Nikolaus Büchner

Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

BackgroundThe increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent.MethodsWe investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes.ResultsMultivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023).ConclusionOur study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile.

Microvascular Endothelial Dysfunction in Obstructive Sleep Apnea Is Caused by Oxidative Stress and Improved by Continuous Positive Airway Pressure Therapy

Background: Endothelial dysfunction has recently been demonstrated in obstructive sleep apnea (OSA), but the underlying mechanisms are not entirely understood. Oxidative stress is a typical feature of OSA. Objectives: We investigated the influence of oxidative stress and continuous positive airway pressure (CPAP) on microvascular endothelial function in OSA. Methods: Endothelial function of forearm resistance vessels was assessed by strain gauge venous occlusion plethysmography after intra-arterial infusion of the endothelium-independent vasodilator sodium nitroprusside (1.6, 3.2, and 4.0 µg/min) and the endothelium-dependent vasodilator acetylcholine (Ach, 15, 30 and 40 µg/min) in patients with (n = 11) and without (n = 8) OSA (apnea-hypopnea index ≧15/h). These measurements have been repeated after local intra-arterial infusion of the antioxidant vitamin C (25 µg/min). Furthermore, 6 patients have been reevaluated after 6 months of OSA treatment. Results: Patients with OSA demonstrated impaired endothelial function compared to those without OSA. Thus, related to baseline flow, the increase in forearm blood flow induced by Ach was blunted in patients with OSA (148.7 ± 29.7% in OSA vs. 233.6 ± 45.7% in controls, p = 0.001). This difference, however, was abolished by co-infusion of vitamin C. Endothelial function markedly improved following treatment in 5 of 6 OSA patients. Conclusions: This study strongly suggests that microvascular endothelial function is affected by OSA predominantly through increased oxidative stress, and treatment of OSA may improve endothelial function mainly by reducing oxidative stress. The role of oxidative stress-induced endothelial dysfunction as a potential promoter of atherosclerosis and an increased cardiovascular risk in patients with OSA should be investigated in further controlled studies.

Eosinophilic gastroenteritis in a young girl – long term remission under Montelukast

BackgroundEosinophilic gastrointestinal disorders are an emerging disease entity characterized by eosinophilic infiltration of the intestinal wall. Oral steroids can be still considered as first line treatment. Unfortunately relapses are quite common. Usually long term low-dose prednisone or immunosuppressive therapy is required, which is especially problematic in young patients. Thus a reliable steroid sparing agent with low side effects suitable for long term use is needed. There are strong hints to a similar pathophysiology of eosinophilic gastrointestinal disorders to that of asthma. Indeed leukotriene D4 plays an important role in the recruitment of eosinophils into the intestinal tissue causing damage. This patho-mechanism provides the rationale for the treatment with a leukotriene D4 receptor antagonist. Recently there have been first reports about successful short term use of Montelukast in eosinophilic gastrointestinal disorders.Case presentationWe report the case of a 17 year old girl with a long history of severe abdominal complaints leading to several hospitalizations in the past. Mimicking the picture of an intestinal tuberculosis she received an anti mycobacterial treatment without any success. Marked eosinophilia in blood, ascites and tissue samples of the intestinal tract finally lead to the diagnosis eosinophilic gastroenteritis. Tapering off prednisone caused another severe episode of abdominal pain. At that point leukotriene antagonist Montelukast was started at a dose of 10 mg once daily. Steroids could be tapered off completely within six weeks. The patient has been free of symptoms for over two years by now. Routine examinations, blood tests and endoscopy have rendered regular results. So far no side effects were noted.ConclusionHere report about successful long term remission of eosinophilic gastroenteritis under Montelukast. Further randomized control trials are required to asses the full benefits of Montelukast therapy in the whole spectrum of eosinophilic gastrointestinal disorders.

Modifying effects of the R389G beta1-adrenoceptor polymorphism on resting heart rate and blood pressure in patients with obstructive sleep apnoea.

