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Therapy with noninvasive ventilation in patients with obstructive sleep apnoea: Effects on atherogenic lipoprotein phenotype
Medical Hypotheses 73 (2009) 441–444
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Therapy with noninvasive ventilation in patients with obstructive sleep apnoea: Effects on atherogenic lipoprotein phenotype Ruzena Tkacova a,*, Manfredi Rizzo b, Kaspar Berneis c a
Department of Respiratory Medicine and Tuberculosis, Faculty of Medicine, P.J. Safarik University and L. Pasteur Teaching Hospital, Rastislavova 43, Kosice 041 90, Slovakia Department of Internal Medicine and Emerging Diseases, University of Palermo, Italy c Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Switzerland b
a r t i c l e
i n f o
Article history: Received 20 March 2009 Accepted 22 March 2009
s u m m a r y Patients with obstructive sleep apnoea are at increased risk of atherosclerotic morbidity and mortality. Abnormalities in lipid metabolism that occur in response to chronic intermittent hypoxia in patients with sleep-disordered breathing may increase the cardiovascular risk in an already susceptible population. Atherogenic lipoprotein phenotype and small, dense LDL have an independent predictive role for future cardio- and cerebro-vascular events in patients with the metabolic syndrome. Therefore, testing the hypothesis that therapy of obstructive sleep apnoea may reduce atherogenic lipoprotein phenotype might have significant clinical implications. We suggest that abolition of obstructive sleep apnoea by continuous positive airway pressure results in reductions in circulatory levels of small, dense LDL by improvements in oxygen saturation, reductions in oxidative stress, improvements in insulin sensitivity, and reductions in triglyceride biosynthesis. Testing the proposed hypothesis may contribute to improvements in clinical management of patients with obstructive sleep apnoea by early recognition of atherogenic dyslipidaemia followed by both, vigorous treatment of the underlying sleep-disordered breathing by noninvasive ventilation and targeted therapeutic modulation of hypertriglyceridaemia, low HDL-cholesterol and increased levels of small, dense LDL. Implementing this strategy to patients with obstructive sleep apnoea may potentially contribute to substantial reduction of their high cardiovascular risk. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Obstructive sleep apnoea (OSA), a prevalent medical condition in developed countries, is emerging as a major cardiovascular risk factor. In the community, among predominantly white men and women with mean BMI of 25–28 kg m 2, approximately one in every five adults has at least mild OSA, and one in every 15 has at least moderate OSA [1]. Acutely, repetitive apnoeas and hypopnoeas during sleep result in systemic hypoxaemia, and trigger surges in sympathetic nervous system activity, blood pressure and heart rate. Chronically, patients with OSA are at increased risk of atherosclerotic morbidity and mortality [2] resulting from high risk of arterial hypertension [3], metabolic syndrome [4], systemic inflammation and oxidative stress [5]. Early signs of atherosclerosis have been observed already in patients with OSA free of overt cardiovascular diseases [6]. Until now, no studies addressed the role of atherogenic lipoprotein phenotype (ALP) and low-density lipoproteins size and subclasses in accelerated atherosclerosis due to OSA. Since obes-
* Corresponding author. Tel./fax: +421 55 615 2664. E-mail addresses: [email protected], [email protected] (R. Tkacova). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.03.031
ity with/without the metabolic syndrome is present in the majority of patients with OSA, causal relationships between OSA and metabolic abnormalities is difficult to establish. Obesity per se increases the risk of elevations in total cholesterol in association with increases in low-density lipoprotein (LDL) cholesterol levels [7]. Therefore, the current lack of information on the relationship between OSA and ALP may reflect the methodological difficulties resulting from the confounding effects of underlying obesity. Nevertheless, epidemiological studies suggest that OSA may contribute to hypercholesterolemia independently of obesity [8,9]. Therefore, abnormalities in lipid metabolism that occur in response to chronic intermittent hypoxia (CIH) in OSA may increase the cardiovascular risk in an already susceptible population. In turn, therapy using noninvasive ventilation by continuous positive airway pressure (CPAP) may reduce oxidative stress [10–13], improve insulin sensitivity [14–17] and reduce total serum cholesterol and triglyceride levels [14,18,19]. Since small, dense LDL have an independent predictive role for future cardio- and cerebro-vascular events [20], testing the hypotheses on the independent link between OSA and ALP, and on the potential of CPAP therapy in reducing the cardiovascular risk by decreasing levels of small, dense LDL may have significant clinical implications.
