Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome

Background: Marfan syndrome (MFS) is an inherited connective tissue disorder characterized by ectopia lentis, aortic root dilation and dissection and specific skeletal features. Obstructive sleep apnea (OSA) in MFS has been described earlier but the prevalence and its relation with the cardiovascular risk is still controversial. This study aimed to further investigate these aspects. Methods: In this prospective longitudinal study, we performed an attended polysomnography in 40 MFS patients (60% women, 37 +/- 12.8 years) and evaluated several cardiovascular parameters through echocardiography, resting electrocardiogram, 24 hr-Holter monitoring and serum NT-ProBNP measurements. Results: We found that OSA was present in 42.5% of the patients and that higher body mass index was the most important factor associated with the presence of OSA. We observed that overweight was present in 27.5% of the patients in the whole cohort and in 55.6% if >40 years. Furthermore, when evaluating the impact of OSA on the cardiovascular system, we observed that patients with OSA tended to have higher systolic blood pressure, larger distal aortic diameters and a higher prevalence of ventricular arrhythmia. These differences were, however, not significant after adjusting for confounders. Conclusions: Our study shows a high prevalence of OSA and a high prevalence of overweight in MFS patients. We found some trends between OSA and cardiovascular features but we could not establish a solid association. Our study, however might be underpowered, and a multicenter collaborative study could be very useful to answer some important open questions

The effect of respiratory event type and duration on heart rate variability in suspected obstructive sleep apnea patients

Abstract. Obstructive sleep apnea (OSA) patients have often reduced long-term heart rate variability (HRV) which is a known risk factor for several cardiovascular diseases such as hypertension and stroke. Albeit OSA being actively studied, it has remained uncharacterized how the duration and type of respiratory events affect the heart rate (HR), i.e. RR intervals, and ultra-short-term HRV during and immediately after the individual respiratory events. This study aimed to investigate whether the changes in ultra-short-term HRV and HR are modulated by the duration and type of the individual respiratory events and whether these changes are sex-specific. It was hypothesized that longer respiratory events cause higher ultra-short-term HRV and greater differences between RR intervals during and after the respiratory event. Moreover, it was hypothesized that the higher HRV and greater differences in HR are associated with apneas and men stronger than hypopneas and women. Electrocardiograms (ECG) of 862 suspected OSA patients were collected during clinical polysomnography (PSG) at the Princess Alexandra Hospital (Brisbane, Australia) and they were analyzed retrospectively. Ultra-short-term HRV was studied with time-domain parameters determined from the ECG segments measured during (in-event) and 15 seconds after (post-event) the respiratory event. The respiratory events of all subjects were divided into groups based on the sex, the type of the respiratory events (apneas and hypopneas), and the duration of the respiratory events (10–20 s, 20–30 s, over 30 s). A clear bradycardia-tachycardia rhythm associated with respiratory events was observed. The ultra-short-term HRV and the difference between in- and post-event RR intervals increased with increasing respiratory event duration. However, the difference between in- and post-event HRV parameter values decreased with increasing duration of the respiratory events. Furthermore, higher ultra-short-term HRV and a greater decrease in RR interval were observed in apneas and men. Based on the results, the duration and type of the respiratory events modulate the HR and ultra-short-term HRV during and after the respiratory events, and these phenomena appear to be sex-specific. Therefore, considering the characteristics of respiratory events and ultra-short-term HRV could be useful in OSA diagnostics when estimating the OSA-related cardiac consequences. A scientific article based on the results of this thesis, Hietakoste et al. Longer apneas and hypopneas are associated with greater ultra-short-term HRV in OSA, has been submitted to a peer-reviewed scientific journal.Tiivistelmä. Uniapneapotilailla havaitaan usein matalaa pitkän aikavälin sykevälivaihtelua, jonka tiedetään myös olevan riskitekijä useille sydän- ja verisuonisairauksille. Ei kuitenkaan tiedetä, miten uniapneaan liittyvät erimittaiset hengityskatkot tai niiden tyyppi vaikuttavat yksittäisten hengityskatkojen aikaiseen ja jälkeiseen ultralyhyeen sykevälivaihteluun ja sydämen lyöntien väliseen kestoon, ts. RR-intervalleihin. Tässä tutkimuksessa tavoitteena oli tutkia ultralyhyen sykevälivaihtelun ja RR-intervallien sukupuolisidonnaisia muutoksia eri mittaisten apneoiden ja hypopneoiden aikana ja jälkeen. Hypoteesina oli, että pidemmät hengityskatkot aiheuttavat suurempia muutoksia hengityskatkojen aikaisen ja jälkeisen keskimääräisen RR-intervallien kestojen välille ja siten korkeampaa ultralyhyttä sykevälivaihtelua. Oletettiin myös, että apneat aiheuttavat suurempia muutoksia kuin hypopneat ja havaitut muutokset ovat suurempia miehillä kuin naisilla. Potilasaineisto koostui 862 uniapneasta epäillyn potilaan sydänsähkökäyristä (EKG), jotka oli mitattu Prinsessa Alexandran sairaalassa (Brisbane, Australia) osana kliinistä unipolygrafiaa. Ultralyhyen sykevälivaihtelun määrittämiseen käytettiin keskimääräistä RR-intervallien kestoa ja aikatason sykevälivaihteluparametreja, jotka määritettiin hengityskatkojen aikaisista ja jälkeisistä (15 s hengityskatkon jälkeen) EKG-segmenteistä. Tutkittavat hengityskatkot jaettiin ryhmiin niiden tyypin (apneat ja hypopneat) ja keston (10–20 s, 20–30 s ja yli 30 s) perusteella. Lisäksi miesten ja naisten hengityskatkoja tutkittiin erikseen. Tutkimuksessa havaittiin, että hengityskatkojen aikaisten ja jälkeisten RR-intervallien ero sekä ultralyhyt sykevälivaihtelu kasvoivat hengityskatkojen keston kasvaessa riippumatta sukupuolesta tai hengityskatkojen tyypistä. Havaittiin myös, että ero hengityskatkojen aikaisten ja jälkeisten sykevälivaihteluparametrien arvojen välillä pieneni hengityskatkojen pidentyessä riippumatta sukupuolesta tai hengityskatkojen tyypistä. Apneat kuitenkin aiheuttivat suuremman muutoksen kuin hypopneat, ja muutokset olivat suurempia miehillä. Tulosten perusteella hengityskatkojen tyyppi ja kesto vaikuttavat ultralyhyeen sykevälivaihteluun ja RR-intervalleihin. Ultralyhyen sykevälivaihtelun ja hengityskatkojen ominaisuuksien huomioonottaminen uniapnean diagnostiikassa voisi olla hyödyllistä arvioitaessa taudin vakavuutta ja sydänterveyteen liittyviä riskejä. Tämän tutkimuksen tuloksista on kirjoitettu tieteellinen artikkeli Hietakoste ym. Longer apneas and hypopneas are associated with greater ultra-short-term HRV in OSA, joka on lähetetty vertaisarvioitavaksi alan kansainväliseen tieteelliseen julkaisusarjaan

