REZUMAT ENGLEZA DOCTORAT APNEE

8/7/2019 REZUMAT ENGLEZA DOCTORAT APNEE

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UNIVERSITY OF MEDICINE AND PHARMACY GR. T. POPA" IAI

SUMMARY OF THE PHD THESIS

CORRELATIONS BETWEEN SLEEP APNEA SYNDROME,METABOLIC SYNDROME AND AUTONOMIC NEUROPATHY

PhD student: Lovin Sinziana

Coordinators:

Prof. Dr. Dr. George Ioan PandeleUniversity of Medicine and Pharmacy "Gr T. Popa Iai, Romania

Prof. Dr. Traian MihaescuHospital of Pneumology, Iai , RomaniaUniversity of Medicine and Pharmacy "Gr T. Popa " Iai , Romania

CONTENTS

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1. INTRODUCTION .................................................................................................................. p.3

2. THEORETICAL PART........................................................................................................... p.3

I. Sleep pathology as a cardiometabolic risk factor ........................................................p.3

II. Obstructive sleep apnea-hypopnea syndrome (OSAHS) ............................................p.4

III. Metabolic syndrome and OSAHS ..............................................................................p.5

IV. Autonomic dysfunction and

OSAHS.........................................................................p.6

3. ORIGINAL RESEARCH

I. Metabolic syndrome and its components in patients with OSAHS.............................p.7II. Body composition in patients with OSAHS .............................................................p.11

III. Clinical evidence of autonomic dysfunction in patients with OSAHS....................p.14

IV. Pulse transit time and its variations in patients with OSAHS...............................p.16

V. Heart rate variability in patients with OSAHS ........................................................p.18

4. PERSPECTIVES OPENED BY THE THESIS ...................................................................p.21

5. CONCLUSIONS ..................................................................................................................p.22

6. BIBLIOGRAPHY ................................................................................................................ p.23

7. CURRICULUM VITAE.p.25

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II. Obstructive sleep apnea-hypopnea syndrome (OSAHS) definition, classification,severity, consequences

Sleep disturbed breathing (SDB) is a group of respiratory conditions occurring duringsleep, causing daytime sleepiness and systemic complications (9, 10).

SDB can be divided into several categories : obstructive sleep apnea syndrome(OSAHS) with a related condition: upper airway resistance syndrome (UARS), central sleepapnea-hypopnea syndrome, alveolar hypoventilation syndrome and various overlap syndromes(9, 10).

Obstructive sleep apnea syndrome (OSAHS) is a condition characterized by repetitive breathing pauses exceeding 10 seconds during sleep, upper airway dynamic narrowing withrepetitive desaturations and multiple micro-arousals leading to abnormal sleep architecture,daytime somnolence and serious cardiovascular and metabolic complications.

Diagnostic and severity criteria for OSAHS (1, 9, 10):

- Subjective: Daytime somnolence or at least two of the following: nocturnal gasping / multipleawakenings / non-restorative sleep / fatigue / concentration problems and

- Objective (mandatory): > 5 obstructive events per hour of sleep on sleep study(polysomnography)

Obstructive apnea = cessation of the oro-nasal airflow 10 seconds accompanied by thoraco-abdominal respiratory effort

Obstructive hypopnea = 50% reduction in oro-nasal flow for 10 s with thoraco-abdominalrespiratory effort

OSAHS is mild if apnea-hypopnea index per hour of sleep (AHI) is between 5 and 15,moderate for an AHI between 15 and 30 and severe for an AHI over 30/hour.

The classical risk factors for OSAHS include male sex and obesity; the most suggestivenocturnal manifestations are: snoring interrupted by breathing pauses, nocturia, sweating andrestless sleep, while the most suggestive diurnal manifestations include somnolence, impairedmemory and concentration, gastro-esophageal reflux, hypertension and impaired libido (9).

The gold standard for the diagnosis of SDB, narcolepsy, central and peripheral motor disturbances in sleep is the complete supervised polysomnography with the concomitantassessment of: electroencephalogram (at least two channels), electromyogram, eye movements(electrooculogram), airflow (thermistor or cannula), thoraco-abdominal respiratory movements(piezoelectric transducers with elastic bands), microphone (snoring), pulsoximetry,electrocardiogram, video surveillance. This method is able to certify the diagnosis of obstructivesleep apnea syndrome and to analyze sleep architecture, but is costly and time consuming.Therefore, in patients with high probability for SDB, a satisfactory method is cardio-respiratory

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polygraphy , a simplified version of polysomnography, which examines the airflow, therespiratory thoraco-abdominal movements and pulsoximetry, but does not certify sleep or examine sleep stages.

Chronic increase in adrenergic tone, endothelial dysfunction, autonomic neuropathy,

hypoxia, increased levels of pro-inflammatory cytokines, pro-coagulant status and atherogenicmetabolic imbalances are the major mechanisms by which OSAHS acts as a cardiovascular risk factor. Most of the newly diagnosed OSAHS patients have hypertension, which may be

previously unknown in about half of cases. The presence of untreated OSAHS accelerates thedevelopment of atherosclerotic lesions and precipitates the emergence of acute coronary andcerebral events. OSAHS prevalence in patients with a history of stroke is 44-72% and apneic

patients have a risk for stroke 4 times higher than those without sleep apnea. OSAHS increasesthe risk for ventricular and supraventricular arrhythmias and sudden death. Atrial fibrillation hasa prevalence of 32% in patients with OSAHS and with an anatomically normal heart (11-14).

The differential diagnosis includes other sleep disturbed breathing conditions and other

causes of daytime somnolence (sleep deprivation, narcolepsy, etc.), other causes of nocturnaldyspnoea ( left ventricular failure, nocturnal asthma) and other upper airway disorders whichmimic snoring (nocturnal stridor).

The treatment aims the suppression of apneas, of desaturations and of micro-arousals inall sleep stages and the most effective method is to maintain the upper airway patency by acontinuous positive air pressure generated by the CPAP (Continuous Positive Airways Pressure)or BiPAP (Bi-level Positive Airways Pressure) devices through a nasal or facial masks. nCPAP(nasal Continuous Positive Airways Pressure) is validated for the treatment OSAHS since 1981.The therapeutic pressure is determined by manual or automatic titration (10, 15).

