T. Douglas Bradley

Obstructive sleep apnoea and its cardiovascular consequences

Obstructive sleep apnoea (OSA) is a common disorder in which repetitive apnoeas expose the cardiovascular system to cycles of hypoxia, exaggerated negative intrathoracic pressure, and arousals. These noxious stimuli can, in turn, depress myocardial contractility, activate the sympathetic nervous system, raise blood pressure, heart rate, and myocardial wall stress, depress parasympathetic activity, provoke oxidative stress and systemic inflammation, activate platelets, and impair vascular endothelial function. Epidemiological studies have shown significant independent associations between OSA and hypertension, coronary artery disease, arrhythmias, heart failure, and stroke. In randomised trials, treating OSA with continuous positive airway pressure lowered blood pressure, attenuated signs of early atherosclerosis, and, in patients with heart failure, improved cardiac function. Current data therefore suggest that OSA increases the risk of developing cardiovascular diseases, and that its treatment has the potential to diminish such risk. However, large-scale randomised trials are needed to determine, definitively, whether treating OSA improves cardiovascular outcomes.

High prevalence of unrecognized sleep apnoea in drug-resistant hypertension

Objectives To determine the prevalence of obstructive sleep apnoea (OSA) in adult patients with drug-resistant hypertension, a common problem in a tertiary care facility. Design Cross-sectional study. Setting University hypertension clinic. Patients and methods Adults with drug-resistant hypertension, defined as a clinic blood pressure of ⩾ 140/90 mmHg, while taking a sensible combination of three or more antihypertensive drugs, titrated to maximally recommended doses. Each of the 41 participants completed an overnight polysomnographic study and all but two had a 24 h ambulatory blood pressure measurement. Results Prevalence of OSA, defined as an apnoea-hypopnoea index of ⩾ 10 obstructive events per hour of sleep, was 83% in the 24 men and 17 women studied. Patients were generally late middle-aged (57.2 ± 1.6 years, mean ± SE), predominantly white (85%), obese (body mass index, 34.0 ± 0.9 kg/m2) and taking a mean of 3.6 ± 0.1 different antihypertensive medications daily. OSA was more prevalent in men than in women (96 versus 65%, P = 0.014) and more severe (mean apnoea–hypopnoea index of 32.2 ± 4.5 versus 14.0 ± 3.1 events/h, P = 0.004). There was no gender difference in body mass index or age. Women with OSA were significantly older and had a higher systolic blood pressure, lower diastolic blood pressure, wider pulse pressure and slower heart rate than women without OSA. Conclusions The extraordinarily high prevalence of OSA in these patients supports its potential role in the pathogenesis of drug-resistant hypertension, and justifies the undertaking of a randomized controlled trial to corroborate this hypothesis.

Suppression of Central Sleep Apnea by Continuous Positive Airway Pressure and Transplant-Free Survival in Heart Failure A Post Hoc Analysis of the Canadian Continuous Positive Airway Pressure for Patients With Central Sleep Apnea and Heart Failure Trial (CANPAP)

Background— In the main analysis of the Canadian Continuous Positive Airway Pressure (CPAP) for Patients with Central Sleep Apnea (CSA) and Heart Failure Trial (CANPAP), CPAP had no effect on heart transplant–free survival; however, CPAP only reduced the mean apnea-hypopnea index to 19 events per hour of sleep, which remained above the trial inclusion threshold of 15. This stratified analysis of CANPAP tested the hypothesis that suppression of CSA below this threshold by CPAP would improve left ventricular ejection fraction and heart transplant–free survival. Methods and Results— Of the 258 heart failure patients with CSA in CANPAP, 110 of the 130 randomized to the control group and 100 of the 128 randomized to CPAP had sleep studies 3 months later. CPAP patients were divided post hoc into those whose apnea-hypopnea index was or was not reduced below 15 at this time (CPAP-CSA suppressed, n=57, and CPAP-CSA unsuppressed, n=43, respectively). Their changes in left ventricular ejection fraction and heart transplant–free survival were compared with those in the control group. Despite similar CPAP pressure and hours of use in the 2 groups, CPAP-CSA–suppressed subjects experienced a greater increase in left ventricular ejection fraction at 3 months (P=0.001) and significantly better transplant-free survival (hazard ratio [95% confidence interval] 0.371 [0.142 to 0.967], P=0.043) than control subjects, whereas the CPAP-CSA–unsuppressed group did not (for left ventricular ejection fraction, P=0.984, and for transplant-free survival, hazard ratio 1.463 [95% confidence interval 0.751 to 2.850], P=0.260). Conclusions— These results suggest that in heart failure patients, CPAP might improve both left ventricular ejection fraction and heart transplant–free survival if CSA is suppressed soon after its initiation.

