a University of Padova, Padua, Italy
b Medical University of Gdansk, Poland
* Correspondence to: Professor Paolo Palatini, M.D., Clinica Medica 4 University of Padova via Giustiniani, 2-35128 Padova, Italy. Tel.: +39-49-8212278; fax: +39-49-8754179
E-mail address: palatini{at}unipd.it
This editorial refers to "Plasma homocysteine in obstructive sleep apnoea"2 by A. Svatikova et al. on page 1325
Sleep-disordered breathing syndromes are recognised as an important factor for increased morbidity in cardiovascular diseases.1,2 They are characterised by the presence of repetitive episodes of ventilation cessation (apnoea), or airflow reduction (hypopnoea), or both during sleep. This leads to hypoxia, hyperkapnia, several-fold increase in chemoreflex-activated sympathetic activity with consequent peaks in blood pressure exceeding 200/100 mmHg, increased heart rate, frequent arousals, and sleep fragmentation.
In the diagnosis of sleep-related disorders, apnoea is defined as cessation of airflow for a minimum of 10 s while hypopnoea is defined as at least a 30% reduction in airflow accompanied by at least a 4% decrease in oxygen saturation.3 The sleep apnoea syndromes are divided into obstructive (OSA) and central (CSA) types. OSA is characterised by apnoeas associated with continuous respiratory efforts, despite cessation of airflow, while CSA is characterised by apnoeas without concurrent respiratory efforts. OSA is generally more prevalent than CSA, especially in obese subjects, while CSA seems to dominate in heart failure patients.2,4 Severity of sleep apnoea syndromes is measured with the apnoea/hypopnoea index (AHI) number of apnoeas/hypopnoeas per hour and is divided into three classes: mild, moderate and severe. Mild sleep apnoea is defined as AHI 514, moderate as AHI 1530 and severe as AHI more than 30. However, even mild sleep apnoea is associated with important clinical consequences.
OSA is associated with many cardiovascular and metabolic disorders, including hypertension, coronary artery disease, myocardial infarction, arrhythmias, stroke, congestive heart failure, and diabetes, and several large epidemiological studies have shown that OSA is not uncommon and that it often remains undiagnosed. It should be noted that around 40% of OSA subjects have hypertension and more than 70% of patients with resistant hypertension have underlying OSA. In fact, in the recent Seventh Report of the Joint National Committee on Prevention, Diagnosis, Evaluation and Treatment of High Blood Pressure, sleep apnoea is listed as the first identifiable cause of hypertension.5 The presence of habitual snoring, a marker for sleep-disordered breathing syndrome, is associated with a more than 2-fold risk of developing type 2 diabetes mellitus over a 10-year period independently of obesity and other co-variates.6 Prevalence of sleep-disordered breathing is very high in such conditions as congestive heart failure or stroke (3782% and 4372%, respectively) and treatment of sleep-disordered breathing syndromes significantly improves outcome in these clinical settings.4,7
OSA and associated cardiovascular/metabolic disorders share many common risk factors, including overweight/obesity, age, gender (higher prevalence in males) and smoking. However, even these common risk factors explain only a part of the association between sleep apnoea and cardiovascular/metabolic diseases. This observation prompted many investigators to search for other established cardiovascular risk factors which might be the linchpin between sleep apnoea and co-existent cardiovascular diseases. One of these potential risk factors is hyperhomocysteinemia.
Homocysteine is an intermediate product in the metabolism of one of the essential amino acids, methionine. Vitamin B6, B12, and folic acid are important co-factors in homocysteine metabolism and homocysteine level is a good indicator of their deficiencies. Several large studies, both prospective and retrospective, indicated an independent association between hyperhomocysteinemia and cardiovascular disease or all-cause mortality. It has been estimated that hyperhomocysteinemia is responsible for about 10% of total risk of cardiovascular disease and reduction of elevated plasma homocysteine may prevent up to 25% of cardiovascular events.8 The importance of homocysteine as a cardiovascular risk factor is underlined by the fact that cardiovascular risk associated with hyperhomocysteinemia is thought to be equivalent to that of smoking or hyperlipidemia.8
In this issue of the Journal, Svatikova and colleagues addressed the question of whether raised homocysteine levels exist in OSA subjects which might, at least in part, explain increased cardiovascular morbidity in this group of patients. They evaluated the effect of various sleep study protocols and sleep disturbances on the level of homocysteine in 32 OSA patients and 44 closely matched controls. Their results showed that homocysteine levels were not elevated in OSA subjects, in comparison to matched controls, at any time point in the study. Moreover, the diurnal variation of homocysteine levels was preserved in OSA patients and was not influenced by CPAP treatment. In addition, the authors provided evidence that disturbed sleep in subjects without occult OSA also had no effect on homocysteine levels.