III. Metabolic syndrome and obstructive sleep apnea

Metabolic syndrome ( MS) is a pre-diabetic clinical condition reuniting independentmetabolic alterations that imply an increased cardiovascular risk by initiating and perpetuatingvascular degenerative inflammatory process, in which insulin resistance is the central pathogenicelement. Epidemiological studies have shown that MS is a major risk for both cardiovascular disease and diabetes. The current criteria for diagnosis of MS are those set by the InternationalDiabetes Federation in 2004. (16)

-Central obesity: waist circumference above 94 cm (M) / 80 cm (F)-With two of the following:

HDL cholesterol < 40 mg / dL (M); 150 mg / dL (1.7 mmol / l) Blood pressure > 130/85 mmHg Fasting blood glucose 100 mg / dl or previous diagnosis of diabetes or glucose

intolerance

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According to literature data, the prevalence of MS in the general adult population is between 22% and 39%. (17)

The association of visceral obesity, systemic inflammation, atherogenic dyslipidemia andhyperinsulinemia make OSAHS a systemic disease, not just a local anomaly of the upper airway

(18). Obesity is the main risk factor for OSAHS, although sleep apnea can occur in leanindividuals. In addition to the mechanical effect of excessive fat deposition, metabolic activityof the adipose tissue plays an important pathogenic role in OSAHS. Inflammatory cytokines,insulin resistance, atherogenic dyslipidemia and visceral adiposity are common features of themetabolic syndrome (MS) and of OSAHS, both conditions being associated with major cardiovascular risk factors. (19)

IV. Autonomic dysfunction and OSAHS

Autonomic neuropathy is defined by alterations of autonomic function due to damagedsympathetic or parasympathetic nerve fibers. Diabetes mellitus (DM) is the most common cause

of autonomic neuropathy. The most important clinical manifestations are the cardiovascularautonomic neuropathy (such as resting tachycardia and orthostatic hypotension) (20).

The most popular clinical tests for cardiovascular a utonomic dysfunction are the Ewing tests:

1.Heart rate response to Valsalva maneuver: forced blocked expiration in a mouth piece setat approximately 40 mm Hg for 15 seconds, followed by sharp expiration. A ratio between thelongest RR interval during the maneuver and the shortest RR interval following the maneuver (Valsalva ratio) below 1.5 is considered pathological

2. Heart rate response to deep breathing: 5 seconds inspiration and deep expiration for 1

minute. The E / I ratio (maximum RR / minimum RR) below 1.3 is pathological.

3. Heart rate response to standing: RR intervals at 15 and at 30 seconds after the suddenstanding up are reported . A 30/15 ratio below 1.5 is p athologic:

4. The postural pressure response: blood pressure (BP) is measured after 15 minutes in supine position, then immediately after standing up. A decrease of more than 30 mmHg in systolic BP:abnormal.

Power spectral analysis is based on the ECG recording for five minutes or 24 hours andanalyzed in time or frequency domain. A good correlation with the results of conventional tests

was demonstrated.In OSAHS, the respiratory pause equals a Mueller maneuver with vagal stimulation. The

Hypoxemia and hypercapnia following apneas stimulates chemoreceptors, which increasessympathetic tone, concomitantly with the arousal following apnea. The sympathetic stimulationcan be quantified in real time by electrophysiologic methods (microneurography). Thesympathetic tone remains elevated during daytime (increased levels of plasma and urinarycatecholamines). This increased sympathetic tone causes vasoconstriction and increased

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myocardial oxygen consumption. The alternative desaturation-reoxygenation cycles releaseactive oxygen species and increase levels of proinflammatory cytokines (21-23).

The clinical evidence of autonomic dysfunction in OSAHS includes erectile disturbances,hypertension, and abnormalities of clinical tests for dysautonomy (the Ewing battery). The

laboratory evidence include: high serum and urinary catecholamine levels, abnormal ABPM profile (non-dipper, inverse dipper, permanent hypertension), acute repetitive nocturnal increasesin blood pressure (invasive Finapress monitoring), changes in pulse transit time, sympatheticsurges measured by microneurography, abnormal heart rate variability at Holter ECG monitoringwith spectral analysis of the heart rate. (21-25).

ORIGINAL RESARCH

I. Metabolic syndrome and its components in patients with OSAHS

1.Aims

To calculate the prevalence of the metabolic syndrome and its components in a large group of patients with OSAHS compared to patients addressed to the same sleep laboratory in whichOSAHS is absent.

To study the correlations between the components of the metabolic syndrome and certainclinical characteristics of patients with OSAHS

To analyze the effect of treatment by CPAP on the components of metabolic syndrome andrelated conditions (sedentarism)

2.Material, methods

Type of study: prospective, observational, on a period of two years and six months.The evaluation of clinical parameters, metabolic and polygraphic / polysomnographic diagnosiswas performed at baseline, at 3 months, 6 months and 1 year.

Patients: 335 patients in whom polygraphy or polysomnography met the quality criteriafor correct interpretation were included. Medical history, Epworth sleepiness questionnaire,

physical examination, repeated blood pressure measurement, laboratory metabolic tests and physical activity were assessed. The complete re-evaluation was possible at 3 months in 321 of the patients, at 6 months in 298 of the patients and at 1 year in 274 of the patients. All the

patients signed the informed consent for enrollment.

Cardio-respiratory polygraphy was performed using a portable device(SOMNOcheck Effort, 2005, Weinmann, Germany). Video-monitored fullpolysomnography was performed using the SomnoLab Weinmann version 2.1, 2005,Germany, as previously described in the theoretical part.

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Symptomatic patients (with somnolence, snoring, or breathing pauses during sleep )with an apnea-hypopnea index (AHI) of more than 5 per hour of sleep had an indicationfor CPAP. Adherence to CPAP therapy was defined as the use of the machine for at least 4hours /night, 70% of nights.

Daily physical activity was assessed using a belt pedometer (Kasper-Richter, Germany)which was worn for one week at baseline, and during re-evaluation. Metabolic evaluationincluded clinical and paraclinical markers defining the metabolic syndrome.

Statistical data processing used SPSS 11.5 and Excel 2000. Gross descriptivestatistical parameters were calculated for all variables. Data were expressed as average, standarddeviation (SD), median, module, minimum and maximum value for numerical variables of continuous type and frequency for the categorical. For evidence of statistically significantdifferences on subgroups, the following statistical tests were used: one-way ANOVA for normally distributed continuous variables type, Wilcoxon sum-of-ranks for the variables withnon Gaussian distribution, paired/unpaired t-Students test where appropriate. Likelihood of a

particular type of response was evaluated using odds ratio (OR) with confidence intervaldefinition (CI) and comparison between frequencies with chi square test. Correlations betweendata sets were performed using Pearsons correlation coefficient.