Non-linear HRV analysis to quantify the effects of intermittent hypoxia using an OSA rat model

© 2019 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting /republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other worksIn this paper, a non-linear HRV analysis was performed to assess fragmentation signatures observed in heartbeat time series after intermittent hypoxia (IH). Three markers quantifying short-term fragmentation levels, PIP, IALS and PSS, were evaluated on R-R interval series obtained in a rat model of recurrent apnea. Through airway obstructions, apnea episodes were periodically simulated in six anesthetized Sprague-Dawley rats. The number of apnea events per hour (AHI index) was varied during the first half of the experiment while apnea episodes lasted 15 s. For the second part, apnea episodes lasted 5, 10 or 15 s, but the AHI index was fixed. Recurrent apnea was repeated for 15-min time intervals in all cases, alternating with basal periods of the same duration. The fragmentation markers were evaluated in segments of 5 minutes, selected at the beginning and end of the experiment. The impact of the heart and breathing rates (HR and BR, respectively) on the parameter estimates was also investigated. The results obtained show a significant increase (from 5 to 10%, p 0.9) between these markers and BR, as well as with the ratio given by HR/BR. Although fragmentation may be impacted by IH, we found that it is highly dependent on HR and BR values and thus, they should be considered during its calculation or used to normalize the fragmentation estimatesPeer ReviewedPostprint (published version

Depression and Obstructive Sleep Apnea (OSA)

