Lena Lavie

Interindividual Heterogeneity in the Hypoxic Regulation of VEGF Significance for the Development of the Coronary Artery Collateral Circulation

BACKGROUND The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF). METHODS AND RESULTS We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9+/-0.2 versus 3.2+/-0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals. CONCLUSIONS This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.

All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age

The objective of this study was to assess whether an increasing severity of sleep apnoea is associated with increased all-cause mortality hazards and to assess whether the syndrome is associated with excess mortality, in comparison with the general population. Participants included 14,589 adult males, aged 20–93 yrs, referred to the sleep clinics with suspected sleep apnoea or diagnosed with sleep apnoea. Altogether, 372 deaths were recorded after a median follow-up of 4.6 yrs. The crude all-cause mortality rate was 5.55/1,000 patient yrs, increasing with apnoea severity. Cox proportional analysis revealed that both respiratory disturbance index (RDI) and body mass index significantly influenced all-cause mortality hazard but there was no interaction between them. Males with respiratory disturbance index >30 had a significantly higher mortality hazard rate than the reference group of males with RDI ≤10. Comparing mortality rates of males with moderate/severe sleep apnoea to the general population revealed that only males aged <50 yrs showed an excess mortality rate. The hazard of mortality in sleep apnoea increases with apnoea severity as indexed by respiratory disturbance index. Moderate and severe levels of sleep apnoea are moderately associated with an increased risk of all-cause mortality, in comparison with the general population, particularly in males aged <50 yrs. The lack of information about possible confounders and treatment effects should be taken into consideration in the interpretation of these results.

Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is a highly prevalent breathing disorder in sleep that is an independent risk factor for cardiovascular morbidity and mortality. A large body of evidence, including clinical studies and cell culture and animal models utilising intermittent hypoxia, delineates the central role of oxidative stress in OSAHS as well as in conditions and comorbidities that aggregate with it. Intermittent hypoxia, the hallmark of OSAHS, is implicated in promoting the formation of reactive oxygen species (ROS) and inducing oxidative stress. The ramifications of increased ROS formation are pivotal. ROS can damage biomolecules, alter cellular functions and function as signalling molecules in physiological as well as in pathophysiological conditions. Consequently, they promote inflammation, endothelial dysfunction and cardiovascular morbidity. Oxidative stress is also a crucial component in obesity, sympathetic activation and metabolic disorders such as hypertension, dyslipidaemia and type 2 diabetes/insulin resistance, which aggregate with OSAHS. These conditions and comorbidities could result directly from the oxidative stress that is characteristic of OSAHS or could develop independently. Hence, oxidative stress represents the common underlying link in OSAHS and the conditions and comorbidities that aggregate with it.

Risk Factors for Cardiovascular Disease in Women with Subclinical Hypothyroidism

Overt hypothyroidism may result in accelerated atherosclerosis and coronary heart disease (CHD) presumably because of the associated hypertension, hypercholesterolemia, and hyperhomocysteinemia. As many as 10%-15% of older women have subclinical hypothyroidism (SH) and thyroid autoimmunity. Whether SH is associated with risk for CHD is controversial. We examined 57 women with SH and 34 healthy controls. SH was defined as an elevated thyrotropin (TSH) (>4.5 mU/L) and normal free thyroxine (FT(4)) level (8.7-22.6 nmol/L). None of the patients had been previously treated with thyroxine. In all participants we determined blood pressure, body mass index (BMI), and fasting TSH, FT(4), antibodies to thyroid peroxidase and thyroglobulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, folic acid, vitamin B(12), creatinine, and total plasma homocysteine levels. The SH and control groups did not differ in their total homocysteine values. Mean diastolic blood pressure was increased in SH patients versus controls (82 vs. 75 mm Hg; p < 0.01). Mean values of TC, HDL-C, LDL-C, triglycerides, TC/HDL-C, and LDL-C/HDL-C were not different in patients with SH compared with controls. Individual analysis revealed that the percentage of patients with SH having hypertension (20%), hypertriglyceridemia (26.9%), elevated TC/HDL-C (11.5%), and LDL-C/HDL-C (4%) ratios were higher than the percentages in controls. Hyperhomocysteinemia (> or = 10.98 micromol/L) was observed in 29.4% of SH and was not significantly different from the percentage in controls (21.4%). No significant correlation between TSH and biochemical parameters was detected. We conclude that subclinical hypothyroidism in middle-aged women is associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio. This may increase the risk of accelerated atherosclerosis and premature coronary artery disease in some patients.