3. Results:

The mean age in the total group of 335 patients was 52.3 11.9 years. There were 55women and 280 men in the group . 235 patients were diagnosed with OSAHS . In the remaining100 patients, obstructive or central sleep apnea syndrome were excluded.

In OSAHS group (235 patients), there were 22 women and 213 men, mean age was 53.1

8.4, mean AHI 40.6 23.9/ h, mean Epworth sleepiness score 16.2 5.1, mean BMI 33.1 5.47kg / m 2 , mean neck 44.6 2.75 cm, mean abdominal circumference 115 12.5 cm. Of the235 patients with OSAHS: 40 were diagnosed with mild OSAHS (AHI 9.15 3.16 / h; fourwomen, 36 men), 48 with modetate OSAHS (AHI 21.8 4.5/h; eight women, 40 men), 147with severe OSAHS (AHI 55.4 17.1 / h; 10 women, 137 men).

Of the 235 patients with OSAHS: 44 patients refused CPAP titration; 151 acceptedCPAP titration for 1 night, of whom: 62 refused CPAP, 129 initiated therapy (of whom 35dropped out after 2 months to 1 year), 4 were inappropriate users and 90 were compliant.Patients were allocated to two major categories according to compliance, for ease of dataanalysis: 90 compliant and 145 noncompliant to CPAP.

The comparison between clinical parameters of compliant and noncompliant patientsusing ANOVA test revealed no statistically significant differences, except for the AHI andsleepiness. Comparisons using the t-Students test and Wilcoxons test revealed that compliant

patients were: more physically inactive (p = 0.0003), older (p = 0.012), more obese (p = 0.013).There was higher percentage of women than compliant group (OR = 3.9143, (95% CI = 1.5286 -10.0236).

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Table I. Characteristics of the patients in the compliant and noncompliant groups

Compliant Noncompliant No. 90 145AHI (/ h) 49.7 24.2 34.9 21.8

Women 15 (16%) 7 (4.8%)Men 75 (84%) 138 (95.2%)Age (years) 54.9 8.6 52.1 8.1BMI (kg/m 2) 34.3 4.9 32.36 2.1Somnolence (/24) 19.1 3.55 14.36 5.1Activity

(steps/day)2485.7

1487.43628 1631.5

Of the 235 patients with OSAHS, 140 met the diagnostic criteria for the metabolicsyndrome (60%) versus 29% in the non-OSAHS group (OR = 3.608, CI = 2.1787 - 5.975).

In patients with OSAHS, neck perimeter correlated with AHI weaker than BMI (r =0.34). Abdominal perimeter correlated with AHI stronger than the neck perimeter (r = 0.62).There was a strong negative correlation between HDL and AHI (r = - 0.62). Serum triglyceridesdid not correlate significantly with AHI (r = 0.025). Blood pressure were poorly correlated withthe severity of OSAHS (r = 0.2 for SBP; 0.1 for DBP). The strongest correlation was found

between negative between physical activity (number of steps per day) and AHI (r = - 0.86).

AHI had an asymmetric distribution, with a skewness index of 0.306. Therefore,classical division of OSAHS in mild, moderate and severe according to the AHI is notappropriate to separate subgroups of patients by severity of OSAHS. Patients were assigned tosubgroups according to quartiles (parameter values dividing a group into 4 subgroups of equal

frequencies). Patients of the 4-th quartile (with the most severe OSAHS) were mode somnolentand more sedentary than those of the 1-st quartile and showed higher values of basal glucose,lower HDL levels and higher blood pressure values compared the 1-st quartile (p < 0.05 atStudents t test). There was a paradoxically lower total cholesterol level in the 4-th quartilecompared to the 1-st quartile (p < 0.05 at Students t test).

At 3 months, physical activity group of 235 patients with OSAHS increased by 55%,29%somnolence, abdominal perimeter decreased by 2.6%, BMI by 2.9%, total cholesteroldecreased by 9%, HDL increased by 21%, LDL decreased by 6.8%, blood glucose decreased by8%, systolic blood pressure decreased by 5% and diastolic fell 2.3%. All differences betweenthe valuation at 3 months and baseline were statistically significant (p less than 0.05). The

differences were much lower at 6 months and 1 year.

The group of 90 compliant patient, physical activity increased by 72% at 3 months,somnolence decreased by 54%, BMI decreased by 5%, abdominal perimeter decreased by 5.5%,total cholesterol decreased by 10%, HDL increased by 40%, LDL decreased by 11.5%, serumglucose decreased by 16%, systolic blood pressure decreased by 7% and diastolic pressure by3% (p < 0.05 at Students paired t test). At 6 months at 1 year, these benefits have maintained,without further significant changes.

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The group of 145 noncompliant patients, physical activity increased by 6%, somnolencedecreased by 13%, abdominal perimeter of decreased by 0.6%, BMI decreased by 1,4 %,cholesterol decreased by 8%, HDL increased by 9%, triglycerides decreased by 9%, LDLdecreased by 4%, glucose decreased by 3,6%, systolic blood pressure decreased by 5.7% anddiastolic pressure by 2.45%.

For comparison of from baseline 3 months between compliant and noncompliant groupon CPAP, we used Students paired t test, which revealed significant differences for all changesin parameters, except for the change diastolic blood pressure and in total cholesterol.

Fig. 1. Percentage of differences in parameters at 3 months versus baseline in compliantand in noncompliant groups

4. Discussions

There is remarkable proportion of patients with severe OSAHS (63%), whichmatches the data in the literature (26). According to literature data, the prevalence of MS in adultgeneral population is estimated between 22 and 39% (16, 17). In the studied patients, MS is

present in 60% of the patients with OSAHS.

The patients in the control group cannot be considered "healthy" because they werereferred to the sleep laboratory for specific symptoms (snoring, nocturnal dyspnoea, drowsiness,etc).