For over two decades clinical studies have been conducted which suggest the existence of a relationship between depression and Obstructive Sleep Apnea (OSA). Recently, Ohayon underscored the evidence for a link between these two disorders in the general population, showing that 800 out of 100,000 individuals had both, a breathing-related sleep disorder and a major depressive disorder, with up to 20% of the subjects presenting with one of these disorders also having the other. In some populations, depending on age, gender and other demographic and health characteristics, the prevalence of both disorders may be even higher: OSA may affect more than 50% of individuals over the age of 65, and significant depressive symptoms may be present in as many as 26% of a community-dwelling population of older adults. In clinical practice, the presence of depressive symptomatology is often considered in patients with OSA, and may be accounted for and followed-up when considering treatment approaches and response to treatment. On the other hand, sleep problems and specifically OSA are rarely assessed on a regular basis in patients with a depressive disorder. However, OSA might not only be associated with a depressive syndrome, but its presence may also be responsible for failure to respond to appropriate pharmacological treatment. Furthermore, an undiagnosed OSA might be exacerbated by adjunct treatments to antidepressant medications, such as benzodiazepines. Increased awareness of the relationship between depression and OSA might significantly improve diagnostic accuracy as well as treatment outcome for both disorders. In this review, we will summarize important findings in the current literature regarding the association between depression and OSA, and the possible mechanisms by which both disorders interact. Implications for clinical practice will be discussed

Relationship between sleep stages and HRV response in obstructive sleep apnea patients

Patients suffering from obstructive sleep apnea (OSA) usually present an increased sympathetic activity caused by the intermittent hypoxia effect on autonomic control. This study evaluated the relationship between sleep stages and the apnea duration, frequency, and type, as well as their impact on HRV markers in different groups of disease severity. The hypnogram and R-R interval signals were extracted in 81 OSA patients from night polysomnographic (PSG) recordings. The apnea-hypopnea index (AHI) defined patient classification as mild-moderate (AHI30, n=37). The normalized power in VLH, LF, and HF bands of RR series were estimated by a time-frequency approach and averaged in 1-min epochs of normal and apnea segments. The autonomic response and the impact of sleep stages were assessed in both segments to compare patient groups. Deeper sleep stages (particularly S2) concentrated the shorter and mild apnea episodes (from 10 to 40 s) compared to light (SWS) and REM sleep. Longer episodes (>50 s) although less frequent, were of similar incidence in all stages. This pattern was more pronounced for the group of severe patients. Moreover, during apnea segments, LF nu was higher (p=0.044) for the severe group, since V LF nu and HF nu presented the greatest changes when compared to normal segments. The non-REM sleep seems to better differentiate OSA patients groups, particularly through VLF nu and HF nu (p<0.001). A significant difference in both sympathetic and vagal modulation between REM and non-REM sleep was only found within the severe group. These results confirm the importance of considering sleep stages for HRV analysis to further assess OSA disease severity, beyond the traditional and clinically limited AHI values.Clinical relevance—Accounting for sleep stages during HRV analysis could better assess disease severity in OSA patients.Peer ReviewedPostprint (published version

Veränderte autonome Funktion bei Patienten mit obstruktiver Schlafapnoe im Wachzustand