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R. Tkacova et al. / Medical Hypotheses 73 (2009) 441–444
Hypothesis OSA is characterized by repeated episodes of upper airway occlusion during sleep that are associated with hypoxia (Fig. 1). In patients with severe OSA, such episodes occur with a frequency of >30 apnoeas and hypopnoeas per hour of sleep (AHI, apnoea– hypopnoea index); in very severe cases the frequency of apnoeic episodes may reach 60–90 episodes per hour. By definition, apnoeas and hypopnoeas last longer than 10 s, and their typical duration is 20–40 s. Each apnoea is associated with oxygen desaturation and periodic dips in transcutaneous PO2 to values as low as 30–40% is seen in some patients. Consequently, in patients with severe OSA, the cumulative overnight load of CIH may be very high. For example, during 6 hours of sleep, a patient with an AHI of 60 events per hour, mean duration of respiratory events of 20 s and mean lowest SaO2 of 60% experiences 120 min of significant hypoxaemia every night. Consequently, apnoea-related multiple cycles of hypoxia/reoxygenation have profound physiologic consequences, and represent a potent stimulus of reactive oxygen species formation and systemic oxidative stress in these patients [5]. In turn, abolition of OSA by CPAP results in substantial improvements in oxygen saturation thus markedly reducing the overall load of nocturnal CIH (Fig. 1) [21]. Several lines of evidence link CIH and oxidative stress to lipid metabolism impairment. Exposure of human macrophages to hypoxia causes accumulation of triglyceride containing cytosolic lipid droplets [22] that is attributable to increased triglyceride biosynthesis, and reduced b-oxidation of fatty acids. In animal models of CIH, hypoxic stimulus results in increases in fasting serum total cholesterol, phospholipids and triglyceride levels, in association with increases in liver triglycerides content [23–25]. In addition, epidemiological data from large cohorts of patients with OSA indicate a relationship between the severity of OSA and total serum cholesterol and triglyceride levels [8], and between the severity of oxygen desaturation and insulin resistance [26]. Importantly, we have recently shown that effective treatment of OSA with CPAP results in reductions in total serum cholesterol levels and markers of oxidative stress [14]. Hypertriglyceridaemia and insulin resistance, two central metabolic features of OSA were associated with ALP and elevated small, dense LDL in populations of patients other than OSA [20,27,28]. Taken together, we hypothesize that CIH due to repetitive apnoeas in OSA may represent an independent mechanism contributing to the formation of ALP (Fig. 2), and that effective therapy for OSA using noninvasive ven-
Obstructive sleep apnoea
Chronic intermittent hypoxia
Oxidative stress
Insulin resistance
Hypertriglyceridaemia Hypercholesterolemia
Atherogenic lipoprotein phenotype Small, dense LDL Fig. 2. Putative mechanisms that likely contribute to the formation of atherogenic lipoprotein phenotype in patients with obstructive sleep apnoea.
tilation may improve ALP and reduce the levels of small, dense LDL (Fig. 3). Discussion Pathogenetic link between chronic intermittent hypoxia and lipid metabolism disturbances in animal models Besides the experimental evidence that CIH induces insulin resistance in lean mice [29], several experimental studies indicate that CIH results also in dyslipidaemia and changes in liver lipid content [23–25]. In lean mice, exposure to CIH led to increases in fasting serum triglyceride, HDL-cholesterol, and phospholipid levels, in association with increases in liver triglyceride content [23,24]. In obese mice, CIH caused a 30% increase in triglyceride and phospholipid liver content [25]. Several mechanisms of CIH-induced hypertriglyceridemia and hypercholesterolemia were analysed in subsequent studies. In lean mice, CIH increased liver mRNA expression and protein levels of SREBP-1, the key transcription factor of lipid biosynthesis in liver, and of steraoyl-coenzyme A desaturase 1 (SCD-1), an important gene of triglyceride and phospholipids biosynthesis controlled by SREBP-1. CIH also reduced protein levels of the HDL receptor SR-B1, which is a regulator of cholesterol uptake by the liver [23]. Moreover, in genetically obese ob/ob mice, upregulation of triglyceride and phospholipid biosynthesis resulting from upregulation of mitochondrial glycerol-3-phosphate acyltransferase was
Fig. 1. Polysomnographic recording from a patient with obstructive sleep apnoea before and during therapy with continuous positive airway pressure (CPAP). Abbreviations: EEG, electroencephalography; SpO2, transcutaneous oxygen saturation.