Although there is clear evidence for CPAP with respect to the benefits on daytimealertness, metabolism and blood pressure control, adherence to CPAP effect on weight loss andincreased physical activity remain controversial: some studies report no increase in physicalactivity or body weight, while other studies report weight gain under CPAP. (19, 27)

The novelty of this study is the high percentage of weight loss in CPAP compliant patients (5.5%), much higher than ever reported. Noncompliant patients lost 1.4% of their weight, which can be explained by the complete medical care of these patients, regardless of

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their compliance to CPAP. There is an unexpected discrepancy between the 1.4% weight lossand the much lower decrease in abdominal circumference (0.6%) in the noncompliant group,which may suggest that these patients did not lose visceral fat in the same proportion as thecompliant patients. The dramatic decrease of sleepiness in compliant patients may explain their 72% increase in daily activity, which may have promoted weight loss, in addition to other

molecular mechanisms improved by the correct treatment of OSAHS, which were not analyzedin this study.

5. Conclusions

-The prevalence of the metabolic syndrome in patients diagnosed with OSAHS is 60%, similar to that reported in the literature and higher than in non-OSAHS patients.

-All the components of the metabolic syndrome and certain related conditions (sedentarism)treatment improved under specific treatment by CPAP more evidently than in patients withOSAHS and non-compliance to treatment under the same pharmacological and educational

intervention.

II. Body composition in patients with OSAHS

1. Aim of the study:

To analyze the link between the body composition compartments, the traditional markersof general and cervical obesity and the severity of OSAHS expressed by AHI.

2. Material, methods:

We have selected 31 patients with OSAHS (21 men, 9 women, mean age 45.1 years)who have all underwent complete overnight supervised video-polysomnography includingelectroencephalogram (2 channels), electrocardiogram (1 channel), electrooculogram, chin andleg electromyogram, nasal flow, thoracic and abdominal movements, snoring, body position,

pulse-oxymetry, and audio-video recording (SomnoLab-version 5, Weinmann, Germany). Thecriteria for the diagnosis of OSAHS were an apnea-hypopnea index (AHI) above 5 per hour of sleep, associated with self-reported daytime sleepiness. Only patients without clinical edemawere selected for the study. The mean AHI for the whole group was 29.6/ hour. They weredivided into 3 groups according to the AHI: mild OSAHS (n = 10, mean AHI 10.9/h), moderateOSAHS (n = 10, mean AHI 23.9/h), and severe OSAHS (n = 10, mean AHI 53.9/h).

Body composition (body fat, body water and dry lean mass) was assessed by bioelectricimpedance assay (BIA), using a medical hand-held, battery operated bio-impedance analyzer with two main cable leads, working at a fixed frequency of 50 kHz ( Bodystat 1500 - Medical ,2004, Bodystat Ltd, Isle of Man). Written consent was obtained for all measurements and for data use. The results were expressed in percent of the total body mass.

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Other measurements included neck and abdominal circumferences and body massindex (BMI = weight/height 2). Pearsons coefficient (r) was used to express correlations betweenAHI and the following parameters: BMI, neck and abdominal circumferences, body fat, dry leanmass, and body water. We compared anthropometric and body composition measurements

between the 3 groups (mild, moderate and severe) using the Wilcoxon Sum-of-Ranks (Mann-

Whitney) test for comparing relatively small unmatched samples, with a significance threshold p= 0.05.

3. Results

Mean BMI and mean age were higher in the severe OSAHS group compared to the mildand the moderate OSAHS group, but the differences were not statistically significant (p > 0.05).

Body fat percentage, body water percentage, abdominal circumference, and neck circumference were significantly higher and dry lean mass was significantly lower in the severeOSAHS group compared to the mild OSAHS group (p < 0.01).

Table III. Body composition compartments in the studied groupMin Max Mean SD

Fat (%) 19,00 38,00 30,4000 4,74429

Water (%) 37,00 54,00 47,0467 4,94129

Dry lean mass (%) 10,00 34,00 22,6467 6,98164

Abdominal circumference and body composition compartments were also different between severe and moderate OSAHS groups (p < 0.05). Neck circumference and dry lean masswere significantly different between the mild and the moderate OSAHS groups (p < 0.05)..

The correlation between AHI and age was weak (r = 0.34). The correlation between AHI and BMI was also weaker than expected (r = 0.38). AHI correlated moderatelywith neck circumference (r = 0.54), with neck circumference corrected by height (r = 0.60), andstronger with body fat percentage (r = 0.67), with body water percentage (r = 0.69) and withabdominal circumference (r = 0.75). There was a strong negative correlation between AHI anddry lean mass percentage (r = - 0.92).

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Figure 2 . Body composition components (percents of the total body mass) in the mild, moderateand severe OSAHS groups (p < 0.05 represents a significant diference between groups using theWilcoxon Sum-of-Ranks test).

4.Discussions

In our study, the severity of OSAHS expressed by the apnea-hypopnea index correlatedwith body fat and with abdominal circumference stronger than with regional and cervicalobesity, which suggest that abdominal adiposity may predict OSAHS severity better than neck circumference and general body mass index.

Most of the existing evidence shows a good correlation between body fat percentage(estimated by anthropometric measurements and bio-impedance) and the severity of OSAHS. [7,8] In one of the studies, body fat percentage estimated by bio-impedance predicted the risk for OSAHS, contributing to the pre-test probability. (28) Visceral fat determined by computedtomography seems to predict the risk for OSAHS more accurately than BMI or body fat

percentage. (28, 29) All these data are in agreement with our results, confirming the superiorityof body fat percentage and visceral fat deposition over cervical and general obesity as markersfor the risk and the severity of OSAHS. The role of abdominal adiposity on OSAS severity iswell known (both the mechanical and the metabolic role), but body water has been less studied.

This is the first study on body water in OSAHS and its correlation with the severity of thedisease. Body water distribution is altered in OSAHS. Nocturnal pulmonary hypertension,increased atrial natriuretic peptide release, altered renin-angiotensin-aldosterone activity, andhigh levels of endothelin could be the mechanisms of the altered fluid distribution in OSAHS,causing nocturnal polyuria, peripheral edema and hemoconcentration. (29)

We have selected patients without any clinical edema, for a higher accuracy of bodywater assessment using BIA. The significant difference in body water between mild and severe

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OSAHS and the strong positive correlation between body water and AHI suggest a degree of subclinical edema in the severe OSAHS patients.

