Association of Lipid Profile with Sleep-Disordered Breathing in Patients with Acute Ischemic Stroke

Abstract

Background: Sleep-disordered breathing (SDB) and hyperlipidemia belong to known stroke risk factors. There is an increasing evidence that chronic intermittent hypoxia is independently associated with dyslipidemia. However, the clinical evidence linking SDB with dyslipidemia is poorly described. In this study, we aimed to find possible association between lipoprotein levels and sleep apnea parameters in acute ischemic stroke patients.

Methods: 90 patients with acute cerebral ischemia were prospectively enrolled. Blood samples were obtained in a fasting condition within 24 hours after the stroke onset for the analysis of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG). SDB was assessed using standard overnight polysomnography.

Results: SDB was present in 50%, hypercholesterolemia in 52.2%, and hypertriglyceridemia in 20% of the subjects. In linear regression analysis, apnea–hypopnea index (AHI) was the only independent variable significantly associated with LDL levels (β = 0.220, P = 0.04) and TC (β = 0.240, P = .02). Likewise, AHI (β = 0.258, P = .01) with diastolic blood pressure (β = 0.204, P = .05) were the only predictors of cholesterol ratio (TC/HDL) in linear regression analysis. We failed to find any significant association of sleep apnea parameters with the levels of TG and HDL in the regression analyses.

Conclusion: The results of our study suggest no significant association of sleep apnea parameters with TG and HDL. However, AHI was significantly associated with TC, LDL, and cholesterol ratio in patients with acute ischemic stroke.

Keywords

Acute ischemic stroke lipid profile cholesterol triglycerides sleep-disordered breathing

Background

Hypercholesterolemia is a traditional risk factor for the development of atherosclerosis and vascular diseases, including stroke. According to the guidelines of American Heart Association/American Stroke Association, a serum lipid profile, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol, should be performed in patients with ischemic stroke.^{1, 2} In Europe, the prevalence of dyslipidemia in stroke patients is 38% to 46%.^3-5

Sleep-disordered breathing (SDB) also represents one of the independent risk factors for stroke and is present in 72% of subjects with ischemic stroke.^{6, 7} Moreover, the patients with SDB appear to have an increased dyslipidemia and the latest evidence suggests indirect independent association.^{8, 9} Nevertheless, the clinical evidence linking SDB with dyslipidemia is limited.¹⁰

The aim of this study was to explore the association of lipoprotein levels with SDB measurements in patients with acute ischemic stroke. We are not aware of any previous studies describing such association in the acute stroke setting.

Methods

We prospectively enrolled patients hospitalized in the stroke unit of the First Department of Neurology, Comenius University, Bratislava, with the diagnosis of acute ischemic stroke. The diagnosis of stroke was confirmed clinically and hemorrhagic etiology was excluded by computed tomography or magnetic resonance imaging. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the baseline severity of stroke.¹¹ Only the patients suffering with mild-to-moderate stroke severity (NIHSS < 15) were included into the study. Subjects with the impaired consciousness, agitated confusion, acute chest infection, or the ones who refused to participate were excluded from the study. Demographic data and clinical characteristics, including age, gender, body mass index (BMI), waist circumference, neck circumference, blood pressure, history of arterial hypertension, diabetes mellitus, nicotine abuse, and use of lipid-lowering therapy, were recorded. In the detailed search for possible confounders for dyslipidemia, we reviewed medical records of all patients for the presence of diabetes mellitus, excessive alcohol intake, and premorbid use of lipid-lowering therapy.^{12, 13} Out of 175 recruited patients, we initially excluded 41 subjects due to premorbid use of lipid-lowering therapy and 44 subjects due to history of diabetes mellitus or newly diagnosed diabetes mellitus in a stroke unit settings. The study was approved by the local ethics committee and all subjects provided an informed consent.