Oxidative Stress—A Unifying Paradigm in Obstructive Sleep Apnea and Comorbidities

Obstructive sleep apnea (OSA), a highly prevalent breathing disorder in sleep, characterized by intermittent and recurrent pauses in respiration, has emerged as an independent risk factor for cardiovascular morbidity and mortality. Accumulated evidence implicates the apnea-related multiple cycles of hypoxia/reoxygenation in promoting the formation of reactive oxygen species and inducing oxidative stress. The ramifications of oxidative stress are pivotal; they can cause damage to biomolecules, and alter cellular functions, but they also function as signaling molecules in physiologic and pathophysiologic conditions. Oxidative stress alters signaling pathways and activates inflammatory/immune responses via increased interactions of blood cells with endothelial cells, facilitating endothelial cell injury and dysfunction. Such events can promote atherosclerosis and the development of cardiovascular morbidities in OSA. Oxidative stress is also a crucial component of obesity and metabolic disorders such as dyslipidemia and type 2 diabetes mellitus/insulin resistance, which cluster with OSA and involve inflammatory pathways as well. These converging lines of evidence point at oxidative stress as the unifying paradigm underlying the cardiovascular morbidity in OSA and very likely also in promoting the metabolic disorders associated. If left untreated, this cascade of events may eventually lead to overt cardiovascular morbidity.

The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function.

BACKGROUND Obstructive sleep apnea (OSA) is associated with endothelial dysfunction. In the current study, we assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF). METHODS A total of 16 subjects participated (11 men and 5 women; mean [+/- SD] age, 54.0 +/- 8.3 years; mean body mass index, 28.0 +/- 3.1 kg/m(2)), 12 of whom completed the 1-year evaluation. Apnea severity, levels of oxidative stress markers, and EF were assessed after 3 months and 1 year of receiving treatment. For comparison, 6 untreated patients underwent two evaluations 9 months apart, and 10 non-OSA individuals were assessed once as a reference group. The results are presented as the mean +/- SD. RESULTS The mean apnea-hypopnea index (AHI) decreased significantly from 29.7 +/- 18.5 events/h before treatment to 17.7 +/- 11.1 events/h after 3 months of treatment and 19.6 +/- 11.5 events/h after 1 year of treatment (p < 0.005 for both). The mean Epworth sleepiness scale score decreased significantly from 12.4 +/- 6.0 before treatment to 10.2 +/- 6.6 after 3 months of treatment and 7.8 +/- 3.8 after 1 year of treatment (p < 0.001 for both). The mean EF improved significantly from 1.77 +/- 0.4 before treatment to 2.1 +/- 0.4 after 3 months of treatment (p < 0.05) and 2.0 +/- 0.3 after 1 year of treatment (p = 0.055), which were similar to the values of the reference group. Thiobarbituric acid-reactive substance (TBARS) levels decreased from 18.8 +/- 6.2 nmol malondialdehyde (MDA)/mL before treatment to 15.8 +/- 3.9 MDA/mL after 3 months of treatment (p = 0.09) and 15.5 +/- 3.2 nmol MDA/mL after 1 year of treatment (p < 0.05). There was a correlation between the improvement in AHI and in EF or TBARS levels (r = 0.55; p = 0.05). The untreated control group remained unchanged. CONCLUSIONS The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. We think that these data are encouraging and that they justify the performance of larger randomized controlled studies.

Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea.

Abstract: Obstructive sleep apnea (OSA), a breathing disorder in sleep characterized by intermittent hypoxia and sleep fragmentation, constitutes an independent risk factor for cardiovascular morbidity. Investigating how this breathing disorder modulates immune responses may facilitate understanding one of the risk factors for atherosclerosis. T cells play a significant role in atherogenesis and plaque development via cytokine production and by directly contributing to vascular injury. Using flow cytometry and chromium release assays, we found that CD4 and CD8 T cells of OSA patients undergo phenotypic and functional changes and acquire cytotoxic capabilities. Thus, a shift in CD4 and CD8 T cells toward type 2 cytokine dominance with increased IL‐4 expression was noted. IL‐10 expression in T cells was negatively correlated with the severity of OSA, as determined by the apnea‐hypopnea index (AHI), whereas TNF‐α was positively correlated. CD8 T cells of OSA patients expressed a fourfold increase in TNF‐α and CD40 ligand (CD40L), and exhibited an increased OSA severity‐dependent cytotoxicity against endothelial cells. The percentage of CD4+CD28null and cytotoxicity of CD4 T lymphocytes were also significantly higher in OSA patients than in controls. Nasal continuous positive airway pressure (nCPAP) treatment, which ameliorated the severity of OSA, significantly lowered TNF‐α and CD40L expression, and decreased cytotoxicity in CD8 T cells. In conclusion, increased cytotoxicity and cytokine imbalance in CD4 and CD8 T cells may be involved in atherogenesis in OSA. Nasal CPAP treatment ameliorates some lymphocyte dysfunctions and thus may moderate some atherogenic pathways.