Fluid retention and altered fluid distribution are not only consequences of sleep apnea, but they may contribute to the pathogenesis and the severity of upper airway resistance. It has been demonstrated that overnight rostral fluid displacement, both spontaneous (related to

prolonged diurnal sitting) and induced by lower body positive pressure, may play a previouslyunrecognized role in the pathogenesis of obstructive sleep apnea in nonobese men, independentlyof body weight. The mechanism is increased upper airway resistance caused by upper airwayedema consecutive to fluid migration from the legs to the neck. (30, 31) Our data are inagreement to these findings and add to the current knowledge the fact that fluid retentioncorrelates with the severity of OSAHS. It remains is however unclear to what extent theincreased body water percentage is the consequence or the cause of sleep apnea severity.

The very strong negative correlation between dry lean mass and AHI suggests a possiblerole played by muscle depletion in upper airway collapsibility. Unfortunately, our study couldnot discriminate the role of body fat as a confounder on body water and on dry lean mass,

because the small size of our case series made multiple regression analysis unfeasible.

5. Conclusions:

We conclude that the severity of OSAHS correlates with body fat and with body water stronger than with general and cervical obesity and that abdominal adiposity may predictOSAHS severity better than neck circumference. Future studies on larger groups should focus onthe role of body composition compartments as independent predictors of OSAHS and itsseverity.

III. Clinical evidence of autonomic dysfunction in patients with OSAHS

1. Aim: to highlight the clinical manifestations of autonomic dysfunction in patientswith OSAH, using the Ewing tests.

2. Material and methods

We studied 27 patients with OSAHS (21 men, 6 women, average age 44.4 years) wereexplored in the Sleep Laboratory of the Pneumology Hospital in Iai from January to June 2007and 27 patients without OSAHS evaluated same laboratory.

Exclusion criteria were: age over 70 years, beta blocker medication, chronic alcoholism(history and liver enzymes), diabetes or abnormal oral glucose tolerance testing, other causes of

disautonomy (porphyria, renal failure, etc.).The diagnosis of OSAHS was established by full polysomnography (SomnoLab version

5, Weinmann, Germany).

The autonomic stress tests were: heart rate response to Valsalva maneuver, the heartrate response to deep breathing, the heart rate response to standing and the postural pressureresponse.

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The heart rate response to Valsalva maneuver: The subject was instructed to execute theValsalva maneuver for 15 s, and then suddenly to release his breath. The R-R intervals of theECG were examined and the ratio of the longest R-R during release to the shortest R-R intervalduring strain calculated (Valsalva ratio).

The heart rate response to deep breathing : This was performed in the supine position.

The subject took a slow deep breath over 5 s and exhaled over 5 s for a period of 1 min. The ratio(E/I) of the mean of the maximum R-R intervals during deep expiration (six breaths) to the meanof the minimum R-R intervals during deep inspiration (six breaths) was calculated.

The heart rate response to standing up. A continuous ECG was recorded, whilst thesubject rose suddenly from the supine to the upright position. R-R intervals of beats 15 and 30after standing were recorded and a 30/15 ratio calculated.

The postural response in blood pressure. Blood pressure was recorded by aneroidsphygmomanometer, with the subject lying after 5 min rest. The subject was instructed to standup quickly and the BP recorded immediately. The difference in systolic blood pressure (SBP)was calculated ("postural response").

During the maneuvers, the heart rate was assessed using the polysomnographic recording.Testing time was 20.30.

3. Results:

The average age in the study population was 44.4 14.2 years. AHI in OSAHS groupwas 30.3 20.9.

Table IV. Clinical autonomic parameters in the OSAHS group

The average values fall within normal limits, but the minimum values are subnormal.

In the OSAHS group, there were 11 patients with abnormal Valsalva ratio, 10 patientswith abnormal E / I ratio, seven patients with abnormal15 to 30 ratio and 6 patients withabnormal postural abnormal pressor response.

Chi squared test:

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Valsalva ratio Mean

SD

1.7874

0.48 E/I ratio MeanSD

2.0170 0.62

15 -30 ratio MeanSD

1.6452 0.2

Postural pressureresponse

MeanSD

26.1111 10.5


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2 = 8, p less than 0.05, which pleads for preferential distribution of abnormalities in testsassessing abnormal response to respiratory maneuvers.

All results were strongly negatively correlated with AHI (r = -0.84 for the Valsalva ratio,r = -0.84 for the E / I ratio, r = -0.79 for 15 to 30 ratio, r = 0, 76 for the postural response).

The 27 patients without OSAHS had similar ages (45.4 11.2 years). All test results in patients without OSAHS show better values than those with OSAHS, except for the postural pressor response, which showed an average pathological value: a decrease of 37 mmHg whilestanding. Analysis of medical records of these patients showed that they presented asthenicsyndromes of different etiologies (chronic liver disease, psychiatric disorders, paraneoplazicsyndrome etc), which may be related to the orthostatic hypotension.

For other parameters, the number of patients with pathological results were: 6 pathological Valsalva ratio, compared to 11 in group OSAHS; 4 ratio E / I disease, comparedwith 10 in group OSAHS; 4 ratio 15 to 30 pathological , versus 7 in group OSAHS.

4. Discussions:

Preferential distribution of abnormalities in tests assessing abnormal response torespiratory maneuvers is due to cardio-respiratory reflexes amputation (as Hering-Breuer reflex)in patients with OSAHS, where pleural pressure variations repeated mechanical excitation upper respiratory tract "blunts" these responses. These results are consistent with the literature (23).

In this study there is a better selection of patients with OSAHS in terms of possibleetiology of diabetic neuropathy (glucose tolerance test was not performed in previous studies).

5. Conclusions:

-Patients with pathological results OSAHS have pathologic results in tests involving cardio-respiratory reflexes more frequently than other tests

-The proportion of patients in our study OSAHS with Ewing abnormal tests was higher thanthose without OSAHS, except for the postural pressure response

IV. Pulse transit time and its variations in patients with OSAHS

1. Aims: theevaluation of autonomic dysfunction in patients with OSAHS using the

pulse transit time (PTT) and the heart rate (HR).

2. Patients, methods: The study group included 30 patients who were selected after theexclusion of the main causes of autonomic neuropathy: glucosemetabolism disorders,alcoholism, porphyria, renal failure. These patients were investigated in the Sleep Laboratory of the Pneumology Hospital Jasi in 2006 with the Alice 5 polysomnographic system, Respironics,USA. The patients were divided into comparable groups: 12 with mild OSAHS, 10 with mediumOSAHS and 9 with severe OSAHS.