R. Tkacova et al. / Medical Hypotheses 73 (2009) 441–444
Therapy of OSA with noninvasive ventilation
Apnoea-hypopnoea index
Oxygen saturation
Oxidative stress
Insulin sensitivity
Triglycerides LDL - cholesterol
Atherogenic lipoprotein phenotype Small, dense LDL Fig. 3. Potential beneficial effects of obstructive sleep apnoea treatment with continuous positive airway pressure (CPAP) that may result in reductions in small, dense LDL and in reductions in cardiovascular risk.
observed [25]. Importantly, the degree of hyperlipidaemia and changes in hepatic SCD-1 levels are critically dependent on the severity of CIH [24]. In obese mice, exposure to CIH increased circulatory cholesterol [30]. Taken together, experimental data suggest that the stimulus of CIH that characterizes OSA may contribute to profound impairment in lipid metabolism and to the development of both hypercholesterolemia and hypertriglyceridaemia. Oxidative stress and its reversal by CPAP therapy Retention, oxidation, and accumulation of oxidized LDL are an early phenomenon in the process of atherogenesis [31]. Therefore, hypercholesterolemia in patients with OSA may be particularly detrimental as a consequence of increased lipid peroxidation [32]. Indeed, CIH is a potent stimulus of LDL oxidation, and may represent one of the key mechanisms of CIH-induced atherosclerosis [33]. Multiple studies confirmed the presence of increased levels of oxidative stress markers in the circulation [10,13], vascular endothelium [11], and exhaled breath [12] in patients with OSA. Importantly, the degree of oxidative stress was related to the severity of sleep-disordered breathing and the concurrent nocturnal hypoxaemia [13]. Conversely, effective therapy with CPAP over one night significantly reduced the circulatory levels of oxidative stress, and this reduction was maintained at least after two months of therapy [13]. In agreement, increases in plasma levels of total antioxidant status were observed after one year of therapy with CPAP in another study [10]. Glucose and lipid metabolism impairment in OSA and its reversal by CPAP therapy Several independent epidemiological studies reported increased risk of insulin resistance and/or metabolic syndrome in patients with sleep-disordered breathing [26,33]. Ip et al. [26] have shown that each additional apnoea and hypopnoea per hour of sleep increases fasting plasma insulin and insulin resistance by 0.5%, and this effect is independent of obesity. Moreover, a cause–effect relationship between hypoxia and glucose intolerance has been shown by studies in healthy subjects [34]. In turn, abolition of obstructive apnoeas and hypopnoeas by effective treatment of OSA with CPAP may improve insulin sensitivity in patients compliant with CPAP [14–17]. Besides the influence on glucose metabolism, sleep-disordered breathing adversely affects other cardiovascular risk factors such as lipid metabolism. In the large cross-sectional epidemiological
443
study (Sleep Heart Health Study) in which 6440 primary healthy subjects were screened for sleep apnoea, a significant correlation of the AHI and the total serum cholesterol levels in males and with the HDL-cholesterol and triglyceride levels in females was observed [8]. Importantly, HDL from subjects with OSA has impaired ability to prevent the oxidation of LDL, and the severity of OSA is the most important determinant of the degree of HDL dysfunction [32]. Observational studies suggest that therapy with CPAP results in significant reductions in total cholesterol in patients with OSA and concurrent metabolic syndrome [14,18,19]. Nevertheless, up to date no randomized trials data are available on the effects of long-term abolishment of OSA by noninvasive ventilation on serum lipids. Triglyceridaemia seems to be the main determinant of LDL subclass distribution. In fact, the formation of small, dense LDL particles is mostly observed in presence of a hypertriglyceridaemic state, with an increased exchange of triglycerides from triglyceride-rich lipoproteins to LDL and HDL particles in exchange of cholesteryl esters through the action of cholesteryl ester transfer protein [35]. This phenomenon leads to the generation of lipoproteins that are good substrates for hepatic lipase that regulates total plasma LDL concentrations as well as the production of smaller, more dense LDL from larger, more buoyant precursors [36]. As a consequence of that, predictive value of small dense LDL is usually reduced when triglyceride levels are taken into account. For example, in a recently published analysis from the EPIC-Norfolk prospective population study, predictive power for cardiovascular events of LDL particle number and size was lost after adjustment for HDL cholesterol and triglyceride levels [37]. We have recently shown that hypertriglyceridaemia and insulin resistance are strongly associated with small, dense LDL in different categories of subjects, including those with polycystic ovary syndrome [27], metabolic syndrome [20] and peripheral artery disease [28]. Subjects with a predominance of small dense LDL have a greater than two fold increased risk for developing type-2 diabetes independent of age, sex, glucose tolerance and body mass index and it has been calculated that an increase in LDL size may be associated with a 16% decrease in the risk of developing diabetes [38]. Subjects with the insulin resistance syndrome have an elevated prevalence of small, dense LDL [39] and this has been confirmed for diabetics, in both men and women [40,41]. In addition, using a euglycemic clamp technique to categorise individuals as insulin-sensitive, insulin-resistant, or type 2 diabetic, more severe states of insulin resistance were associated with smaller LDL size [42]. Testing the hypothesis Treatment of OSA by CPAP leading to the abolishment of apnoeas and hypopnoeas during sleep in association with improvements in oxygen saturation might result in alleviation of ALP and reductions in the levels of small, dense LDL. Two main approaches are in sight to test this hypothesis. First, observational cohort studies in well defined large groups of patients with OSA and various degree of nocturnal oxygen desaturation may add important insights on the effects of CPAP on ALP in such patients. Second, randomized controlled trials with CPAP may provide the strongest evidence of the potential to reverse ALP and reduce small, dense LDL by alleviation of obstructive apnoeas and chronic nocturnal hypoxaemia. Conclusions The recognition of excessively high cardiovascular morbidity and mortality in patients with OSA has alerted respiratory and cardiovascular researchers over the last decade. Major public health