OSA (obstructive sleep apnoea) stimulates sympathetic nervous activity and elevates resting HR (heart rate) and BP (blood pressure). In the present study in a cohort of 309 untreated OSA patients, the resting HR and BP during the daytime were correlated with AHI (apnoea/hypopnea index) and compared with patients with R389R (n = 162), R389G (n = 125) and G389G (n = 22) genotypes of the beta1-adrenoreceptor R389G polymorphism. We analysed the impact of the genotype on the decline of HR and BP in a subgroup of 148 patients (R389R, n = 86; R389G, n = 54; G389G, n = 8) during a 6-month follow-up period under CPAP (continuous positive airway pressure) therapy during which cardiovascular medication remained unchanged. In untreated OSA patients, we found an independent relationship between AHI and resting HR (beta = 0.096, P < 0.001), systolic BP (beta = 0.09, P = 0.021) and diastolic BP (beta = 0.059, P = 0.016). The resting HR/BP, however, did not differ among carriers with the R389R, R389G and G389G genotypes. CPAP therapy significantly reduced HR [-2.5 (-1.1 to -4.0) beats/min; values are mean difference (95% confidence intervals)] and diastolic BP [-3.2 (-1.5 to -5.0) mmHg]. The decline in HR was more significantly pronounced in the R389R group compared with the Gly(389) carriers [-4.1 (-2.3 to -5.9) beats/min (P < 0.001) compared with -0.2 (2.1 to -2.6) beats/min (P = 0.854) respectively; Students t test between groups, P = 0.008]. Diastolic BP was decreased significantly (P < 0.001) only in Gly389 carriers (R389G or G389G) compared with R389R carriers [-5.0 (-2.3 to -7.6) mmHg compared with -2.0 (0.4 to -4.3) mmHg respectively]. ANOVA revealed a significant difference (P = 0.023) in HR reduction between the three genotypes [-4.1 (+/-8.4) beats/min for R389R, -0.5 (+/-9.3) beats/min for R389G and +1.9 (+/-7.2) beats/min for G389G]. In conclusion, although the R389G polymorphism of the beta1-adrenoceptor gene did not influence resting HR or BP in untreated OSA patients, it may modify the beneficial effects of CPAP therapy on these parameters.

The renal resistance index is increased in mild-to-moderate obstructive sleep apnoea and is reduced under continuous positive airway pressure

BACKGROUND Impaired renal function has recently been reported in obstructive sleep apnoea (OSA). The underlying mechanisms, however, are not entirely understood. This study investigated the influence of mild-to-moderate OSA and its treatment on renal haemodynamics as assessed by the renal resistance index (RRI). METHODS RRI has been measured by colour duplex ultrasound in 64 patients with newly diagnosed mild-to-moderate OSA and 61 controls without OSA at baseline and follow-up after 9.9 months. Treatment with continuous positive airway pressure was offered to all patients with OSA (apnoea/hypopnoea index ≥ 5/h). RESULTS Increased values of RRI (≥ 1 SD [8.9%] above the age-adjusted normal value) were found in 41 out of 64 (64.0%) OSA patients when compared with 20 out of 61 (32.8%) controls (P < 0.001). The corresponding mean RRI was 70.50 ± 9.01 vs 66.51 ± 8.33 (P = 0.012). In multivariate analyses, the influence of OSA on RRI was independent from hypertension, diabetes mellitus, age and baseline renal function. At follow-up, RRI decreased only in patients with effective OSA treatment but remained unchanged in ineffectively treated OSA patients and controls. CONCLUSIONS For the first time, this prospective controlled observational study demonstrates an impairment of renal haemodynamics in OSA as measured by an increased RRI. These changes of renal blood flow may identify OSA patients at high risk of declining renal function. Both parenchymal and vascular renal diseases are proposed as pathomechanisms for this association. An effective treatment of OSA resulted in a decreased RRI, suggesting an improvement in renal perfusion. Further studies are needed to elucidate the role of impaired renal haemodynamics in OSA.

Pathophysiologie der Hypertonie : Was gibt es Neues?

ZusammenfassungDie Pathophysiologie der primären Hypertonie ist nach wie vor ungeklärt und erscheint komplexer als je zuvor. Es ist daher nicht das Ziel dieser Übersicht, alle neuen wissenschaftlichen Erkenntnisse auf diesem Gebiet darzustellen. Die Aufteilung der arteriellen Hypertonie erfolgt nach klinischen Kriterien in primäre und sekundäre Formen. Die Autoren diskutieren die Pathophysiologie der Hypertonie, die eng mit drei häufigen Krankheitsentitäten assoziiert ist und große Überlappungen mit der primären Hypertonie zeigt: chronische Nierenerkrankungen, obstruktive Schlafapnoe (OSA) und Hyperaldosteronismus. Insbesondere für chronische Nierenerkrankungen und OSA spielt die Aktivierung des sympathischen Nervensystems eine entscheidende Rolle. Nach Überzeugung der Autoren ist die Hypertonie als Folge einer dieser drei Erkrankungen viel häufiger als bisher angenommen und macht möglicherweise 20% der hypertensiven Population aus. Die Kenntnis der zugrundeliegenden Pathophysiologie erlaubt eine frühe Diagnose und leitet die optimale Therapie dieser hypertensiven Patienten.AbstractThe pathophysiology of primary hypertension is still unresolved and appears more complex than ever. It is beyond the scope of this article to review all new scientific developments in this field. On clinical grounds, hypertension is divided into primary and secondary forms. Here, the authors discuss the pathophysiology of hypertension associated with three common disease entities showing a large overlap with primary hypertension: chronic kidney disease (CKD), obstructive sleep apnea (OSA), and hyperaldosteronism. Especially in CKD and OSA, the activation of the sympathetic nervous system plays a crucial role. It is the authors’ belief that hypertension due to these three diseases is more common than previously appreciated and may account for about 20% of the hypertensive population. The knowledge of the underlying pathophysiology allows early diagnosis and guides optimal treatment of these hypertensive patients.