Obstructive sleep apnoea syndrome

Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te

Unexpected survival advantage in elderly people with moderate sleep apnoea

Sleep‐disordered breathing is much more prevalent in elderly people than in middle‐aged or young populations, but its clinical significance in this age group is unclear. This study investigated retrospectively the rates of all‐cause mortality in elderly people (≥ 65 years) with a laboratory diagnosis of sleep apnoea, and compared their rates of mortality with that of age‐, gender‐ and ethnicity‐matched national mortality data. Survival of 611 elderly people was ascertained after a follow‐up of 5.17 ± 1.13 years. Their age was 70.4 ± 4.8 years, body mass index 30.4 ± 5.9 kg m−2 and respiratory disturbance index (RDI) 28.9 ± 20.1 events h−1. Seventy‐five (12.27%) patients died during the follow‐up period. In comparison with the demographically matched cohort from the general population, the standardized mortality rate of the sleep laboratory cohort was 0.67 [95% confidence interval (CI): 0.53–0.88; χ2 = 11.69, P < 0.0006]. When calculated separately for patients with RDI < 20 (no/mild apnoea), RDI 20–40 (moderate apnoea) and RDI > 40 events h−1 (severe apnoea) there was a significant survival advantage for the moderate group with a standardized mortality rate of 0.42 (P < 0.0002), while elderly people with no/mild apnoea tended to have lower mortality and those with severe sleep apnoea had the same mortality as the matched population cohorts. Cox regression analysis revealed that sleep latency and comorbidities but not sleep apnoea severity were associated independently with mortality. The survival advantage of elderly people with moderate sleep apnoea, combined with recent findings on the potential cardioprotective effects of chronic intermittent hypoxia, raise the possibility that apnoeas during sleep may activate adaptive pathways in the elderly.

Diabetes Mellitus Prevalence and Control in Sleep-Disordered Breathing: The European Sleep Apnea Cohort (ESADA) Study

BACKGROUND OSA is associated with an increased risk of cardiovascular morbidity. A driver of this is metabolic dysfunction and in particular type 2 diabetes mellitus (T2DM). Prior studies identifying a link between OSA and T2DM have excluded subjects with undiagnosed T2DM, and there is a lack of population-level data on the interaction between OSA and glycemic control among patients with diabetes. We assessed the relationship between OSA severity and T2DM prevalence and control in a large multinational population. METHODS We performed a cross-sectional analysis of 6,616 participants in the European Sleep Apnea Cohort (ESADA) study, using multivariate regression analysis to assess T2DM prevalence according to OSA severity, as measured by the oxyhemoglobin desaturation index. Patients with diabetes were identified by previous history and medication prescription, and by screening for undiagnosed diabetes with glycosylated hemoglobin (HbA1c) measurement. The relationship of OSA severity with glycemic control was assessed in diabetic subjects. RESULTS T2DM prevalence increased with OSA severity, from 6.6% in subjects without OSA to 28.9% in those with severe OSA. Despite adjustment for obesity and other confounding factors, in comparison with subjects free of OSA, patients with mild, moderate, or severe disease had an OR (95% CI) of 1.33 (1.04-1.72), 1.73 (1.33-2.25), and 1.87 (1.45-2.42) (P < .001), respectively, for prevalent T2DM. Diabetic subjects with more severe OSA had worse glycemic control, with adjusted mean HbA1c levels 0.72% higher in patients with severe OSA than in those without sleep-disordered breathing (analysis of covariance, P < .001). CONCLUSIONS Increasing OSA severity is associated with increased likelihood of concomitant T2DM and worse diabetic control in patients with T2DM.