Blood tests were performed within 24 hours after the stroke onset. The blood samples were obtained in fasting condition following morning and processed in the local hospital laboratory. Parameters, including TC, TG, HDL, and LDL, were set using an enzymatic colorimetric method (Cobas Mira Plus, Roche Diagnostics GmbH, Montclair, NJ, USA).

Cholesterol ratio, a useful and simple index of vascular risk, was calculated as TC/HDL.¹⁴

The sleep study was performed within 7 days after the stroke onset. All patients underwent standard overnight polysomnography in a sleep laboratory settings using Alice 5 device (Philips-Respironics, the Netherlands). Standardized criteria were used for scoring of sleep parameters and respiratory events. Examiners were blinded to the baseline characteristics of the study population. Apnea was defined as the cessation or the reduction of airflow of ≥90% for >10 s and hypopnea as a reduction in airflow of ≥50% for >10 s with oxygen desaturation of >3%. Respiratory effort related arousals (RERAs) were estimated by flattening of the inspiratory airflow profile associated with an arousal when airflow changes did not meet apnea or hypopnea criteria. Apnea–hypopnea index (AHI), desaturation index (DI), arousal index (AI), and saturation of blood with oxygen were recorded. Respiratory disturbance index (RDI) was defined as the total number of apneas, hypopneas, and RERAs per hour of sleep.¹⁵

Categorical variables were expressed as numbers and pro-portions (%), continuous variables as means, standard deviation, or median, interquartile range, and minimal and maximal values. To determine the relationships between lipoprotein measurements and the baseline characteristics of the study population, Pearson or Spearman correlation coefficients were used. Stepwise multiple linear logistic regression analysis was used to identify the factors contributing to the levels of particular lipoprotein. P values < .05 were considered as statistically significant. SPSS version 18 (SPSS Inc., Chicago, IL, USA) was used for the statistical analyses.

Results

Our study population consisted of 29 females (32.2%) and 61 males (67.8%) with acute ischemic stroke with mean age of 63.1±12.9 years and mean NIHSS of 4.5±2.5. Hypercholesterolemia was present in 47 patients (52.2%) and hypertriglyceridemia in 18 patients (20%). Out of 90 study subjects, 45 (50%) suffered SDB. Characteristics of the study population are included in Table 1. Association of lipoprotein levels with baseline characteristics of the study population is included in Table 2. We found significant positive correlation of TC levels with AHI (r = 0.240, P = .02). AHI (β = 0.240, P = .02) was the only independent variable significantly associated with TC levels in linear multiple regression analysis. Significant positive correlation was found between HDL cholesterol levels and female sex (r = 0.291, P = .005) and significant inverse correlation between minimal saturation of blood and oxygen (r = -0.239, P = .02). Female sex (β = 0.291, P = .005) was the only independent variable significantly associated with HDL cholesterol levels in linear multiple regression analysis. We found significant positive correlation of LDL cholesterol levels with AHI (r = 0.220, P = .04). AHI (β = 0.220, P = .04) was the only independent variable significantly associated with LDL cholesterol levels in linear multiple regression analysis. We found significant positive correlation of TG levels with BMI (r = 0.253, P = .02), diastolic blood pressure (r = 0.220, P = .04), and smoking (r = 0.237, P = .03) as well as significant inverse correlation with age (r = -0.256, P = .02). Smoking (β = 0.259, P = .01) and BMI (β = 0.237, P = .02) were the only independent variables significantly associated with TG levels in linear multiple regression analysis. We found significant positive correlation of cholesterol ratio with diastolic blood pressure (r = 0.208, P = .049), AHI (r = 0.262, P = .01), and AI (r = 0.214, P = .04). The only independent variables, that were significantly associated with cholesterol ratio in linear multiple regression analysis, were AHI (β = 0.258, P = .01) and diastolic blood pressure (β = 0.204, P = .047).