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The coefficient of variation of the HR was calculated by the polysomnography software(HRV calc) by deviding the standard deviation to the meanHR. PTT was the intervabetween theR wave on ECG and the pulse wave. PTTv were the variations of PTT during apneic episodes.D HR was the heart rate response to apneas assessed manually on different epochs in all sleepstages exept REM (the difference between the maximum postapneic HR and the minimum HR

during apneas).The coefficient of variation of the HR was also was calculated manually (HRVman) on epochs without apneas in all sleep stages except REM stage, which is by definitionunstable in terms of HR.

3. Results:

The values of the apnea-hypopnea index (AHI) in the four groups were:

In 12 patients with mild OSAHS: AHI = 8.09 0.85 In the 10 patients with moderate OSAHS: AHI = 22.9 4.6 In those nine with severe SAOHS: AHI 56.4 14.6

Table V. Parameters of polysomnographic markers of dysautonomy

Min Max Average S DHRV calc 0.04 0.60 0.2548 0.16500HRV man 0.06 0.49 0.1920 0.12195D HR 9.00 28.00 17.0000 5.06623PTT V 13.00 56.00 37.6774 12.40719TTP mean 245.00 439.00 366 612 57.70192

All parameters studied were negatively correlated with AHI. The values of all studied

parameters were significantly lower in the group with severe apnea compared to mild apneagroup (p < 0.05).

Fig. 3. PTTv in mild, moderate and severe OSAHS groups

999N=

PTTV SEVERPTTVMEDIUPTTVUSOR

60

50

40

30

20

10

4

4. Discussion:

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Pulse transit time (PTT) the time taken by the pulse wave from aortic valve to a peripheral artery (the interval between the R wave on ECG and the pulse wave on pulsoximetry), being inversely proportional to arterial wall stiffness and sympathetic tone. During apnea, thereis an increase of pulse transit time, followed by a sudden drop after the apnea, corresponding to asympathetic discharge. The fact that changes in pulse transit time (PTT) reflects autonomic

response to apnea made this parameter a part of diagnostic algorithm in OSAHS, now beingincluded in polysomnography software systems (204, 205).

The novelty of this study is the reduction in the amplitude of the heart rate and pulsetransit time variability in patients with severe OSAHS.

5. Conclusions:

- Autonomic response to apneas is altered in patients with severe OSAHS

-Heart rate variability is altered in patients with severe OSAHS, which can be demonstrated on

apnea-free epochs of non-REM sleep

- Pulse-transit time is lower in subjects with severe OSAHS compared to those with mildOSAHS

V. The heart rate variability in patients with OSAHS

1. Aim: to study the heart rate variability (HRV) in OSAHS patients and the effect of CPAP on HRV

2. Material and methods: 42 patients with moderate to severe OSAHS (apnea-

hypopnea index 15 AHI / h) aged less than 60 years and with an indication for CPAP wereinvestigated in the Railways Hospital Galati during 2008 - 2010 and followed up for 3 monthswith respect to the presence and severity of OSAHS and to the HRV parameters. Other major causes of autonomic dysfunction were excluded: alcoholism, diabetes, myocardial infarction,heart failure, anti-arrhythmic therapy, renal failure. All patients underwent the nocturnalcardio-respiratory polygraphy (polygraph Somnocheck Effort - Weinmann, Germany). HRVwas assessed by spectral analysis in time and frequency domains on Holter ECG monitoring /24h (Digitrack Plus for Windows 2000 Zymed, USA) at baseline, during the first week of CPAPand at 3 months after initiation of CPAP. The selected patients had no episodes of atrialfibrillation or more than 1% extrasystolic beats that would have interfered with HRV analysis.The time domain HRV parameters included SDNN (standard deviation of all NN intervals) and

RMSSD (the square root of the mean of the sum of the squares of differences between adjacent NN intervals) and the frequency domain parameters included total power (TP), high frequencycomponent (HF), low frequency component (LF) and the low frequency/high frequency ratio(L/H).

3. Results:

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Of the 44 patients, five were women and 39 men. The mean age was 50.45 7.6 years and theAHI was 29.38 14.32 / h. The descriptive parameters of the study group are shown in Table VI.

Table VI. VFC time domain parameters at baseline in the first week ( 1) and threemonths under CPAP ( 3)

Min Max Average SDSDNN 100 289 181.886

440.21987

SDNN 1 78 140 101.2045

15.65557

SDNN 3 99 170 128.0455

20.13438

RMSSD 13 45 27.5682 8.91927RMSSD1

8 28 12.7273 3.82382

RMSSD3

12 38 21.8182 6.16167

1 = first week of CPAP, 3 = 3 months under CPAP

There was a strong negative correlation between the AHI and the SDNN (r = - 0.59). Theother time domain HRV parameter, RMSSD, also correlated negatively with AHI (r = - 0.55). Inthe frequency domain, the parameter expressing the parasympathetic modulation (HF) alsocorrelated negatively with AHI (r = - 0.452). LF parameter, which expresses the modulation of sympathetic and parasympathetic components, was negatively correlated with AHI (r = - 546).For the ratio L / H, which expresses simpato-parasympathetic balance, there was a weak negative

correlation with the AHI (r = - 0.28), which was not statistically significant. The correlation between the total spectral power and AHI was significantly negative (r = -0.44)

Table VII. VFC parameters in frequency domain at baseline, in the first week and threemonths under CPAP

Min Max Average SDHF 730 170

01058.8636

258.20684

HF1

450 1500

687.9545 177.75839

HF3

510 2000

934.2045 243.15021

LF 730 2500

1467.7500

567.78718

LF1 500 2100

1234.5455

454.36618

LF3 770 2800

1313.4091

409.29857

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LH 0.6 2 1.5098 0.58482LH1 0.75

4 1.5939 0.70710

LH3

0.7 4 1.4607 0.51963

TP 1800 5700 3679.0909 883.42836

TP1 1200

3500

2303.4091

513.12967

TP3 1800

4000

3182.0455

560.59180

1 = first week of CPAP, 3 = 3 months under CPAP

Given the asymmetric distribution of the value of AHI, we divided the patients in thestudy into four separate groups of equal frequency values AHI: 17 / h 25 / h 35 / h, called

"quartiles" by convention. Comparing HRV parameters in time and frequency domains in theextreme quartiles 1 and 4 using the paired Students t test, significant differences were found for all parameters except for total spectral power.

