IL, USA) with t-test for comparisons between two groups. A P-value of < 0.05 was considered statistically signi cant.

Declarations Data Availability
Source data for Fig. 1 is available online. All other source data is available upon reasonable request from the corresponding author.  * CVE include hypertension emergency, coronary heart disease, arrhythmia or sudden cardiac death, acute or chronic heart failure, CVA; + to +++: slight to heavy.
The blood pressure level of each group was significantly different from that of control groups (the blood pressure level was in the normal range).    Notes: When patients with OOHS or NOOHS also suffer from type 2 diabetes and/or cancer, it means that they may develop cardiovascular, diabetes, and cancer (CDC) strips. Figure 1 A. Healthy subject with normal BMI, no obstructive sleep apnoea (OSA), no hypertension; B. Subject with obesity-OSAhypertension (OOHS); C. Subject with non-obesity-OSA-hypertension (NOOHS). We usually call obesity as "a shaped, but not sounded killer", OSA as "a sounded, but not shaped killer", hypertension as "not shaped and sounded killer". Obviously, OOHS is not only "a shaped and sounded killer" at night, but also "a shaped and not sounded killer" at daytime. OOHS which marks the coexistence of obesity, OSA, and hypertension is a "synthetic killer", and a very high risk factor of coronary heart disease (CHD), acute myocardial infarction (AMI), CVA, and T2D.