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and economic burden of cardiovascular comorbidities in OSA patients fuels the oil into the research in this field, with the ultimate goal to minimize negative cardiovascular consequences of sleepdisordered breathing. Strategies to decrease the high prevalence and associated cardiovascular morbidity of OSA are critically needed [1]. Since ALP and small, dense LDL represent an independent factor of increased cardiovascular risk, testing the proposed hypothesis may have significant clinical implications. If indeed, careful examination of the hypothesis reveals an independent role of OSA-related CIH in the formation of ALP, and confirms that abolition of OSA by CPAP results in reductions of small, dense LDL then researchers and clinicians should be prompted to optimize diagnostic and therapeutic interventions in this high-risk group of patients. Bearing in mind that therapeutic modulation of ALP is probably one of the most effective methods of reducing cardiovascular risk [43], testing the proposed hypothesis might reduce high cardiovascular morbidity and mortality in patients with OSA. Acknowledgements Supported by Slovak Research and Development Agency under the Contract No. APVV-0122-06, Slovakia, and operating Grant VEGA 1/0348/09 of the Ministry of Education, Slovakia. References [1] Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. A population health perspective. Am J Respir Crit Care Med 2002;165:1217–39. [2] Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnea–hypopnea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. [3] Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. New Engl J Med 2000;342:1378–84. [4] Coughlin SR, Mawdsley L, Mugarza JA, et al. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007;29:720–7. [5] Lavie L. Oxidative stress – a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis 2009;51:303–12. [6] Drager LF, Bortolotto LA, Lorenzi MC, et al. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:613–8. [7] Third report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Final report. Circulation 2002;106:3143–421. [8] Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the sleep heart health study. Am J Epidemiol 2001;154:50–9. [9] Robinson GV, Pepperell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnea: data from randomized controlled trials. Thorax 2004;59:777–82. [10] Barcelo A, Barbe F, de la Pena M, et al. Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. Eur Respir J 2006;27:756–60. [11] Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 2008;117:2270–8. [12] Petrosyan M, Perraki E, Simoes D, et al. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath 2008;12:207–15. [13] Christou K, Kostikas K, Pastaka C, Tanou K, Antoniadou I, Gourgoulianis KI. Nasal continuous positive airway pressure treatment reduces systemic oxidative stress in patients with severe obstructive sleep apnea syndrome. Sleep Med 2009;10:87–94. [14] Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134:686–92. [15] Harsch IA, Schahin SP, Radespiel-Troger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169: 156–62. [16] Schahin SP, Nechanitzky T, Dittel C, et al. Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome. Med Sci Monit 2008;14:CR117–21.
[17] Dawson A, Abel SL, Loving RT, et al. CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep. J Clin Sleep Med 2008;4:538–42. [18] Borgel J, Sanner BM, Bittlinsky A, et al. Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels. Eur Respir J 2006;27:121–7. [19] Steiropoulos P, Tsara V, Nena E, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea–hypopnea syndrome. Chest 2007;132:843–51. [20] Rizzo M, Pernice V, Frasheri A, et al. Small, dense low-density lipoproteins (LDL) are predictors of cardio- and cerebro-vascular events in subjects with the metabolic syndrome. Clin Endocrinol 2008. doi:10.1111/j.13652265.2008.03407. [21] Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998;98:2269–75. [22] Bonstrom P, Magnusson B, Svensson PA, et al. Hypoxia converts human macrophages into triglyceride-loaded foam cells. Arterioscler Thromb Vasc Biol 2006;26:1871–6. [23] Li JL, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005;97:698–706. [24] Li J, Savransky V, Nanayakkara A, Smith PL, O’Donnell CP, Polotsky VY. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 2007;102:557–63. [25] Li J, Grigoryev DN, Ye SQ, et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol 2005;99:1643–8. [26] Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002;165:670–6. [27] Berneis K, Rizzo M, Lazzaroni V, Fruzzetti F, Carmina E. Atherogenic lipoprotein phenotype and low-density lipoproteins size and subclasses in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2007;92:186–9. [28] Rizzo M, Pernice V, Frasheri A, Berneis K. Atherogenic lipoprotein phenotype and LDL size and subclasses in patients with peripheral arterial disease. Atherosclerosis 2008;197:237–41. [29] Iiyori N, Alonso LC, Li J, et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007;175:851–7. [30] Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 2002;277:9520–8. [31] Skalen K, Gustafsson M, Rydberg EK, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 2002;417:750–4. [32] Tan KCB, Chow WS, Lam JCM, et al. HDL dysfunction in obstructive sleep apnea. Atherosclerosis 2006;184:377–82. [33] Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE. Sleepdisordered breathing, glucose intolerance, and insulin resistance. The sleep heart health study. Am J Epidemiol 2004;160:521–30. [34] Oltmanns KM, Gehring H, Rudolf S, et al. