Discussion
To our knowledge this is the largest to date meta-analysis investigating the relationship between OSA and echocardiographic parameters of DD. An association between obstructive sleep apnea DD parameters was demonstrated which was independent of other risk factors.
Although cumulative data from observational studies have linked OSA with increased risk of DD, it has been argued that this association is driven mainly by the significant burden of cardiovascular risk factors observed in patients with OSA. To overcome this argument, we only included studies in which OSA patients were free from major cardiac risk factors. Therefore, our study results suggest a direct relationship between OSA and DD.
Of the numerous echocardiographic parameters mentioned, the American society of echocardiography (ASE) guidelines gives prominence to that the mitral inflow velocity ratios of E/A, e′ as an estimation of LV filling pressure, left atrium volume index (LAVI), tricuspid regurgitation velocity and deceleration time in the assessment of the presence of DD. Two principal mechanisms are responsible for DD including impaired ventricular relaxation and increased passive myocardial stiffness (or decreased compliance). In grade I DD, there is impaired relaxation due to increased stiffness of the left ventricular chamber, resulting in slow early diastolic filling. LV relaxation is affected by load, inactivation, and asynchrony. Increased LV afterload leads to delayed and slow relaxation (6).
Sleep related breathing disorders including OSA exert a wide range of deleterious cardiovascular effects via direct and indirectly mechanisms. The repetitive episodes of apnea or hypopnea are associated with intermittent hypoxia, hypercapnia, increasingly negative intrathoracic pressure and sympathetic overdrive which all adversely affect the cardiovascular system. The hemodynamic and metabolic sequela of OSA result in endothelial dysfunction, increased inflammation, atherogenesis, hypertension, arrhythmias, and increased left ventricular transmural pressures. The combination of increased afterload and elevated heart rate contribute to left ventricular hypertrophy. Patients with OSA have been found to have increased levels of catecholamines and aldosterone suggesting activation of the renin-angiotensin-aldosterone axis (RAAS system), through the sympathetic overdrive, which in turn leads to cardiac fibrosis and remodeling contributing to impairment of myocardial relaxation, left ventricular stiffness and consequently to DD(3).
In agreement with the results of our analysis is the study by Butt et al (12) who provided a comprehensive assessment of LV structural and functional parameters using 2D and 3D echocardiography in moderate-severe OSA patients who were free of other concomitant confounder morbidities. The study included 120 otherwise healthy subjects with no evidence of cardiovascular disease, dyslipidemia or diabetes mellitus and were stratified into 3 groups based on the severity of sleep apnea and the presence of hypertension. The OSA group which included patients with AHI >15 and no hypertension (n=40) were compared with matched disease control subjects who had essential hypertension but no OSA (N=40) and healthy control subjects who had neither hypertension nor OSA (N=40). It was demonstrated that patients with OSA and hypertension compared to the healthy subjects had higher left ventricular mass index and impaired systolic (decreased S systolic velocity) and diastolic function (E/A, IVRT, and E/e′). OSA patients were also found to have greater LAVI and lower ejection fraction as assessed by 3D echocardiography. Therapy with CPAP (mean duration of 6 months) resulted in significant structural changes (reduction in the LV mass and PWT/IVST) and improvement on the echocardiographic parameters of systolic and diastolic function.
On the contrary Kim et al (18) in a similar study with 62 patients classified into 3 groups (mild to moderate OSA, severe OSA, and control subjects) failed to detect significant correlation between OSA and DD. It was found that patients with OSA had decreased early diastolic velocity compared to control subjects but otherwise no differences in terms of E/A, isovolumic relaxation time, deceleration time, and pulmonary vein systolic/diastolic pulmonary vein velocity ratio were detected among the groups. Masa JF in a prospective study enrolled 196 patients with obesity hypoventilation syndrome and concomitant OSA treated with either NIV or CPAP. It was demonstrated that NIV and CPAP therapies improved left ventricular DD, reduced left atrial diameter, and pulmonary artery pressures at 3 years suggesting an association between sleep apnea and DD.
The prevalence of OSA has increased substantially in the past decade and it is expected to continue to rise due to the obesity epidemic, yet it is believed that OSA remains underdiagnosed (3). A major reason for underdiagnosis is that most patients with heart failure (HF) and sleep disordered breathing (SDB) do not complain of daytime sleepiness despite having significantly less sleep time. Another important factor that is that HF by itself or standard medications like beta-blockers in the treatment of HF can also cause fatigue masking SDB symptoms and thus offering an alternative to SDB leading to its underdiagnosis. This highlights the need to adopt a low threshold to test for sleep apnea in the context of HF.
With the increasing number of patients with HFpEF and the continued focus on reducing the rate of associated hospital admissions, comprehensive assessment of diastolic parameters and evaluation for those patients with HFpEF is an important aspect of cardiac testing. While all those with DD may not have HFpEF, when present this portends a worse prognosis. Grading of diastolic function is an important predictor of outcome. Longitudinal studies have shown an increased rate of all-cause mortality in patients with DD (24). Redfield and associates demonstrated an increased mortality risk in patients with DD when controlled for age, sex, and EF (25).
Therefore, it appears the early recognition of DD and HFpEF would be of clinical value, leading to more aggressive prevention and therapeutic strategies to ameliorate HF related symptoms or reduce disease progression. The association between OSA and DD underscores the need for increased level of awareness of such association among clinicians, and to have a low threshold for echocardiographic assessment of diastolic function.
To date the treatment of DD is treatment of the underlying etiology. The potential cardioprotective effects of CPAP or other therapy for OSA may offer a therapeutic tool for the treatment of DD in patients with OSA.