Sleep Apnea in Marfan's Syndrome: Increased Upper Airway Collapsibility During Sleep

doi:10.1378/chest.108.3.631

Chest

Volume 108, Issue 3, September 1995, Pages 631-635

https://doi.org/10.1378/chest.108.3.631 Get rights and content

Marfan's syndrome is a hereditary disorder characterized by a defect in connective tissue, resulting in tissue laxity. It is associated with a high prevalence of obstructive sleep apnea (OSA). The aim of this study was to determine whether excessive upper airway collapsibility during sleep is an important pathophysiologic factor predisposing these individuals to OSA. We measured upper airway closing pressures (UACP) during sleep in 12 patients with Marfan's syndrome and 6 age-, and height-, and weight-matched control subjects. Ten of the patients had OSA, defined as an apnea/hypopnea index >5. All patients with Marfan's syndrome, including the two patients without OSA, demonstrated increased upper airway collapsibility during sleep, with a mean UACP of −2.5 ± 0.5 cm H₂O during slow-wave sleep (SWS). In contrast, only two control subjects demonstrated upper airway closure. However, this was at significantly higher suction pressures, with a mean UACP of −5.6 ± 0.4 cm H₂O during SWS (p<0.005). These data suggest that patients with Marfan's syndrome have abnormally increased upper airway collapsibility during sleep. It is possible that this is related to the characteristic connective tissue defect of this disorder.

Section snippets

METHODS

We studied 12 patients with Marfan's syndrome (8 men, 4 women) who had previously undergone standard nocturnal polysomnography as part of a prevalence study.⁷ All of these patients had been randomly recruited from the Marfan clinic at our institution. Ten of the patients in this study were randomly recruited from the original cohort; the remaining two patients were specifically selected because they were the only nonsnoring, nonapneic patients. We compared them with six age-, height-, and

RESULTS

Anthropomorphic data are presented in Table 1. Patients had mean age of 34 ± 3 years, mean height of 183 ± 3 cm, and mean weight of 73 ± 4 kg. Control subjects were well matched for age, height, and weight. The control group consisted of five men and one woman, while the patient group consisted of eight men and four women. Ten of the 12 patients were previously shown to have mild to moderate OSA on standard polysomnography, with a mean AHI of 25 ± 4/h (range, 6 to 48), and mean minimum oxygen

DISCUSSION

In a previous study, we showed that 64% of randomly recruited patients with Marfan's syndrome (n=25) had OSA, with a mean AHI of 20 ± 3.⁷ These patients are quite different from the typical sleep apnea population—they are tall, thin, and young. Therefore, it is possible that different mechanisms are important in the pathogenesis of OSA in this group. Our data herein demonstrate that patients with Marfan's syndrome have significantly increased upper airway collapsibility during sleep compared

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Cited by (50)