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 2004;169:1231–7. [35] Guerin M, Le Goff W, Lassel TS, Van Tol A, Steiner G, Chapman MJ. Atherogenic role of elevated CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes: impact of the degree of triglyceridemia. Arterioscler Thromb Vasc Biol 2001;21:282–8. [36] Rizzo M, Taylor JM, Barbagallo CM, Berneis K, Blanche PJ, Krauss RM. Effects on lipoprotein subclasses of combined expression of human hepatic lipase and human apoB in transgenic rabbits. Arterioscler Thromb Vasc Biol 2004;24: 141–6. [37] El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. J Am Coll Cardiol 2007;49:547–53. [38] Austin MA, Mykkanen L, Kuusisto J, et al. Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women. Circulation 1995;92:1770–8. [39] Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest 1993;92:141–6. [40] Selby JV, Austin MA, Newman B, et al. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 1993;88:381–7. [41] Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:1496–502. [42] Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453–62. [43] Nesto RW. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. Am J Cardiovasc Drug 2005;5:379–87.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Therapy with noninvasive ventilation in patients with obstructive sleep apnoea: Effects on atherogenic lipoprotein phenotype Ruzena Tkacova a,*, Manfredi Rizzo b, Kaspar Berneis c a
Department of Respiratory Medicine and Tuberculosis, Faculty of Medicine, P.J. Safarik University and L. Pasteur Teaching Hospital, Rastislavova 43, Kosice 041 90, Slovakia Department of Internal Medicine and Emerging Diseases, University of Palermo, Italy c Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Switzerland b
a r t i c l e
i n f o
Article history: Received 20 March 2009 Accepted 22 March 2009
s u m m a r y Patients with obstructive sleep apnoea are at increased risk of atherosclerotic morbidity and mortality. Abnormalities in lipid metabolism that occur in response to chronic intermittent hypoxia in patients with sleep-disordered breathing may increase the cardiovascular risk in an already susceptible population. Atherogenic lipoprotein phenotype and small, dense LDL have an independent predictive role for future cardio- and cerebro-vascular events in patients with the metabolic syndrome. Therefore, testing the hypothesis that therapy of obstructive sleep apnoea may reduce atherogenic lipoprotein phenotype might have significant clinical implications. We suggest that abolition of obstructive sleep apnoea by continuous positive airway pressure results in reductions in circulatory levels of small, dense LDL by improvements in oxygen saturation, reductions in oxidative stress, improvements in insulin sensitivity, and reductions in triglyceride biosynthesis. Testing the proposed hypothesis may contribute to improvements in clinical management of patients with obstructive sleep apnoea by early recognition of atherogenic dyslipidaemia followed by both, vigorous treatment of the underlying sleep-disordered breathing by noninvasive ventilation and targeted therapeutic modulation of hypertriglyceridaemia, low HDL-cholesterol and increased levels of small, dense LDL. Implementing this strategy to patients with obstructive sleep apnoea may potentially contribute to substantial reduction of their high cardiovascular risk. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Obstructive sleep apnoea (OSA), a prevalent medical condition in developed countries, is emerging as a major cardiovascular risk factor. In the community, among predominantly white men and women with mean BMI of 25–28 kg m 2, approximately one in every five adults has at least mild OSA, and one in every 15 has at least moderate OSA [1]. Acutely, repetitive apnoeas and hypopnoeas during sleep result in systemic hypoxaemia, and trigger surges in sympathetic nervous system activity, blood pressure and heart rate. Chronically, patients with OSA are at increased risk of atherosclerotic morbidity and mortality [2] resulting from high risk of arterial hypertension [3], metabolic syndrome [4], systemic inflammation and oxidative stress [5]. Early signs of atherosclerosis have been observed already in patients with OSA free of overt cardiovascular diseases [6]. Until now, no studies addressed the role of atherogenic lipoprotein phenotype (ALP) and low-density lipoproteins size and subclasses in accelerated atherosclerosis due to OSA. Since obes-
* Corresponding author. Tel./fax: +421 55 615 2664. E-mail addresses: [email protected], [email protected] (R. Tkacova). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.03.031
ity with/without the metabolic syndrome is present in the majority of patients with OSA, causal relationships between OSA and metabolic abnormalities is difficult to establish. Obesity per se increases the risk of elevations in total cholesterol in association with increases in low-density lipoprotein (LDL) cholesterol levels [7]. Therefore, the current lack of information on the relationship between OSA and ALP may reflect the methodological difficulties resulting from the confounding effects of underlying obesity. Nevertheless, epidemiological studies suggest that OSA may contribute to hypercholesterolemia independently of obesity [8,9]. Therefore, abnormalities in lipid metabolism that occur in response to chronic intermittent hypoxia (CIH) in OSA may increase the cardiovascular risk in an already susceptible population. In turn, therapy using noninvasive ventilation by continuous positive airway pressure (CPAP) may reduce oxidative stress [10–13], improve insulin sensitivity [14–17] and reduce total serum cholesterol and triglyceride levels [14,18,19]. Since small, dense LDL have an independent predictive role for future cardio- and cerebro-vascular events [20], testing the hypotheses on the independent link between OSA and ALP, and on the potential of CPAP therapy in reducing the cardiovascular risk by decreasing levels of small, dense LDL may have significant clinical implications.