Background: Patients with obstructive sleep apnea (OSA) show impaired cardiac autonomic function with heterogeneous profiles of heart rate variability (HRV) during sleep-wake states. However, the effect of OSA and its severity on autonomic modulation assessed by HRV during the wake period in a large multicenter clinical cohort is unclear. Methods: A total of 1247 participants (426 non-OSA controls and 821 OSA patients, according to apnea-hypopnea index≥5) were globally recruited from the Sleep Apnea Global Interdisciplinary Consortium. HRV measures were computed from 5-minute ECG data in wake status with relaxed tidal breathing prior to the sleep onset, using time-domain, frequency-domain and non-linear approaches. Differences in HRV measurements were estimated among groups using analysis of covariance, adjusted for age, gender, body mass index, race/ethnicity, comorbidities and sites. Results: OSA patients exhibited significantly reduced time-domain variations (SDNN, SDANN1, RMSSD, pNN50) and less complexity of cardiac rhythms (Shannon entropy, Fwshannon, Forbword) compared to non-OSA subjects. Those with severe OSA had considerably lower HRV compared to in comparison to other groups, both in time-domain and non-linear measurements. Compared to patients with OSA, those with severe OSA had reduced HRV based on SDNN (adjusted mean [95% CI]: 37.40 [34.55, 40.25] vs.46.19 [43.77, 48.60] ms; p<0.0001), SDANN1 (17.98.0 [15.87, 20.10] vs. 22.77 [20.97, 24.56] ms; p<0.0001), RMSSD (21.51 [19.59, 23.42] vs.27.98 [26.35, 29.60] ms; p<0.0001), pNN50 (5.1% [3.7%, 6.5%] vs. 9.2% [8.0%, 10.4%]; p=0.0001), Shannon entropy (1.8 [1.8, 1.9] vs. 2.0 [2.0, 2.1]; p<0.0001), Fwshannon 2.7 [2.6, 2.7] and Forbword (37 [35, 38] vs. 33[32, 34]; p=0.0001). There were no significant differences in overall frequency-domain metrics. Among obese patients, there is an increase in sympathetic tone in patients with severe OSA with higher LF/HF ratio compared to those without OSA (4.2 vs. 2.7; p = 0.009). Conclusions: HRV is significant correlative with OSA severity. OSA patients show reduced HRV patterns during pre-sleep wakefulness compared to individuals without OSA, especially patients with severe OSA having significantly decreased time-domain HRV metrics and less complex non-linear HRV dynamics. Only obese OSA patients show enhanced sympathetic activity with increased LF and LF/HF. Thus, HRV could be a promising tool to investigate autonomic modulation and cardiovascular pathophysiology in patients with OSA.Patienten mit obstruktiver Schlafapnoe (OSA) zeigen eine eingeschränkte kardiale autonome Funktion mit heterogenen Profilen der Herzratenvariabilität (HRV) im Wachzustand und im Schlaf. Die Wirkung von OSA und ihrer Schwere auf die autonome Modulation, die durch HRV während der Wachphase in einer großen multizentrischen klinischen Kohorte bewertet wurde, sind jedoch unklar. Methoden: Insgesamt 1247 Probanden (426 ohne OSA und 821 Patienten mit OSA, basierend auf dem Apnoe-Hypopnoe-Index ≥ 5) wurden weltweit aus einem globalen interdisziplinären Konsortium für Schlafapnoe rekrutiert (the Sleep Apnea Global Interdisciplinary Consortium, SAGIC). Die HRV-Parameter wurden während einer Periode von 5-minütigen Wachheit mit Spontanatmung vor der eigentlicher Schlafstudie unter Verwendung von Zeitbasis-, Frequenzbasis- und nichtlinearen Methoden berechnet. Unterschiede in den HRV-Parametern wurden zwischen den Gruppen unter Verwendung von Kovarianzanalysen bewertet, wobei Alter, Geschlecht, Body-Mass-Index, Ethnizität, Komorbiditäten und Standort des Schlaflabors kontrolliert wurden. Ergebnisse: Patienten mit OSA zeigten im Vergleich zu Personen ohne eine OSA signifikant geringere Variationen der Parameter in der Zeitbasis (SDNN, SDANN1, RMSSD, pNN50) und eine geringere Komplexität der Herzschläge (Shannon-Entropie, Fwshannon, Forbword). Diejenigen mit schwerer OSA hatten im Vergleich zu allen anderen Gruppen eine auffallend reduzierte HRV, sowohl in den Zeitbasis als auch in nichtlinearen Parametern. Im Vergleich zu Patienten ohne OSA hatten Patienten mit schwerer OSA eine niedrigere HRV basierend auf SDNN (adjustierter Mittelwert [95% CI]: 37.40 [34.55, 40.25] vs.46.19 [43.77, 48.60] ms; p<0.0001), SDANN1 (17.98.0 [15.87, 20.10] vs. 22.77 [20.97, 24.56] ms; p<0.0001), RMSSD (21.51 [19.59, 23.42] vs.27.98 [26.35, 29.60] ms; p<0.0001), pNN50 (5.1% [3.7%, 6.5%] vs. 9.2% [8.0%, 10.4%]; p=0.0001), Shannon entropy (1.8 [1.8, 1.9] vs. 2.0 [2.0, 2.1]; p<0.0001), Fwshannon 2.7 [2.6, 2.7] and Forbword (37 [35, 38] vs. 33[32, 34]; p=0.0001). Bei Ergebnissen der Methoden im Frequenzbereich wurden insgesamt keine signifikanten Unterschiede gefunden. Bei adipösen Patienten gibt es einen Anstieg des sympathischen Tonus bei schwerer OSA mit einem höheren LF/HF-Verhältnis im Vergleich zu adipösen nicht-OSA-Patienten (4,2 vs. 2,7; p = 0,009). Schlussfolgerungen: Die HRV korreliert signifikant mit dem Schweregrad der OSA. OSA Patienten zeigen im Wachzustand reduzierte HRV-Messwerte im Vergleich zu Personen ohne OSA, insbesondere Patienten mit schwerer OSA zeigen deutlich verringerten HRV-Messwerten in der Zeitbasis und weniger komplexitatin parametern der nichtlinearen HRV-Dynamik. Nur adipöse OSA-Patienten zeigen eine sympathische Hyperaktivität mit erhöhtem LF und LF/HF. Somit könnte HRV zusätzliche Informationen über die autonome Modulation und die kardiovaskuläre Physiologie bei OSA-Patienten liefern