Respiratory manifestations of Marfan's syndrome
2015, Revue des Maladies Respiratoires
Le syndrome de Marfan est une maladie génétique rare liée à la mutation du gène FBN1, codant la fibrilline. Les atteintes cardiovasculaires, squelettiques et ophtalmologiques sont les plus fréquentes, mais la maladie peut toucher le poumon. Les pneumothorax atteignent 5 à 11 % des patients. Le rôle favorisant des déformations thoraciques (pectus excavatum et carinatum) ou des blebs reste débattu. Leur prise en charge est identique à celle de tout pneumothorax spontané, mais le risque de récidive est élevé. Le pectus excavatum touche jusqu’à 60 % des patients, le plus souvent sans retentissement fonctionnel. En cas de mauvaise tolérance, un traitement chirurgical peut être envisagé par la technique de Nuss. La prévalence du syndrome d’apnées obstructives du sommeil semble élevée dans le syndrome de Marfan, et sa présence pourrait contribuer à la dilatation aortique. La responsabilité des anomalies cranio-faciales associées aux apnées du sommeil a été évoquée, sans certitude à ce jour. Il est important pour un pneumologue d’évoquer le diagnostic de syndrome de Marfan chez un patient présentant des pneumothorax spontanés récidivants ou une déformation thoracique, car la prise en charge précoce de l’atteinte cardiaque conditionne le pronostic.
Marfan's syndrome is a rare genetic disorder caused by a mutation of the gene FBN1, coding for the protein fibrillin-1. Cardiovascular, musculoskeletal and ophthalmic manifestations are the most commonly observed, but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients. Rib cage abnormalities (pectus excavatum or pectus carinatum) and apical blebs may contribute to their occurrence. Treatment does not require any specific procedure but there is an increased risk of recurrence. Pectus excavatum affects up to 60% of the patients, without any functional impairment in most cases. Surgery may be required (using the Nuss procedure) in case of cardiovascular or psychological symptoms. Marfan's syndrome is frequently associated with obstructive sleep apnoea, which may itself contribute to aortic dilatation. Some studies suggest a potential role of craniofacial abnormalities in the pathogenesis of sleep apnea in these patients. Pulmonologists should consider Marfan's syndrome when treating patients for recurrent spontaneous pneumothorax or rib cage abnormalities, since early detection of cardiac abnormalities improves the prognosis significantly.
Increased upper airway collapsibility in a mouse model of Marfan syndrome
2015, Respiratory Physiology and Neurobiology
Citation Excerpt :
The results from this work shows that Pcrit in MFS is reduced independently of weight gain, which could be translated in a higher risk of collapsibility of the upper airway in MFS patients with substantially relatively low body mass index. This increase in collapsibility can explain the higher prevalence of sleep-disordered breathing described in patients with MFS with regard to the general population (Cistulli and Sullivan, 1995; Kohler et al., 2009). The prevalence of OSA in MFS patients has important clinical implications since OSA can worsen the cardiovascular problems inherent to MFS.
Marfan syndrome (MFS) is a genetic disorder caused by mutations in the FBN1 gene that codifies for fibrilin-1. MFS affects elastic fiber formation and the resulting connective tissue shows abnormal tissue laxity and organization. Although an increased prevalence of obstructive sleep apnea among patients with MFS has been described, the potential effects of this genetic disease on the collapsible properties of the upper airway are unknown. The aim of this study was to assess the collapsible properties of the upper airway in a mouse model of MFS Fbn1(^C1039G/+) that is representative of most of the clinical manifestations observed in human patients. The upper airway in wild-type and Marfan mice was cannulated and its critical pressure (P_crit) was measured in vivo by increasing the negative pressure through a controlled pressure source. P_crit values from MFS mice were higher (less negative) compared to wild-type mice (−3.1 ± 0.9 cmH₂O vs. −7.8 ± 2.0 cm H₂O) suggesting that MFS increases the upper airway collapsibility, which could in turn explain the higher prevalence of OSA in MFS patients.
Connective Tissue Diseases
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
Marfan's syndrome: Clinical manifestations in the oral-craniofacial area, biophysiological roles of fibrillins and elastic extracellular microfibers, and disease control of the fibrillin gene
2013, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
Since French investigator Bernard-Jean Antoine Marfan's first report in 1896 on malformations of the head and bone system, the clinical manifestations of Marfan's syndrome have now been well established. Marfan's syndrome is a multisystem disorder that commonly affects the connective tissue associated with craniofacial skeletal lesions and cardiopulmonary disorders including sleep apnea. This article reviews current knowledge of craniofacial abnormalities in Marfan's syndrome and its genetic backgrounds.
A strong correlation was found between maxillae/mandibular retrognathia, a long face, and a highly arched palate, and there were also many cephalometric features. Patients with Marfan's syndrome had severe periodontitis, with the majority of periodontal fibers being collagen, elastic, and oxytalan. Fibrillin-1 has been associated with microfibers and the gene of Marfan's syndrome is FBN1, which encodes fibrillin-1, a major microfibrillar protein. Activation of the signaling of TGF-β is thought to cause the pathogenesis of the cardiovascular abnormalities associated with this syndrome. The bone matrix, including fibrillin-1 and -2 in the major structural components of extracellular microfibrils, is the preeminent storage site of TGF-β and BMP.