Polysomnography in acute African trypanosomiasis.

Sirs: Sleeping sickness is one of the sleep disorders listed in the International Classification of Sleep Disorders (3.C.1). To date there have been only few reports of sleep studies in chronic sleeping sickness [1, 2, 3] and, to our knowledge, no reports of sleep studies in acute sleeping sickness. We describe a case of acute African trypanosomiasis with disturbed sleep following travel to the tropics and the results of the sleep studies in this patient. A 47-year-old woman was admitted to hospital because of high remittent fever, insomnia during night, hypersomnia by day, and jaundice. Symptoms had started 5 days prior to admission, 7 days after returning from a 20-day trip to Zambia, Zimbabwe, and Tanzania. The patient had a fever of 39.2°C, an ulcerated and indurated lesion of 3 cm in diameter at the right first carpometacarpal joint, discrete nontender axillary lymphadenopathy on the right side, and jaundice. Abdominal ultrasound, chest radiography, and echocardiography on the day of admission were completely normal. Three blood cultures and microscopy of blood smears isolated no organisms. During the next 2 days her condition deteriorated, fever rose to 40.9°C, she became more sleepy during the day and was restless at night, and developed multiorgan failure with hepatitis, myocarditis, nephritis, pancreatitis, polyserositis, and disseminated intravascular coagulation. Again, microscopy of peripheral blood smears was performed, and this time trypanosomes were found. The indirect fluorescent antibody test for African trypanosomiasis was initially negative but turned positive (1:20) during the following 3 days. Due to the history, clinical findings, and microscopy results acute infection with Trypanosoma brucei rhodesiense with septic and multiorgan involvement was diagnosed. Treatment with suramin was initiated immediately, and she recovered completely over the following days. Lumbar puncture was performed on day 9 of suramin treatment, when there were no more trypanosomes in the peripheral blood smear, and the platelet count was normal; this yielded no direct evidence of central nervous system involvement. Total protein level of the spinal fluid was slightly elevated (0.65 g/l), but there was an increase neither in cells nor in the IgM level. Free immunoglobulin light chains were not present. Polysomnography was performed according to widely accepted methods on days 7, 9, and 15 and 6 months after the onset of trypanosomiasis [4]. Sleep was staged manually using the methods of Rechtschaffen and Kales [5], and arousals and leg movements were classified according to ASDA recommendations [6, 7]. Sleep examination revealed a poor sleep efficiency and decreased slow wave sleep, while the amount of arousals and awakenings was increased (Table 1). Furthermore, the patient had periodic limb movements (PLM) during sleep with a PLM index of 27.2/h and a PLM arousal and wake index of 11.7/h. Repeat polysomnographic measurements during follow-up showed an increase in sleep efficiency and amount of slow wave sleep and a decrease in arousals and awakenings, but PLM remained. MRI of the brain conducted on day 10 of disease onset showed a small angioma at the right frontal pole and was otherwise unremarkable. Mobile long-term EEG recording (24 h duration) was performed on day 22. The eight-channel monitoring revealed an alpha rhythm (10/s) with recurrent short naps (nonrapid eye movement sleep 2) during the day. Night recording confirmed polysomnographic data showing a poor sleep efficiency with frequent awakenings and arousals. At sleep onset generalized high theta activity and steep potentials were observed. There were no signs of encephalitis. Laboratory examination on day 25 after onset of the disease showed normal values for vitamin B1, vitamin B6, and vitamin E. The nerve conduction study using surface electrodes to record compound muscle action potentials revealed prolonged conduction velocity of the right peroneal nerve (38 m/s), left tibial nerve (34 m/s), and left LETTER TO THE EDITORS

[Pathophysiology of hypertension: what's new?].