Effects of sildenafil on autonomic nervous function during sleep in obstructive sleep apnea

OBJECTIVE: To evaluate the effects of sildenafil on the autonomic nervous system in patients with severe obstructive sleep apnea. METHODS: Thirteen male patients with severe obstructive sleep apnea (mean age 43±10 years with a mean body mass index of 26.7±1.9 kg/m²) received a single 50-mg dose of sildenafil or a placebo at bedtime. All-night polysomnography and heart rate variability were recorded. Frequency domain analysis of heart rate variability was performed for the central five-minute sample of the longest uninterrupted interval of slow wave and rapid eye movement sleep, as well as for one-minute samples during apnea and during slow wave and rapid eye movement sleep after resumption of respiration. RESULTS: Compared to the placebo, sildenafil was associated with an increase in the normalized high-frequency (HFnu) components and a decrease in the low/high-frequency components of the heart rate variability ratio (LF/HF) in slow wave sleep (p<0.01 for both). Differences in heart rate variability parameters between one-minute post-apnea and apnea samples (&#916;= difference between resumption of respiration and apnea) were assessed. A trend toward a decreasing magnitude of &#916;LF activity was observed during rapid eye movement sleep with sildenafil in comparison to placebo (p=0.046). Additionally, &#916; LF/HF in SWS and rapid eye movement sleep was correlated with mean desaturation (sR= -0.72 and -0.51, respectively, p= 0.01 for both), and &#916; HFnu in rapid eye movement sleep was correlated with mean desaturation (sR= 0.66, p= 0.02) and the desaturation index (sR= 0.58, p = 0.047). CONCLUSIONS: The decrease in arousal response to apnea/hypopnea events along with the increase in HFnu components and decrease in LH/HF components of the heart rate variability ratio during slow wave sleep suggest that, in addition to worsening sleep apnea, sildenafil has potentially immediate cardiac effects in patients with severe obstructive sleep apnea

The effects of obstructive sleep apnea on autonomic function during steady-state exercise

Abstract Purpose: The aim of this study is to assess autonomic function by analyzing heart rate variability (HRV) at rest and during submaximal exercise in OSA patients and a non-OSA control group. Methods: Subjects were classified as OSA (n=10) or non-OSA (n=16) based on results from an at-home sleep assessment. Height, weight, waist and neck circumferences, and body composition were collected during the first visit for each subject. Physical activity during the day and nocturnal movement were assessed over a period of 4 days, including 3 weekdays and 1 weekend day, using accelerometers. HRV and blood pressure were recorded at rest (visit 2) and during a submaximal graded exercise test (visit 3). HRV variables that were not normally distributed were log transformed before statistical analysis. Independent samples t-tests were used to establish differences between groups. Pearson correlations were calculated to determine relationships between OSA and HRV in terms of age and BMI. If there was a significant correlation between variables and age and/or BMI, then a repeated measures ANCOVA was used with age or BMI as the covariate. If there was not a significant correlation, a repeated measures ANOVA was utilized. Results: At rest, the OSA group had lower SDNN, RMSSD, and Total Power (p\u3c0.05). A higher LF-HF ratio was found in the control group than the OSA group during exercise (p\u3c0.05). LFnu and HFnu were trending towards significance, both higher in the OSA group (p=0.066 and p=0.075, respectively) during exercise indicating that the OSA group did not experience parasympathetic withdrawal. All subjects participate in about 30 minutes of moderate physical activity daily. Discussion: Results suggest that the OSA population may have increased autonomic dysfunction during exercise due to sympathetic dominance and a blunted parasympathetic response during steady-state exercise. Potential mechanisms for autonomic imbalances include decreased chemoreceptor and baroreceptor sensitivity. Further research with a larger OSA sample group is necessary