The application of CPAP resulted in the collapse of HRV parameters in the first week below normal values, except for the ratio L / H, which increased slightly. At 3 months under CPAP, the HRV parameters increased significantly, without reaching the values at baseline.Values at 3 months were normal.

Fig. 4. Graphical representation of RMSSD at baseline, in the first week and threemonths under CPAP

RMSSD3RMSSD1RMSSD

U n

d e

f i n e

d e r r o r

# 6 0 8 7 5

- C a n n o

t o p e n

t

30

20

10

4. Discussion:

In patients with SAOHS, hiper-variability of the heart rate as a response to apneas anddoes not have the significance of autonomic neuropathy. This hipervariable nocturnal heart rateis closely associated with the presence of OSAHS, thus being a part of the pretest diagnosticagorythm.

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The "blunting" of this variability represents the autonomic dysfunction, which is difficultto assess in a condition characterized by nocturnal heart rate variations. The literature datalinking the severity of OSAHS and the VFC parameters are controversial: some authors report adirect correlation between the severity SAOHS (expressed by AHI) and HR hipervariability (24),while other authors show decreased autonomic response to apnea in some patients with severe

OSAHS (33).

The novelty of the study is the evaluation of the VFC parameters at diagnosis, at theinitiation of CPAP (when the autonomic dysfunction is revealed by expose the disappearance of apneas) and then after 3 months of treatment, when these parameters are normalized.

This is the first study in which latent autonomic neuropathy is being unmasked by thestart of CPAP.

Although baseline values of some parameters like SDNN were found pathologically highat baseline, expressing the hipervariability in time domain, the negative correlation of the HRV

parameters with AHI expressed a latent autonomic dysfunction, confirmed by lower values of these parameters in the 4-th quartile at CPAP application.

A shortcoming of this study is the absence of retesting for OSAHS after three months of treatment, which could probably reveal a lowering of the AHI, given that patients underwent, inaddition to CPAP treatment, lifestyle change and management of complex comorbidities.

5. Conclusions:

- Patients with OSAHS present a deterioration in heart rate variability directly proportional tothe disease severity.

- Decreased heart rate variability is unmasked by the disappearance of respiratory pauses at theinitiation of CPAP.

- After three months of treatment, VFC parameters normalize, regardless of the severity of OSAHS.

FUTURE PERSPECTIVES OPENED BY THE THESIS

The two research directions, the metabolic implications of OSAHS and the autonomicdysfunction related to OSAHS follow the two main mechanisms by which sleep apnea acts as acardiovascular risk factor.

In the studies included in this thesis, there has been a better selection of patients in termsof confounding factors than in other studies. The novelties of the studies addressing autonomicdysfunction are "unmasking" of the autonomic neuropathy in the first week under CPAP and thedecreased amplitude of the pulse transit time variability in relation to the severity of OSAHS.

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In patients studied from the point of view of metabolic syndrome, the novelties includethe significant weight loss under CPAP and a closer correlation of the severity of OSAHS with

body composition than with classical markers of obesity.

The research work for this theses has resulted in a review in Pneumologia, an international

original article, three presentations at the European Respiratory Congress, one of them awardedwith the Gold Sponsorship of the Respiratory European Society, a prize for Excellency from theMedical College of Galati, and a European Marie Curie fellowship in sleep research.

The perspectives opened by this thesis include positive results of the multifactorialapproach involving metabolic syndrome patients and sleep apnea syndrome. Separate approachto sleep apnea by CPAP treatment without dietary intervention, pharmacological and increasing

physical activity did not lead to significant weight loss in previous studies. The metabolicintervention without compliance to CPAP led to less significant improvements than in patientswho have benefited from the complete integrated intervention. Therefore, this morbid association(OSAHS metabolic syndrome) represents a model for intervention and integrated approach by

education, rehabilitation, pharmacologic and specific treatment of sleep apnea syndrome.

Another perspective is the nutritional imbalance of OSAHS: although the majority of patients with are obese, there is an imbalance between body composition compartments, with adeficit in dry lean mass and an excess of fat and water. This imbalance can be compared with

protein malnutrition in other hypoxemic disabling diseases like COPD. One of the perspectivesopened by the sentence refers to the study of possible future improvements in body compositionabnormalities after the restoration of normoxemia by CPAP, completed by the monitoring of cytokines released by hypoxaemia (TNF alpha).

CONCLUSIONS

The prevalence of metabolic syndrome in patients diagnosed with OSAHS in this study is 60%,similar to that reported in the literature and higher by 31% than in the group of patients withoutOSAHS.

Some components of MS and associated clinical conditions are correlated with the severityexpressed by AHI OSAHS: abdominal obesity, sedentary lifestyle, hypo-HDL-emia.

All components of the metabolic syndrome and some related conditions (sedentarism) improveunder the specific CPAP treatment more evidently than in patients with OSAHS who are notcompliant to CPAP, under the same pharmacological and educational intervention.

Body composition is closely correlated with severity markers of OSAHS more evidently thangeneral and regional obesity.

There is a strong negative correlation between the severity of OSAHS and dry lean mass,suggesting a proteo-mineral depletion similar to other disabling diseases with hypoxemia.

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Clinical markers of autonomic dysfunction are correlated with the severity of OSAHS. Patientswith OSAHS frequently present pathological results in autonomic tests involving cardio-respiratory reflexes than in other tests.

The proportion of patients with abnormal results at the autonimic tests was higher than those

without OSAHS, except for the postural blood pressure response.

Autonomic response to apneas is altered in patients with OSAHS, directly proportional to theseverity of the disease.

Decreased heart rate variability is unmasked by the disappearance of respiratory pauses at theinitiation of the CPAP treatment. After three months of treatment, VFC parameters normalize,regardless of the severity of OSAHS.

REFERENCES

1. National Commission on Sleep Disorders Research. Research DHHS Pub. No. 92.Supplier of Documents, U.S. Government Printing Office, Washington, DC, 1992.

2. Mahowald MW, Schenck CH. Insights from studying human sleep disorders. Nature2005, 437: 1279-1285.

3. Hammond EC. Some preliminary findings on physical complaints from the ProspectiveStudy of 1,064,004 Men and Women. Am J Public Health Nations Health. 1964, 54:11-23

4. Al Lawati NM, Patel SR, Ayase NT. Epidemiology, Risk Factors, and consequences of obstructive sleep apnea and short sleep duration. Prog Cardiovasc Dis. 2009; 51:285-93

5. Ayase NT, White DP, Manson JE, et al. A Prospective Study of sleep duration andcoronary heart disease in Women. Arch Intern Med. 2003; 163:205-9.