442
R. Tkacova et al. / Medical Hypotheses 73 (2009) 441–444
Hypothesis OSA is characterized by repeated episodes of upper airway occlusion during sleep that are associated with hypoxia (Fig. 1). In patients with severe OSA, such episodes occur with a frequency of >30 apnoeas and hypopnoeas per hour of sleep (AHI, apnoea– hypopnoea index); in very severe cases the frequency of apnoeic episodes may reach 60–90 episodes per hour. By definition, apnoeas and hypopnoeas last longer than 10 s, and their typical duration is 20–40 s. Each apnoea is associated with oxygen desaturation and periodic dips in transcutaneous PO2 to values as low as 30–40% is seen in some patients. Consequently, in patients with severe OSA, the cumulative overnight load of CIH may be very high. For example, during 6 hours of sleep, a patient with an AHI of 60 events per hour, mean duration of respiratory events of 20 s and mean lowest SaO2 of 60% experiences 120 min of significant hypoxaemia every night. Consequently, apnoea-related multiple cycles of hypoxia/reoxygenation have profound physiologic consequences, and represent a potent stimulus of reactive oxygen species formation and systemic oxidative stress in these patients [5]. In turn, abolition of OSA by CPAP results in substantial improvements in oxygen saturation thus markedly reducing the overall load of nocturnal CIH (Fig. 1) [21]. Several lines of evidence link CIH and oxidative stress to lipid metabolism impairment. Exposure of human macrophages to hypoxia causes accumulation of triglyceride containing cytosolic lipid droplets [22] that is attributable to increased triglyceride biosynthesis, and reduced b-oxidation of fatty acids. In animal models of CIH, hypoxic stimulus results in increases in fasting serum total cholesterol, phospholipids and triglyceride levels, in association with increases in liver triglycerides content [23–25]. In addition, epidemiological data from large cohorts of patients with OSA indicate a relationship between the severity of OSA and total serum cholesterol and triglyceride levels [8], and between the severity of oxygen desaturation and insulin resistance [26]. Importantly, we have recently shown that effective treatment of OSA with CPAP results in reductions in total serum cholesterol levels and markers of oxidative stress [14]. Hypertriglyceridaemia and insulin resistance, two central metabolic features of OSA were associated with ALP and elevated small, dense LDL in populations of patients other than OSA [20,27,28]. Taken together, we hypothesize that CIH due to repetitive apnoeas in OSA may represent an independent mechanism contributing to the formation of ALP (Fig. 2), and that effective therapy for OSA using noninvasive ven-
Obstructive sleep apnoea
Chronic intermittent hypoxia
Oxidative stress
Insulin resistance
Hypertriglyceridaemia Hypercholesterolemia
Atherogenic lipoprotein phenotype Small, dense LDL Fig. 2. Putative mechanisms that likely contribute to the formation of atherogenic lipoprotein phenotype in patients with obstructive sleep apnoea.