Discussion

In concordance with previous studies, our results suggest high prevalence of dyslipidemia and SDB in acute ischemic stroke.^{3-5, 7} We found SDB in 50%, hypercholesterolemia in 52.2%, and hypertriglyceridemia in 20% of the patients with acute cerebral ischemia. According to the results of linear regression analysis, AHI was the only independent variable significantly associated with the levels of LDL and TC. Similarly, we found significant association of AHI and diastolic blood pressure with cholesterol ratio, a useful and simple index of vascular risk.¹⁴ In linear regression analysis, there was no significant association of sleep apnea indices with HDL and TG. To the best of our knowledge, this study is the first one exploring the association between lipoprotein levels and SDB measurements in patients with acute ischemic stroke.

Table 1.

Baseline characteristics of the study population

N	90
Age (years)	63.1±12.9
Female sex/male sex	29 (32.2%)/61 (67.8%)
NIHSS	4.5±2.5
Arterial hypertension	73 (81.1%)
Systolic blood pressure (mm Hg)	155.2±24.0
Diastolic blood pressure (mm Hg)	84.9±12.7
Nicotine abuse	25 (27.8%)
Total cholesterol (mmol/l)	5.1±1.2
Hypercholesterolemia (total cholesterol > 5mmol/l)	47 (52.2%)
LDL cholesterol (mmol/l)	3.6±1.1
HDL cholesterol (mmol/l)	1.2±0.3
Triglycerides (mmol/l)	1.5±1.3
Hypertriglyceridemia (TAG > 1.7 mmol/l)	18 (20%)
Cholesterol ratio (total cholesterol/HDL)	4.4±1.1
AHI (n/h)	11.4, 14.2 (0–79.3)
RDI (n/h)	11.9, 18.4 (0.2–84.3)
DI (n/h)	5.7, 13.8 (0–98.4)
Minimal sat (%)	86.8±5.9
Average sat (%)	92.0±6.0
Sleep-disordered breathing (AHI ≥ 5)	45 (50%)
Arousal index (n/h)	10.0, 13.3 (0.9–38.4)

Notes: HDL, high-density lipoprotein; LDL, low-density lipoprotein; NIHSS, National Institutes of Health Stroke Scale; BP, blood pressure; AHI, apnea–hypopnea index; RDI, respiratory disturbance index; DI, desaturation index; sat, saturation of blood with oxygen. Categorical variable expressed as numbers and proportions (%), continuous variables as means ± standard deviation or median, interquartile range, and minimal and maximal values.

Table 2.

Association of lipoprotein levels with baseline characteristics of the study population

	Total cholesterol		HDL cholesterol		LDL cholesterol		Triglycerides		Cholesterol ratio
	r	P	R	P	r	P	R	P	r	P
Age	-0.174	.95	0.169	.11	-0.067	.53	-0.256	.02*	-0.187	.08
	0.174	.10	0.291	.005**	0.119	.27	0.014	.89	-0.086	.42
BMI	-0.088	.41	-0.038	.72	-0.166	.12	0.253	.02*	-0.016	.88
Waist diameter	-0.130	.23	0.005	.96	-0.166	.13	0.008	.94	-0.165	.13
Neck diameter	0.085	.43	0.001	.99	0.031	.78	0.173	.11	0.067	.54
NIHSS	0.133	.21	0.191	.07	0.107	.32	0.077	.47	-0.032	.76
Hypertension	-0.056	.60	0.068	.52	-0.136	.21	0.003	.98	-0.164	.12
Systolic BP	0.160	.13	0.179	.09	0.084	.44	0.110	.30	0.046	.67
Diastolic BP	0.079	.46	-0.084	.43	0.081	.46	0.220	.04*	0.208	.05*
Smoking	0.012	.91	-0.102	.34	-0.045	.68	0.237	.03*	0.074	.49
AHI	0.240	.02*	-0.015	.89	0.220	.04*	0.134	.21	0.262	.01*
RDI	0.160	.13	-0.031	.77	0.109	.33	0.089	.41	0.201	.06
		.09	0.032	.76	0.116	.28	0.151	.16	0.169	.11
Minimal sat	-0.168	.11	-0.239	.02*	-0.090	.41	-0.035	.74	0.073	.49
Average sat	-0.202	.06	-0.109	.31	-0.107	.32	-0.126	.24	-0.066	.54
Arousal index	0.198	.02	-0.055	.61	0.178	.10	-0.051	.64	0.214	.04*