The results of this study are of relevant clinical interest and are similar to those obtained by Lavie and colleagues,9 who also did not find increase in homocysteine levels in otherwise healthy OSA subjects, although they did find increased levels of homocysteine in OSA patients with concurrent ischaemic heart disease or hypertension. The strength of the present study is that the authors avoided several common pitfalls when studying physiological effects in OSA, such as not matching for body weight with controls or the presence of concomitant diseases in the OSA group. It may be of interest to note that the last pitfall is particularly common in many previous studies. The reason for this is that the probability of diagnosis of OSA is increased in subjects with already present, and in many cases unsuccessfully treated, associated diseases. That is why many investigators often included OSA subjects with concomitant diseases in their studies, which may hamper the ability to generalise the results.
This consideration applies also to studies on homocysteine. Taking into account concomitant diseases and/or associated treatment is of crucial importance when evaluating homocysteine levels in a given sample. Both concomitant diseases (for example vascular disease) and specific treatments commonly used in cardiovascular and metabolic syndromes (for example fibrates, niacin, cholestyramine, metformin) influence homocysteine levels.8 Therefore, inclusion of only obese but otherwise healthy subjects without any medication in the study strengthens the results obtained by Svatikova and colleagues. This consideration may also explain why, at variance with the results recently obtained by Jordan and colleagues in a small group of OSA patients, in the present paper homocysteine level was not influenced by CPAP treatment. In fact, over 60% of Jordan and colleagues' patients had hypertension or diabetes. Another possible reason for the discrepant results obtained in the two laboratories is that in the Jordan and colleagues'10 study post-treatment homocysteine was assessed after long-term CPAP treatment.
The relevance of the Svatikova and colleagues' results is further strengthened by the evaluation of the effect of different sleep study protocols, which were characterised by different lengths of undisturbed OSA sleep, on homocysteine levels and by evaluation of the effect of disturbed sleep on homocysteine levels in healthy volunteers. Moreover, the authors' evaluation of the possible influence of OSA on homocysteine was made with several measurements throughout the day and night, taking into account the diurnal variation of homocysteine.
The authors' conclusion, that homocysteine levels are unlikely to contribute to cardiac and vascular morbidity in obese but otherwise healthy OSA patients, may be debatable. Homocysteine and OSA share many common pathophysiological pathways inflicting damage to the cardiovascular system. First, hyperhomocysteinemia is associated with increased endothelin-1 level and decreased nitric oxide bioavailability which may lead to endothelial dysfunction. Following a similar path, in sleep apnoeic subjects, an increase in level of endothelin-1, following OSA sleep, has been noted and a blunted endothelial release of nitric oxide leading to impairment of resistance-vessel endothelium-dependent vasodilation has been described. Second, both hyperhomocysteinemia and OSA increase vascular oxidative stress by increasing the production of highly reactive free oxygen radicals. Third, homocysteine increases the adhesion of leukocytes to the vascular wall by increasing levels of adhesion molecules, like ICAM-1 and VCAM-1, which is conducive to atherosclerosis, a mechanism also seen in OSA subjects. Fourth, both OSA and hyperhomocysteinemia are associated with increase in levels of C-reactive protein, one of the novel cardiovascular risk factors. Last, a facilitation to cloth formation has been reported in OSA subjects as a consequence of increased blood viscosity, raised hematocrit and fibrinogen levels, and increased platelet aggregation, effects which have also been observed in hyperhomocysteinemic patients (for a detailed review see Stanger et al.8 and Shamsuzzaman et al.11). Taking into account all of these similarities, it is reasonable to assume that the sum of the effects of homocysteine and OSA on the cardiovascular system may be higher than the effect of each of these factors alone. Therefore, the level of homocysteine considered tolerable for subjects without OSA might be detrimental and worthy of treatment in subjects with OSA. However, to our knowledge, no study addressed the question of desirable level of homocysteine in OSA patients.
In summary, the present evidence indicates that homocysteine is not elevated in obese, but otherwise healthy, OSA subjects. Nevertheless, there remains several important questions to be answered. The combined effect of OSA and homocysteine on the cardiovascular system may be enhanced, especially in subjects with concomitant cardiovascular diseases and lower levels of homocysteine might be desirable in these individuals. The second and possibly more pressing question is whether CPAP may be effective for reducing homocysteine level in OSA patients with associated cardiovascular diseases in whom higher levels of homocysteine are currently seen.9,10 The data recently reported by Jordan and colleagues10 who found a 30% decrease in homocysteine level with long-term CPAP treatment offer a promising perspective on this point, but these results were obtained in a small sample of patients mostly with hypertension or diabetes. Thus, larger, controlled randomised trials in patients with and without cardiovascular diseases will be required to prove the clinical efficacy of CPAP in reducing homocysteine level in OSA patients.
Footnotes
1 Dr. Winnicki is currently supported by a Grant from the University of Padova, Italy, for Post-Doc Candidates from the European Countries.
2 doi:10.1016/j.ehj.2004.05.018.
References
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