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AHMED ELMASRY MD AIN SHAMS UNIVERSITY PHD UPPSALA UNIVERSITY.

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Presentation on theme: "AHMED ELMASRY MD AIN SHAMS UNIVERSITY PHD UPPSALA UNIVERSITY."— Presentation transcript:

1 AHMED ELMASRY MD AIN SHAMS UNIVERSITY PHD UPPSALA UNIVERSITY

2 CARDIOVASCULAR MORBIDITY AND MORTALITY OBESITY INSULIN RESISTANCE OBESITY (CENTRAL OBESITY) INSULIN RESISTANCE HYPERTENSIONDIABETESDYSLIPIDEMIA SYMPATHO-ADRENAL HYPERACTIVITY COUNTER-REGULATORY MECHANISMS SLEEP DISORDERED BREATHING HYPOXIA HYPOXIA - HYPERCAPNIA AROUSALS AROUSALS ( RERA, HHIA, AIA ) AHMED ELMASRY MODEL 2000

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28 OSAS - INFLAMMATION Despite the early recognition of the strong association between OSA and obesity, and OSA and cardiovascular problems, sleep apnoea has been treated as a "local abnormality" of the respiratory track rather than as a "systemic illness". In 1997, it was the first report that the pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor- alpha (TNF-alpha) were elevated in patients with disorders of EDS and proposed that these cytokines were mediators of daytime sleepiness. Arch Physiol Biochem Oct;114(4):

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30 OSAS - INFLAMMATION In subsequent studies, it was shown that IL-6, TNF-alpha, and insulin levels were elevated in sleep apnoea independently of obesity and that visceral fat was the primary parameter linked with sleep apnoea. Further studies showed that women with the polycystic ovary syndrome (PCOS) were much more likely than controls to have SDB and EDS, suggesting a pathogenetic role of insulin resistance in OSA. Arch Physiol Biochem Oct;114(4):

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34 OSAS - INFLAMMATION Additional accumulated evidence that supports the role of obesity and the associated metabolic aberrations in the pathogenesis of sleep apnoea and related symptoms include: obesity without sleep apnoea is associated with daytime sleepiness; the protective role of gonadal hormones as suggested by the increased prevalence of sleep apnoea in post- menopausal women, the significantly reduced risk for OSA in women on hormonal therapy, partial effects of CPAP in obese patients with apnoea on hypercytokinemia, insulin resistance indices, and visceral fat. Arch Physiol Biochem Oct;114(4):

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36 OSAS - INFLAMMATION Furthermore, the beneficial effect of a cytokine antagonist on EDS and apnoea in obese, male apnoeics and that of exercise and weight loss on SDB and EDS in general random or clinical samples, supports the hypothesis that cytokines and insulin resistance are mediators of EDS and sleep apnoea in humans. In conclusion, accumulating evidence provides support to hypothesis that obesity via inflammation, insulin resistance, visceral adiposity, and central neural mechanisms, e.g. hypofunctioning hypothalamus, play a major role in the pathogenesis of sleep apnoea, sleepiness, and the associated cardiovascular co-morbidities. Arch Physiol Biochem Oct;114(4):

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42 OSAS - INFLAMMATION Intermittent hypoxemia, one of the physiological markers of OSAS, is characterized by transient periods of oxygen desaturation followed by reoxygenation. The cycles of hypoxia-reoxygenation are associated with oxidative stress that, in turn, triggers the activation of pathways that lead to cardiovascular damage. Rev Invest Clin Nov-Dec;60(6):

43 OSAS - INFLAMMATION These pathways include an increased chemoreflex sensitivity that induces the over-activation of the sympathetic nervous system, decreased baroreflex sensitivity, the activation of systemic inflammation pathways mediated primarily by the nuclear transcriptional factor kappaB that favors the development of atherosclerosis through the synthesis of cytokines and the expression of adhesion molecules, endothelial dysfunction with a decreased availability of nitric oxide, dyslipidemia, insulin resistance and stimulation of the renin-angiotensin system. Rev Invest Clin Nov-Dec;60(6):