Notes. HDL, high-density lipoprotein; LDL, low-density lipoprotein; BMI, body mass index; NIHSS, National Institutes of Health Stroke Scale; BP, blood pressure; AHI, apnea–hypopnea index; RDI, respiratory disturbance index; DI, desaturation index; sat, saturation of blood with oxygen.

*P value below .05. **P value below .01.

Chronic intermittent hypoxia belongs to the key mechanisms underlying sleep apnea. Despite the increasing evidence suggesting the independent association of chronic intermittent hypoxia with dyslipidemia, a clear causal relationship between SDB and dyslipidemia is still unknown. Intermittent hypoxia probably leads to the generation of stearoyl-coenzyme A desaturase-1 and reactive oxygen species, peroxidation of lipids, and sympathetic system dysfunction. These mechanisms could possibly link SDB with the development of dyslipidemia.⁹ Although a recent meta-analysis reported an increase in levels of dyslipidemia in subjects with SDB, including TC, LDL, HDL, and TG; the current clinical evidence supporting links between SDB and dyslipidemia is sparse.⁸ In our study, AHI was an independent variable significantly associated with TC, LDL levels, and cholesterol ratio that is consistent with previous findings.

On the other hand, the relationship between lipids and stroke is complex and many other mechanisms in addition to SDB may contribute to the development of dyslipidemia in acute ischemic stroke settings.^{12, 16} Excessive alcohol intake and uncontrolled diabetes mellitus are the most common secondary conditions plausibly contributing to dyslipidemia.¹² Such patients were not included in our analysis. In this study, female sex was the only independent variable significantly associated with HDL cholesterol levels in linear multiple regression analysis. This finding is in concordance with previous epidemiological studies, and women, especially in Westernized societies, are well known to have higher HDL levels than men.¹⁷ We found that smoking and BMI were the only independent variables significantly associated with TG levels in linear multiple regression analysis. This finding was also supported by other authors; smoking is linked to significantly higher serum concentrations of TC, TG, very low density lipoprotein cholesterol, LDL cholesterol, and lower serum concentrations of HDL cholesterol. This association is dose dependent and may provide evidence for a causal relationship.¹⁸ The role of obesity in pathogenesis of dyslipidemia in a population of SDB patients is controversial. However, the association of abdominal obesity with TG and low HDL levels was published.¹⁹ Some of the authors did not find any independent association of SDB with lipid abnormalities, and suggested that dyslipidemia may be linked to obesity and not to SDB per se.²⁰ The possibility of interplay between hypertension and dyslipidemia is unclear. The relationship between the blood pressure and elevated lipid levels has been noted in some studies.^{21, 22} AHI and diastolic blood pressure were the only independent variables significantly associated with cholesterol ratio in linear multiple regression analysis.

Abnormal TC/HDL ratio was the most common variety of dyslipidemia in uncomplicated hypertension in a study of 3182 uncomplicated nondiabetic patients.²³

Our results, in concordance with previous findings, suggest that sleep apnea may belong to promising therapeutic targets to influence hyperlipidemia in acute cerebral ischemia patients. Dyslipidemia may belong to the mechanisms of atherosclerosis in patients with SDB.²⁴ A meta-analysis of randomized controlled trials concluded that continuous positive airways pressure (CPAP) therapy decreases the TC level, especially in SDB patients who were younger, more obese, and who used CPAP for a longer period. However, no effect of CPAP on TG, LDL, or HDL levels was found, so the authors supposed that CPAP may have no clinical importance on lipid metabolism.²⁵