ZusammenfassungDie Pathophysiologie der primären Hypertonie ist nach wie vor ungeklärt und erscheint komplexer als je zuvor. Es ist daher nicht das Ziel dieser Übersicht, alle neuen wissenschaftlichen Erkenntnisse auf diesem Gebiet darzustellen. Die Aufteilung der arteriellen Hypertonie erfolgt nach klinischen Kriterien in primäre und sekundäre Formen. Die Autoren diskutieren die Pathophysiologie der Hypertonie, die eng mit drei häufigen Krankheitsentitäten assoziiert ist und große Überlappungen mit der primären Hypertonie zeigt: chronische Nierenerkrankungen, obstruktive Schlafapnoe (OSA) und Hyperaldosteronismus. Insbesondere für chronische Nierenerkrankungen und OSA spielt die Aktivierung des sympathischen Nervensystems eine entscheidende Rolle. Nach Überzeugung der Autoren ist die Hypertonie als Folge einer dieser drei Erkrankungen viel häufiger als bisher angenommen und macht möglicherweise 20% der hypertensiven Population aus. Die Kenntnis der zugrundeliegenden Pathophysiologie erlaubt eine frühe Diagnose und leitet die optimale Therapie dieser hypertensiven Patienten.AbstractThe pathophysiology of primary hypertension is still unresolved and appears more complex than ever. It is beyond the scope of this article to review all new scientific developments in this field. On clinical grounds, hypertension is divided into primary and secondary forms. Here, the authors discuss the pathophysiology of hypertension associated with three common disease entities showing a large overlap with primary hypertension: chronic kidney disease (CKD), obstructive sleep apnea (OSA), and hyperaldosteronism. Especially in CKD and OSA, the activation of the sympathetic nervous system plays a crucial role. It is the authors’ belief that hypertension due to these three diseases is more common than previously appreciated and may account for about 20% of the hypertensive population. The knowledge of the underlying pathophysiology allows early diagnosis and guides optimal treatment of these hypertensive patients.

A Rare Cause of Pulmonary-Renal Syndrome

Diseases affecting both the lung and the kidney have grave prognosis and serious diagnostic and therapeutic consequences. Here, 3 cases of pulmonary-renal syndrome caused by antiphospholipid syndrome are reported. The patients presented with dyspnea, renal insufficiency, pulmonary infiltrates on chest X-ray and areas of ground glass attenuation on computed tomography of the lungs. There were no signs of infectious disease, vasculitis or myocardial insufficiency. Clinical findings, antiphospholipid levels and histological findings in transbronchial and/or renal biopsy proved the diagnosis of antiphospholipid syndrome. Antiphospholipid syndrome is a comparatively rare disorder which is relevant in the differential diagnosis of diseases affecting both lung and kidney and requires specific therapeutic measures.

[Sleep apnea--treatment improves hypertension].

ZusammenfassungDie obstruktive Schlafapnoe und die arterielle Hypertonie sind sehr häufige, aber leider auch oft nicht erkannte Erkrankungen. Der ursächliche Zusammenhang von Schlafapnoe und Hypertonie ist gesichert. Wahrscheinlich ist die undiagnostizierte Schlafapnoe die häufigste Ursache der früher so genannten „essentiellen“ Hypertonie. Besonders wichtig erscheint daher die Identifikation dieser Patienten. Bei allen Hypertonikern sollten nach Schnarchen, Atemstillständen und Tagesmüdigkeit gefragt werden, der Halsumfang gemessen und ggf. eine ambulante Messung der nächtlichen Atmung (kardiorespiratorische Polygraphie) erfolgen. Insbesondere sollten alle Patienten mit schwer einstellbarer Hypertonie oder fehlender Nachtabsenkung in der 24-h-Blutdruckmessung auf ein obstruktives Schlafapnoesyndrom gescreent werden. Umgekehrt sollten alle Patienten mit Schlafapnoe gezielt auf eine arterielle Hypertonie untersucht werden. Da bei diesen Patienten auch nur eine nächtliche arterielle Hypertonie vorliegen kann, reichen Einzelmessungen am Tage nicht aus, um einen Bluthochdruck sicher auszuschließen.Die CPAP-Therapie („continuous positive airway pressure“) kann den Blutdruck bei hypertensiven Schlafapnoepatienten effektiv senken. Dies gilt besonders für Patienten mit obstruktiver Schlafapnoe und therapierefraktärer Hypertonie. Für nächtliche, durch Schlafapnoe induzierte Blutdruckspitzen scheint die CPAP-Therapie die zurzeit am besten dokumentierte Therapieform zu sein.AbstractObstructive sleep apnea and arterial hypertension are frequent diseases, but they are also often overlooked. There is a causal relationship of sleep apnea and hypertension. Undiagnosed sleep apnea is probably the most important reason for “essential” hypertension. It is important to identify these patients. All hypertensive patients should be asked for snoring, breathing arrest and daytime sleepiness, neck circumference should be measured, and an ambulant sleep apnea monitoring should be performed, if necessary. Especially patients with refractory hypertension or non-dippers should be screened for sleep apnea and patients with sleep apnea should be examined for arterial hypertension.Continuous positive airway pressure (CPAP) can effectively lower blood pressure in the hypertensive sleep apnea patient. This is especially true for the obstructive sleep apnea patient with refractory hypertension. CPAP therapy is probably the best therapy for sleep apnea-induced nocturnal blood pressure rises.