tilation may improve ALP and reduce the levels of small, dense LDL (Fig. 3). Discussion Pathogenetic link between chronic intermittent hypoxia and lipid metabolism disturbances in animal models Besides the experimental evidence that CIH induces insulin resistance in lean mice [29], several experimental studies indicate that CIH results also in dyslipidaemia and changes in liver lipid content [23–25]. In lean mice, exposure to CIH led to increases in fasting serum triglyceride, HDL-cholesterol, and phospholipid levels, in association with increases in liver triglyceride content [23,24]. In obese mice, CIH caused a 30% increase in triglyceride and phospholipid liver content [25]. Several mechanisms of CIH-induced hypertriglyceridemia and hypercholesterolemia were analysed in subsequent studies. In lean mice, CIH increased liver mRNA expression and protein levels of SREBP-1, the key transcription factor of lipid biosynthesis in liver, and of steraoyl-coenzyme A desaturase 1 (SCD-1), an important gene of triglyceride and phospholipids biosynthesis controlled by SREBP-1. CIH also reduced protein levels of the HDL receptor SR-B1, which is a regulator of cholesterol uptake by the liver [23]. Moreover, in genetically obese ob/ob mice, upregulation of triglyceride and phospholipid biosynthesis resulting from upregulation of mitochondrial glycerol-3-phosphate acyltransferase was
Fig. 1. Polysomnographic recording from a patient with obstructive sleep apnoea before and during therapy with continuous positive airway pressure (CPAP). Abbreviations: EEG, electroencephalography; SpO2, transcutaneous oxygen saturation.
R. Tkacova et al. / Medical Hypotheses 73 (2009) 441–444
Therapy of OSA with noninvasive ventilation
Apnoea-hypopnoea index
Oxygen saturation
Oxidative stress
Insulin sensitivity
Triglycerides LDL - cholesterol
Atherogenic lipoprotein phenotype Small, dense LDL Fig. 3. Potential beneficial effects of obstructive sleep apnoea treatment with continuous positive airway pressure (CPAP) that may result in reductions in small, dense LDL and in reductions in cardiovascular risk.
observed [25]. Importantly, the degree of hyperlipidaemia and changes in hepatic SCD-1 levels are critically dependent on the severity of CIH [24]. In obese mice, exposure to CIH increased circulatory cholesterol [30]. Taken together, experimental data suggest that the stimulus of CIH that characterizes OSA may contribute to profound impairment in lipid metabolism and to the development of both hypercholesterolemia and hypertriglyceridaemia. Oxidative stress and its reversal by CPAP therapy Retention, oxidation, and accumulation of oxidized LDL are an early phenomenon in the process of atherogenesis [31]. Therefore, hypercholesterolemia in patients with OSA may be particularly detrimental as a consequence of increased lipid peroxidation [32]. Indeed, CIH is a potent stimulus of LDL oxidation, and may represent one of the key mechanisms of CIH-induced atherosclerosis [33]. Multiple studies confirmed the presence of increased levels of oxidative stress markers in the circulation [10,13], vascular endothelium [11], and exhaled breath [12] in patients with OSA. Importantly, the degree of oxidative stress was related to the severity of sleep-disordered breathing and the concurrent nocturnal hypoxaemia [13]. Conversely, effective therapy with CPAP over one night significantly reduced the circulatory levels of oxidative stress, and this reduction was maintained at least after two months of therapy [13]. In agreement, increases in plasma levels of total antioxidant status were observed after one year of therapy with CPAP in another study [10]. Glucose and lipid metabolism impairment in OSA and its reversal by CPAP therapy Several independent epidemiological studies reported increased risk of insulin resistance and/or metabolic syndrome in patients with sleep-disordered breathing [26,33]. Ip et al. [26] have shown that each additional apnoea and hypopnoea per hour of sleep increases fasting plasma insulin and insulin resistance by 0.5%, and this effect is independent of obesity. Moreover, a cause–effect relationship between hypoxia and glucose intolerance has been shown by studies in healthy subjects [34]. In turn, abolition of obstructive apnoeas and hypopnoeas by effective treatment of OSA with CPAP may improve insulin sensitivity in patients compliant with CPAP [14–17]. Besides the influence on glucose metabolism, sleep-disordered breathing adversely affects other cardiovascular risk factors such as lipid metabolism. In the large cross-sectional epidemiological
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study (Sleep Heart Health Study) in which 6440 primary healthy subjects were screened for sleep apnoea, a significant correlation of the AHI and the total serum cholesterol levels in males and with the HDL-cholesterol and triglyceride levels in females was observed [8]. Importantly, HDL from subjects with OSA has impaired ability to prevent the oxidation of LDL, and the severity of OSA is the most important determinant of the degree of HDL dysfunction [32]. Observational studies suggest that therapy with CPAP results in significant reductions in total cholesterol in patients with OSA and concurrent metabolic syndrome [14,18,19]. Nevertheless, up to date no randomized trials data are available on the effects of long-term abolishment of OSA by noninvasive ventilation on serum lipids. Triglyceridaemia seems to be the main determinant of LDL subclass distribution. In fact, the formation of small, dense LDL particles is mostly observed in presence of a hypertriglyceridaemic state, with an increased exchange of triglycerides from triglyceride-rich lipoproteins to LDL and HDL particles in exchange of cholesteryl esters through the action of cholesteryl ester transfer protein [35]. This phenomenon leads to the generation of