We must admit several limitations of our study. Except of a small sample size and absence of the CPAP therapy, only a standard serum lipid profile was assessed in our patients. More detailed search for lipoprotein subfractions, especially in the patients with stroke, could be beneficial.^26-28 Lipid profiles assessed in our study do not reflect the presence of atherogenic or nonatherogenic lipoprotein profile. Nonatherogenic lipoprotein profile is characterized by higher concentrations of LDL1–2, large HDL, intermediate HDL, and minimal concentrations of LDL3–7 subfractions.^29-32 Atherogenic lipoprotein profile is conversely characterized by increased concentrations of very low density lipoprotein, intermediate density lipoprotein 1–3, small HDL, and mainly high levels of small dense LDL (LDL3–7) subfractions.^33-35 These analyses require future research.

Conclusions

Our results suggest significant association of SDB measurements with TC, LDL, and cholesterol ratio in the patients with acute ischemic stroke. SDB may represent a potential therapeutic target to improve dyslipidemia in acute ischemic stroke. Future prospective large-scale long-term randomized clinical trials are needed to elucidate potential links between SDB and dyslipidemia. Impact of CPAP therapy on improvement of dyslipidemia and recurrence of adverse vascular events must be also further explored.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This work was supported by the Framework Programme for Research and Technology Development, Project: Building of Centre of Excellency for Sudden Cerebral Vascular Events, Comenius University Faculty of Medicine in Bratislava (ITMS:26240120023), cofinanced by European Regional Development Fund. Funding was used to cover the conference fees and publishing costs associated with presentation of this manuscript. The funding body had no role in the design of the study, in collection, analysis, and interpretation of data or in the writing of the manuscript.

Acknowledgements

Authors would like to thank all participants of the study, the staff of the sleep laboratory and stroke unit of the First Department of Neurology, Comenius University, Bratislava.

ORCID iD

Pavel Šiarnik

References

Kwiterovich

PO Jr.

Lipoprotein heterogeneity: diagnostic and therapeutic implications. Am J Cardiol . 2002;90:1–10.

Kernan

Ovbiagele

Black

. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke . 2014;45:2160–2236.

Vemmos

Takis

Georgilis

. The Athens stroke registry: results of a five-year hospital-based study. Cerebrovasc Dis . 2000;10:133–141.

Marti-Vilalta

Arboix

. The Barcelona Stroke Registry. Eur Neurol . 1999;41:135–142.

Moulin

Tatu

Crepin-Leblond

Rumbach

. The Besancon Stroke Registry: an acute stroke registry of 2,500 consecutive patients. Eur Neurol . 1997;38:10–20.

Yaggi

Concato

Kernan

Mohsenin

. Obstructive sleep apnea as a risk factor for stroke and death. N Eng J Med . 2005;353:2034–2041.

Johnson

. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med . 2010;6:131.

Nadeem

Singh

Nida

. Effect of obstructive sleep apnea hypopnea syndrome on lipid profile: a meta-regression analysis. J Clin Sleep Med . 2014;10:475–489.

Adedayo

Olafiranye

Smith

. Obstructive sleep apnea and dyslipidemia: evidence and underlying mechanism. Sleep Breath . 2014;18:13–18.

10.

Drager

Jun

Polotsky

. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes . 2010;17:161–165.

11.

Brott

Adams

Jr, Olinger

. Measurements of acute cerebral infarction: a clinical examination scale. Stroke . 1989;20:864–870.

12.

Vodnala

Rubenfire

Brook

. Secondary causes of dyslipidemia. Am J Cardiol . 2012;110:823–825.

13.

Ozol

Turkay

Kasapoglu

Karamanlı

Yıldırım

. Relationship between components of metabolic syndrome and polysomnographic findings in obstructive sleep apnea. Metab Syndr Relat Disord . 2011;9:13–18.