44 OSAS - INFLAMMATION Other mechanisms proposed include arousals that increase sympathetic activity and exaggerated intrathoracic pressure changes that generate high transmural pressure. Most of these mechanisms respond favorably to treatment with CPAP. A better understanding of the mechanisms of cardiovascular damage opens the possibility of instituting new treatments that will contribute to limiting the cardiovascular consequences associated with OSAS. Rev Invest Clin Nov-Dec;60(6):

45 OSAS - INFLAMMATION OSA is a highly prevalent sleep disorder leading to cardiovascular and metabolic complications. OSA is also a multicomponent disorder, with intermittent hypoxia (IH) as the main trigger for the associated cardiovascular and metabolic alterations. Indeed, recurrent pharyngeal collapses during sleep lead to repetitive sequences of hypoxia–reoxygenation. This IH induces several consequences such as hemodynamic, hormonometabolic, oxidative, and immuno-inflammatory alterations that may interact and aggravate each other, resulting in artery changes, from adaptive to degenerative atherosclerotic remodeling. Seminars in Immunopathology. June 2009, Volume 31, Issue 1, pp

46 OSAS - INFLAMMATION Atherosclerosis has been found in OSA patients free of other cardiovascular risk factors and is related to the severity of nocturnal hypoxia. Early stages of artery alteration, including functional and structural changes, have been evidenced in both OSA patients and rodents experimentally exposed to IH. Impaired vasoreactivity with endothelial dysfunction and/or increased vasoconstrictive responses due to sympathetic, endothelin, and renin–angiotensin systems have been reported and also contribute to vascular remodeling and inflammation. Seminars in Immunopathology. June 2009, Volume 31, Issue 1, pp

47 OSAS - INFLAMMATION Oxidative stress, inflammation, and vascular remodeling can be directly triggered by IH, further aggravated by the OSA-associated hormonometabolic alterations, such as insulin resistance, dyslipidemia, and adipokine imbalance. As shown in OSA patients and in the animal model, genetic susceptibility, comorbidities (obesity), and life habits (high fat diet) may aggravate atherosclerosis development or progression. Seminars in Immunopathology. June 2009, Volume 31, Issue 1, pp

48 OSAS - INFLAMMATION The intimate molecular mechanisms are still largely unknown, and their understanding may contribute to delineate new targets for prevention strategies and/or development of new treatment of OSA-related atherosclerosis, especially in patients at risk for cardiovascular disease. Seminars in Immunopathology. June 2009, Volume 31, Issue 1, pp

49 OSAS - INFLAMMATION The pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS) is not fully understood but is likely multifactorial in origin. Inflammatory processes play an important role in the pathogenesis of atherosclerosis. Circulating levels of several markers of inflammation have been associated with future cardiovascular risk. Prog Cardiovasc Dis Mar-Apr;51(5):392-9.

50 OSAS - INFLAMMATION These include : Cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and selectins Cytokines such as tumour necrosis factor alpha (TNF- alpha) and interleukin 6 (IL-6) Chemokines such as interleukin 8 (IL-8) C-reactive protein (CRP) Prog Cardiovasc Dis Mar-Apr;51(5):392-9.

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52 OSAS - INFLAMMATION There is also increasing evidence that inflammatory processes play an important role in the cardiovascular pathophysiology of OSAS Many of the inflammatory markers associated with cardiovascular risk have been reported as elevated in patients with OSAS. Prog Cardiovasc Dis Mar-Apr;51(5):392-9.

53 OSAS - INFLAMMATION Furthermore, animal and cell culture studies have demonstrated preferential activation of inflammatory pathways by intermittent hypoxia, which is an integral feature of OSAS. The precise role of inflammation in the development of cardiovascular disease in OSAS requires further study, particularly the relationship with oxidative stress, metabolic dysfunction, and obesity. Prog Cardiovasc Dis Mar-Apr;51(5):392-9.

54 OSAS - INFLAMMATION The combination of metabolic syndrome and OSA has been termed “syndrome Z.” The prevalence of both OSA and metabolic syndrome is increasing worldwide, in part linked to the epidemic of obesity. Beyond their epidemiologic relationship, growing evidence suggests that OSA may be causally related to metabolic syndrome. Metab Syndr Relat Disord. Aug 2009; 7(4): 271–277.