The present review highlighted genetic disorders as a mutation of the fibrillin gene of Marfan's syndrome as well as clinical manifestations including cardiovascular lesions in addition to craniofacial characteristics.
Prospective risk stratification of sudden cardiac death in Marfan's syndrome
2013, International Journal of Cardiology
Citation Excerpt :
Rybczynski et al. [23] recently found obstructive (OSA) and central (CSA) sleep apnea in 31% of all MFS patients. It is suggested that upper airway collapsibility, high nasal airway resistance, and craniofacial abnormalities are possible causal mechanisms of OSA in MFS [24–26]. It was also pointed out that sleep apnea was independently associated with decreased LVEF and increased NT-proBNP serum levels [23].
Marfan syndrome (MFS) is a variable, autosomal-dominant disorder of the connective tissue. In MFS serious ventricular arrhythmias and sudden cardiac death (SCD) can occur. The aim of this prospective study was to reveal underlying risk factors and to prospectively investigate the association between MFS and SCD in a long-term follow-up.
77 patients with MFS were included. At baseline serum N-terminal pro-brain natriuretic peptide (NT-proBNP), transthoracic echocardiogram, 12-lead resting ECG, signal-averaged ECG (SAECG) and a 24-h Holter ECG with time- and frequency domain analyses were performed. The primary composite endpoint was defined as SCD, ventricular tachycardia (VT), ventricular fibrillation (VF) or arrhythmogenic syncope.
The median follow-up (FU) time was 868 days. Among all risk stratification parameters, NT-proBNP remained the exclusive predictor (hazard ratio [HR]: 2.34, 95% confidence interval [CI]: 1.1 to 4.62, p = 0.01) for the composite endpoint. With an optimal cut‐off point at 214.3 pg/ml NT-proBNP predicted the composite primary endpoint accurately (AUC 0.936, p = 0.00046, sensitivity 100%, specificity 79.0%). During FU, seven patients of Group 2 (NT-proBNP ≥ 214.3 pg/ml) reached the composite endpoint and 2 of these patients died due to SCD. In five patients, sustained VT was documented. All patients with a NT-proBNP < 214.3 pg/ml (Group 1) experienced no events. Group 2 patients had a significantly higher risk of experiencing the composite endpoint (logrank-test, p < 0.001).
In contrast to non-invasive electrocardiographic parameter, NT-proBNP independently predicts adverse arrhythmogenic events in patients with MFS.
Frequency of Sleep Apnea in Adults With the Marfan Syndrome
2010, American Journal of Cardiology
Citation Excerpt :
Thus, we suggest screening patients with Marfan syndrome even when sleep apnea is not clinically suspected. Cistulli et al2,18,19 suggested upper airway collapsibility, high nasal airway resistance, and craniofacial abnormalities as causal mechanisms of OSA in Marfan syndrome, whereas Kohler et al3 did not find increased frequencies of retrognathia or abnormalities of mean neck circumference, cricomental distance, and Mallampati score in their patients. Kohler et al used ApneaLink type 4 devices (ResMed, MAP Medicine Technology, Martinsried, Germany), which permitted only flow limitations and snoring to be measured3 but which were therefore of limited use for distinguishing OSA from CSA.
Obstructive and central sleep apneas are treatable disorders, which contribute to cardiovascular morbidity in older adults. Younger adults with Marfan syndrome may also be at risk for sleep apnea, but the relation between cardiovascular complications and sleep apnea is unknown. We used MiniScreen8 portable monitoring devices for polygraphy in 68 consecutive adults with Marfan syndrome (33 men, 35 women, 41 ± 14 years old) to investigate frequency of sleep apnea and its relation to cardiovascular morbidity. The apnea–hypopnea index (AHI) was 6 to 15/hour in 14 subjects (mild sleep apnea, 21%), and AHI was >15/hour in 7 subjects (moderate or severe sleep apnea, 10%). Among established risk factors for sleep apnea, only older age (Spearman rho = 0.35, p = 0.004) and body mass index (rho = 0.26, p = 0.03) were associated with increased AHI. Of all cases of apnea, 12 ± 27 were obstructive, 11 ± 25 central, and 3 ± 9 mixed. AHI was associated with decreased left ventricular ejection fraction (rho = −0.33, p = 0.01), increased N-terminal pro–brain natriuretic peptide levels (rho = 0.35, p = 0.004), enlarged descending aortic diameters (rho = 0.44, p = 0.001), atrial fibrillation (phi = 0.43, p = 0.002), and mitral valve surgery (phi = 0.34, p = 0.02). Of these, left ventricular ejection fraction, N-terminal pro–brain natriuretic peptide levels, atrial fibrillation, and mitral valve surgery were associated with AHI independently of age and body mass index. We found similar associations with oxygen desaturation index. In conclusion, sleep apnea exhibits increased frequency in Marfan syndrome and is not predicted by classic risk factors. Obstructive and central sleep apneas may relate to cardiovascular disease variables.

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: Supported by a scholarship from the National Health and Medical Research Council of Australia (Dr. Cistulli).

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Clinical Investigations: Sleep and BreathingSleep Apnea in Marfan's Syndrome: Increased Upper Airway Collapsibility During Sleep

Section snippets

METHODS

RESULTS

DISCUSSION

Prog Cardiovasc Dis

Lancet

J Biol Chem

The Marfan syndrome: diagnosis and management.

N Engl J Med

The Marfan syndrome.

Am Fam Physician

Life expectancy and causes of death in the Marfan syndrome.

N Engl J Med

Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome.

N Engl J Med

Sleep-disordered breathing in Marfan's syndrome.

Am Rev Respir Dis

Snoring and sleep apnoea in men: association with central obesity and hypertension.

Int J Obesity

Immunohistological abnormalities of microfibrillar-fiber system in the Marfan syndrome.

N Engl J Med

Upper airway closing pressures in obstructive sleep apnea.

J Appl Physiol

Clinical Investigations: Sleep and Breathing
Sleep Apnea in Marfan's Syndrome: Increased Upper Airway Collapsibility During Sleep