14.

Lemieux

Lamarche

Couillard

. Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec cardiovascular study. Arch Intern Med . 2001;161:2685–2692.

15.

Iber

CAIS

Chesson

Quan

. The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification . Westchester, IL: American Academy of Sleep Medicine; 2007.

16.

Yaghi

Elkind

. Lipids and cerebrovascular disease: research and practice. Stroke . 2015;46:3322–3328.

17.

National Heart Lung and Blood Institute Lipid Metabolism-Atherogenesis Branch. The Lipid Research Clinics Population Studies Data Book: Volume 1. The Prevalence Study . Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 1980.

18.

Craig

Palomaki

Haddow

. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. BMJ . 1989;298:784–788.

19.

Despres

Moorjani

Tremblay

. Relation of high plasma triglyceride levels associated with obesity and regional adipose tissue distribution to plasma lipoprotein-lipid composition in premenopausal women. Clin Invest Med . 1989;12:374–380.

20.

Sharma

Kumpawat

Goel

Chaturvedi

.. Obesity, and not obstructive sleep apnea, is responsible for metabolic abnormalities in a cohort with sleep-disordered breathing. Sleep Med . 2007;8:12–17.

21.

Selby

Friedman

Quesenberry

CP Jr

. Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol . 1990;131:1017–1027.

22.

Criqui

Cowan

Heiss

Chambless

.. Frequency and clustering of nonlipid coronary risk factors in dyslipoproteinemia. The lipid research clinics program prevalence study. Circulation . 1986;73:I40-I50.

23.

Thakur

Achari

. A study of lipid levels in uncomplicated hypertension. Indian Heart J . 2000;52:173–177.

24.

Borgel

Sanner

Bittlinsky

. Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels. Eur Respir J . 2006;27:121–127.

25.

Guan

Yin

. Effect of continuous positive airway pressure on lipid profile in patients with obstructive sleep apnea syndrome: a meta-analysis of randomized controlled trials. Atherosclerosis . 2014;234:446–453.

26.

Dukat

Oravec

Gavornik

Wawruch

Sabaka

. Size of lowdensity lipoprotein particles in patients after stroke. Pol Arch Med Wewn . 2012;122:30–31.

27.

Oravec

Krivosikova

Krivosik

. Lipoprotein profile in patients who survive a stroke. Neuro Endocrinol Lett . 2011;32:496–501.

28.

Siarnik

Carnicka

Krivosikova

. Association of lipoprotein subfractions with endothelial function and arterial stiffness in acute ischemic stroke. Scand J Clin Lab Invest . 2017;77:36–39.

29.

Oravec

Gruber

Dostal

Mikl

. Hyper-betalipoproteinemia LDL 1,2: a newly identified nonatherogenic hypercholesterolemia in a group of hypercholesterolemic subjects. Neuro Endocrinol Lett . 2011;32:322–327.

30.

Oravec

Dostal

Dukat

Govarnik

. HDL subfractions analysis: a new laboratory diagnostic assay for patients with cardiovascular diseases and dyslipoproteinemia. Neuro Endocrinol Lett . 2011;32:502–509.

31.

Oravec

Dukat

Gavornik

Caprdna

Kucera

. Serum lipoprotein profile in newly recognized arterial hypertension: the role of atherogenic lipoproteins in the pathogenesis of disease. Vnitr Lek . 2010;56:967–971.

32.

Oravec

Dukat

Gavornik

Caprdna

Kucera

. Contribution of the atherogenic lipoprotein profile to the development of arterial hypertension. Bratisl Lek Listy . 2011;112:4–7.

33.

Berneis

Krauss

. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res . 2002;43:1363–1379.

34.

Packard

. Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochem Soc Trans 2003; 31: 1066-1069.

35.

Asztalos

Cupples

Demissie

. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Arterioscler Thromb Vasc Biol . 2004;24:2181–2187.