6. Pinheiro SP, Schernhammer ES Tworoger SS, Michels KB. A Prospective Study onhabitual duration of sleep and incidence of breast cancer in a large cohort of Women.Cancer Res. 2006, 66:5521-5.

7. Taher S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is Associated withreduced leptin, Elevated ghrelin, and increased body mass index. PLoS Med. 2004, 1:E62

8. Spiegel K, R Leproult Van cautery E. Impact of sleep debt on metabolic and endocrinefunction. Lancet. 1999, 354:1435-9.

9. Phillipson EA. Sleep Disorders. In: Murray JF, Nadel JA, eds. Textbook of respiratorymedicine Vol. 2. Philadelphia: WB Saunders, 1988:1841-60.

10. Kryger M, Roth T, dementia W. Principles and Practices of Sleep Medicine, FourthEdition. Philadelphia: Elsevier Saunders 2005: 547-557.

11. McNicholas WT, Bonsignore MR, the Management Committee of EU COST ACTIONB26. Sleep apnoea as an independent risk factor for year cardiovascular disease: currentevidence, basic mechanisms and research priorities. Breathing Eur J 2007, 29 (1): 156-178.

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31. Redolfi S , Yumino D , Ruttanaumpawan P , et al. Relationship between fluid overnightshift and obstructive sleep apnea in nonobese men. Am J Crit Care Med. 2009 February1, 179 (3) :241-6. Epub 2008 November 14.

32. Chiu KL, Ryan CM, Shiota S, et al. Fluid hift by lower body positive pressure increases pharyngeal resistance in healthy subjects. Breathe Am J Crit Care Med. 2006 December

15, 174 (12) :1378-83. Epub 2006 September 2233. Ferini-Strambi L, Zucconi M, Oldani A, Smyrna S. Heart rate variability in snorers withand without obstructive sleep apnea. Chest. 1992 October; 102 (4) :1023-7.

CURRICULUM VITAE

Name: Lovin Sinziana Date of birth: 11/10/1974 Place of birth: Iasi, Romania Marital status: Married, one child Tel. +40 (236) 475764, ext. 120 Fax +40 (236) 411613 Mobile: +40 740 185028 Business address: Railways Hospital Galati, Str. Al. No. Moruzzi. 5-7, code 800 223,

Galati, Romania E-mail: [email protected] Education:

o 1999: Faculty of Medicine, UMF Iasi first class honorso 1993: Highschool "C. Negruzzi "Iasi first class honors

Languages: English, French - fluent Current status:

- Specialist in Internal Medicine - Railways l Hospital Galati, Str. Al. No. Moruzzi. 5-7,Galati, Romania Intern year II in Pneumology - supervisor Prof. Dr. Traian Mihaescu, University "Gr T. Popa"Iasi- Associate Assistant University Lower Danube since October 2007

PhD since September 2010 - University of Medicine and Pharmacy Iasi (double specializationin Internal Medicine and in Pneumology; theme: "The relationship between sleep apnea

syndrome, metabolic syndrome, and vegetative neuropathy)

Career: 1999: medical degree 2000 - 2001: Hospital junior doctor Parhon Hospital, Iasi, Romania 2002 - 2006: Intern in Internal Medicine

25
http://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Redolfi%2520S%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Yumino%2520D%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Ruttanaumpawan%2520P%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Ruttanaumpawan%2520P%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed/16998093%3Fitool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum%26ordinalpos%3D1http://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed/16998093%3Fitool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum%26ordinalpos%3D1mailto:[email protected]://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Redolfi%2520S%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Yumino%2520D%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed%3Fterm%3D%2522Ruttanaumpawan%2520P%2522%255BAuthor%255D%26itool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstracthttp://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed/16998093%3Fitool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum%26ordinalpos%3D1http://translate.google.com/translate?hl=ro&sl=ro&tl=en&prev=_t&u=http://www.ncbi.nlm.nih.gov/pubmed/16998093%3Fitool%3DEntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum%26ordinalpos%3D1mailto:[email protected]


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2002: Junior Assistant University of Medicine and Pharmacy "Gr T. Popa "(MedicalSemiology)

2005: PhD student University of Medicine and Pharmacy "Gr T. Popa "(Medicine) 2006: Specialist in Internal Medicine 2007: Assistant University of Medicine and Pharmacy "Gr T. Popa "(Medical

Semiology) 2007: Specialist in Internal Medicine, Railways Hospital Galati 2007: Associate Assistant Medical Semiology, School of Medicine, University "Lower

Danube" Galati 2009: start of the second specialty (Respiratory Medicine)

Post-graduate courses:

o Marie Curie fellowship in Sleep research (2007 - 2010)o October 2006 - October 2007: Psycho-pedagogyo February-April 2007: General Ultrasoundo May-June 2005: Chest Radiologyo October 2002: Emergency Medicineo March-April 2001: Practical Electrocardiography

Working abroad:- November 2004- April 2005 : Intern in the Respiratory Rehabilitation Center

Henri Bazire, France , with specialized training in respiratory rehabilitation,

non- invasive ventilation, sleep apnea diagnosis and treatment- October 2004 - Intern - Centre Hospitalier Universitaire de Grenoble,

Dpartement de Mdicine Aigue Spcialise Pneumology

Full text publications with relevance for the thesis:

1. Lovin S Cernomaz A, Ionescu G, Mihaescu T. Adherence to treatment in patientswith sleep apnea. Medical Days Galati, in November 2009. ISBN 978-606 -8008-55 - 4; 2009: 22-31

2. Lovin S, Bercea, R, Rusu G, Cojocaru C, Mihaescu T. Body compositioncorrelates with the severity of obstructive sleep apnea syndrome.Multidisciplinary Respiratory Medicine. 2010, 5 (1): 44-49

3. Lovin S Mihaescu T Cernomaz A, Veale D. Pretest probability in OSAS.Pneumologia. 2007 Oct-Dec, 56 (4) :194-201.

Affiliations: European Respiratory Society, European Sleep Research Society, RomanianSociety of Pneumology, University Foundation "Lower Danube"

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Galati, June 2010