55 CARDIOVASCULAR MORBIDITY AND MORTALITY OBESITY INSULIN RESISTANCE OBESITY (CENTRAL OBESITY) INSULIN RESISTANCE HYPERTENSIONDIABETESDYSLIPIDEMIA SYMPATHO-ADRENAL HYPERACTIVITY COUNTER-REGULATORY MECHANISMS SLEEP DISORDERED BREATHING HYPOXIA HYPOXIA - HYPERCAPNIA AROUSALS AROUSALS ( RERA, HHIA, AIA ) AHMED ELMASRY MODEL 2000

56 OSAS - INFLAMMATION We are only beginning to understand the potential mechanisms underlying the OSA–metabolic syndrome interaction. Although there is no clear consensus, there is growing evidence that alterations in the hypothalamic– pituitary axis, generation of reactive oxygen species (ROS) due to repetitive hypoxia, inflammation, and generation of adipokines may be implicated in the changes associated with both OSA and metabolic syndrome. Metab Syndr Relat Disord. Aug 2009; 7(4): 271–277.

57 OSAS - INFLAMMATION Whether some or all of these metabolic alterations mechanistically link OSA to metabolic syndrome remains to be proven, but it is an area of intense scientific interest. Metab Syndr Relat Disord. Aug 2009; 7(4): 271–277.

58 OSAS - INFLAMMATION A number of studies have selectively examined the expression of inflammatory factors in OSAS patients with different conclusions. These different findings may have been contributed to by a number of methodological factors such as small subject numbers, inadequately matched study populations, particularly in terms of BMI, and inclusion of patients with pre-existing cardiovascular or metabolic diseases. Cardiovasc Hematol Agents Med Chem Jan;7(1):76-81.

59 OSAS - INFLAMMATION OSAS is a highly prevalent disease and associated with cardiovascular morbidity and mortality. There is emerging evidence that inflammatory processes leading to endothelial dysfunction play a pivotal role. Various studies have demonstrated elevated inflammatory markers in OSAS patients in comparison to matched control subjects with a significant fall after effective treatment with CPAP. Respir Physiol Neurobiol Sep 30;178(3):

60 OSAS - INFLAMMATION Cell culture and animal studies have significantly enhanced our understanding of the mechanisms of inflammation in OSAS. IH, the hallmark feature of OSAS, leads to a preferential activation of inflammatory pathways with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. Respir Physiol Neurobiol Sep 30;178(3):

61 OSAS - INFLAMMATION There is increasing evidence of elevated inflammatory markers in OSAS with a significant fall after effective treatment with CPAP. This evidence is particularly strong for TNF-alpha, whereas studies on IL6 and CRP have yielded conflicting results possibly due to the confounding effects of obesity. Thorax Jul;64(7):631-6

62 OSAS - INFLAMMATION Cell culture and animal studies have contributed to our understanding of the underlying mechanisms of the association between OSAS and inflammation. Intermittent hypoxia, the hallmark of OSAS, results in activation of pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein (AP). These promote activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro- inflammatory mediators that may lead to endothelial dysfunction. Thorax Jul;64(7):631-6

63 CRP – OSAS – RISK OF CVD Inflammatory processes associated with OSAS may contribute to cardiovascular morbidity in these patients. C-reactive protein (CRP) is an important serum marker of inflammation. They tested the hypothesis that patients with OSAS have increased plasma CRP. After 173 male subjects underwent polysomnography, 94 were considered to have OSAS, 38 CVD, and 56 without CVD. Seventy-nine subjects were considered not to have OSAS and from among these 57 patients without CVD were enrolled as control subjects. Int Heart J Sep;46(5):801-9.

64 CRP – OSAS – RISK OF CVD Serum CRP levels were significantly elevated in the OSAS + CVD group compared to the two other groups (P < 0.05). When they evaluated the association between the serum CRP level and severity of OSAS, CRP levels were positively correlated with AHI in OSAS patients (r = 0.61, P < 0.001) OSAS, as a marker of inflammation and cardiovascular risk, is associated with elevated levels of CRP. According to these results, the link between cardiovascular morbidity and OSAS may be explained by the coexistence of other cardiovascular risk factors such as circulating CRP levels. Int Heart J Sep;46(5):801-9.

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