lipoproteins that are good substrates for hepatic lipase that regulates total plasma LDL concentrations as well as the production of smaller, more dense LDL from larger, more buoyant precursors [36]. As a consequence of that, predictive value of small dense LDL is usually reduced when triglyceride levels are taken into account. For example, in a recently published analysis from the EPIC-Norfolk prospective population study, predictive power for cardiovascular events of LDL particle number and size was lost after adjustment for HDL cholesterol and triglyceride levels [37]. We have recently shown that hypertriglyceridaemia and insulin resistance are strongly associated with small, dense LDL in different categories of subjects, including those with polycystic ovary syndrome [27], metabolic syndrome [20] and peripheral artery disease [28]. Subjects with a predominance of small dense LDL have a greater than two fold increased risk for developing type-2 diabetes independent of age, sex, glucose tolerance and body mass index and it has been calculated that an increase in LDL size may be associated with a 16% decrease in the risk of developing diabetes [38]. Subjects with the insulin resistance syndrome have an elevated prevalence of small, dense LDL [39] and this has been confirmed for diabetics, in both men and women [40,41]. In addition, using a euglycemic clamp technique to categorise individuals as insulin-sensitive, insulin-resistant, or type 2 diabetic, more severe states of insulin resistance were associated with smaller LDL size [42]. Testing the hypothesis Treatment of OSA by CPAP leading to the abolishment of apnoeas and hypopnoeas during sleep in association with improvements in oxygen saturation might result in alleviation of ALP and reductions in the levels of small, dense LDL. Two main approaches are in sight to test this hypothesis. First, observational cohort studies in well defined large groups of patients with OSA and various degree of nocturnal oxygen desaturation may add important insights on the effects of CPAP on ALP in such patients. Second, randomized controlled trials with CPAP may provide the strongest evidence of the potential to reverse ALP and reduce small, dense LDL by alleviation of obstructive apnoeas and chronic nocturnal hypoxaemia. Conclusions The recognition of excessively high cardiovascular morbidity and mortality in patients with OSA has alerted respiratory and cardiovascular researchers over the last decade. Major public health
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and economic burden of cardiovascular comorbidities in OSA patients fuels the oil into the research in this field, with the ultimate goal to minimize negative cardiovascular consequences of sleepdisordered breathing. Strategies to decrease the high prevalence and associated cardiovascular morbidity of OSA are critically needed [1]. Since ALP and small, dense LDL represent an independent factor of increased cardiovascular risk, testing the proposed hypothesis may have significant clinical implications. If indeed, careful examination of the hypothesis reveals an independent role of OSA-related CIH in the formation of ALP, and confirms that abolition of OSA by CPAP results in reductions of small, dense LDL then researchers and clinicians should be prompted to optimize diagnostic and therapeutic interventions in this high-risk group of patients. Bearing in mind that therapeutic modulation of ALP is probably one of the most effective methods of reducing cardiovascular risk [43], testing the proposed hypothesis might reduce high cardiovascular morbidity and mortality in patients with OSA. Acknowledgements Supported by Slovak Research and Development Agency under the Contract No. APVV-0122-06, Slovakia, and operating Grant VEGA 1/0348/09 of the Ministry of Education, Slovakia. References [1] Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. A population health perspective. Am J Respir Crit Care Med 2002;165:1217–39. [2] Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnea–hypopnea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046–53. [3] Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. New Engl J Med 2000;342:1378–84. [4] Coughlin SR, Mawdsley L, Mugarza JA, et al. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007;29:720–7. [5] Lavie L. Oxidative stress – a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis 2009;51:303–12. [6] Drager LF, Bortolotto LA, Lorenzi MC, et al. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:613–8. [7] Third report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Final report. Circulation 2002;106:3143–421. [8] Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the sleep heart health study. Am J Epidemiol 2001;154:50–9. [9] Robinson GV, Pepperell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep apnea: data from randomized controlled trials. Thorax 2004;59:777–82. [10] Barcelo A, Barbe F, de la Pena M, et al. Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment. Eur Respir J 2006;27:756–60. [11] Jelic S, Padeletti M, Kawut SM, et al. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 2008;117:2270–8. [12] Petrosyan M, Perraki E, Simoes D, et al. Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath 2008;12:207–15. [13] Christou K, Kostikas K, Pastaka C, Tanou K, Antoniadou I, Gourgoulianis KI. Nasal continuous positive airway pressure treatment reduces systemic oxidative stress in patients with severe obstructive sleep apnea syndrome. Sleep Med 2009;10:87–94. [14] Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134:686–92. [15] Harsch IA, Schahin SP, Radespiel-Troger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169: 156–62. [16] Schahin SP, Nechanitzky T, Dittel C, et al. Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome. Med Sci Monit 2008;14:CR117–21.
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