Sleep Apnea and Heart Failure Part I: Obstructive Sleep Apnea

Heart failure (HF) affects 5 to 6 million North Americans and is increasing in prevalence.1 Mortality remains high. In Ontario, for example, between 1994 and 1997, approximately 33% of patients diagnosed with HF on first admission to hospital died within 1 year.2 Reductions in mortality demonstrated in randomized clinical trials of pharmacological agents, such as β-receptor blockers3 and angiotensin-converting enzyme inhibitors,4 have been slow to translate into substantial reductions in death and hospitalization rates in community-based HF populations. These figures have remained relatively constant between 1948 and 1997.2,5–7 In more recent clinical trials, the addition of newer agents has had a marginal, neutral, or even adverse impact on the high residual mortality of optimally treated patients.8,9 Accordingly, investigators such as Massie10 have raised the concern that there may be limits to the benefits achievable through conventional pharmacological strategies. Resource-intensive interventions, such as left ventricular assist devices or heart transplantation, are available to only a small minority of patients. Therefore, there remains a need to develop novel, widely applicable, and cost-effective approaches to the therapy of HF. An important limitation to the current guidelines for the evaluation and management of chronic HF is their focus on the patient as he/she presents while awake.1 This approach presupposes that any mechanisms that might contribute to the pathophysiology or progression of HF are quiescent during sleep. Our objective in this review, therefore, is to highlight the pathophysiological and therapeutic implications of co-existing sleep apnea in patients with HF. There are 2 major forms of sleep apnea: obstructive sleep apnea (OSA) and central sleep apnea (CSA). Because their pathophysiologies and clinical implications in the setting of HF are quite different, OSA and CSA will be dealt with separately in the 2 parts of this review. In Part …

Influence of obstructive sleep apnea on mortality in patients with heart failure.

OBJECTIVES This study sought to determine, in patients with heart failure (HF), whether untreated moderate to severe obstructive sleep apnea (OSA) is associated with a higher mortality rate than in patients with mild to no sleep apnea (M-NSA). BACKGROUND Obstructive sleep apnea is common in patients with HF and exposes the heart and circulation to adverse mechanical and autonomic effects. However, its effect on mortality rates of patients with HF has not been reported. METHODS In a prospective study involving 164 HF patients with left ventricular ejection fractions (LVEFs) < or =45%, we performed polysomnography and compared death rates between those with M-NSA (apnea-hypopnea index [AHI] <15/h of sleep) and those with untreated OSA (AHI > or =15/h of sleep). RESULTS During a mean (+/- SD) of 2.9 +/- 2.2 and a maximum of 7.3 years of follow-up, the death rate was significantly greater in the 37 untreated OSA patients than in the 113 M-NSA patients after controlling for confounding factors (8.7 vs. 4.2 deaths per 100 patient-years, p = 0.029). Although there were no deaths among the 14 patients whose OSA was treated by continuous positive airway pressure (CPAP), the mortality rate was not significantly different from the untreated OSA patients (p = 0.070). CONCLUSIONS In patients with HF, untreated OSA is associated with an increased risk of death independently of confounding factors.

Sleep Apnea and Heart Failure Part II: Central Sleep Apnea

In the first part of this 2-part review, we provided a synopsis of the cardiovascular effects of normal sleep and an overview of the diagnostic, pathophysiological, and therapeutic implications of obstructive sleep apnea (OSA) in the setting of heart failure (HF). In this second part, we turn our attention to central sleep apnea (CSA), commonly referred to as Cheyne-Stokes respiration. This breathing disorder has a strikingly higher prevalence in patients with HF as compared with the general population with normal left ventricular function, and when present appears to have adverse prognostic implications. Our objective in Part II of this review is to provide a broad perspective of the pathophysiological and clinical significance of CSA in HF. CSA associated with Cheyne-Stokes respiration is a form of periodic breathing in which central apneas and hypopneas alternate with periods of hyperventilation that have a waxing-waning pattern of tidal volume. Figure 1 illustrates the proposed mechanisms that underlie periodic oscillations in ventilation in HF. Unlike OSA, CSA likely arises as a consequence of HF. Thus, the presence of CSA may alert the physician to the necessity of intensifying HF therapy. The current debate is whether CSA is simply a reflection of severely compromised cardiac function with elevated left ventricular filling pressures, or whether, for the same degree of cardiac dysfunction, CSA exerts unique and independent pathological effects on the failing myocardium. Although there are not yet sufficient data to resolve this controversy within the confines of this review, we will discuss evidence on both sides of this issue. Figure 1. Pathophysiology of central sleep apnea in heart failure (HF). HF leads to increased left ventricular (LV) filling pressure. The resulting pulmonary congestion activates lung vagal irritant receptors, which stimulate hyperventilation and hypocapnia. Superimposed arousals cause further abrupt increases in ventilation and drive PaCO2 …

Obstructive Sleep Apnea The Most Common Secondary Cause of Hypertension Associated With Resistant Hypertension

Recognition and treatment of secondary causes of hypertension among patients with resistant hypertension may help to control blood pressure and reduce cardiovascular risk. However, there are no studies systematically evaluating secondary causes of hypertension according to the Seventh Joint National Committee. Consecutive patients with resistant hypertension were investigated for known causes of hypertension irrespective of symptoms and signs, including aortic coarctation, Cushing syndrome, obstructive sleep apnea, drugs, pheochromocytoma, primary aldosteronism, renal parenchymal disease, renovascular hypertension, and thyroid disorders. Among 125 patients (age: 52±1 years, 43% males, systolic and diastolic blood pressure: 176±31 and 107±19 mm Hg, respectively), obstructive sleep apnea (apnea-hypopnea index: >15 events per hour) was the most common condition associated with resistant hypertension (64.0%), followed by primary aldosteronism (5.6%), renal artery stenosis (2.4%), renal parenchymal disease (1.6%), oral contraceptives (1.6%), and thyroid disorders (0.8%). In 34.4%, no secondary cause of hypertension was identified (primary hypertension). Two concomitant secondary causes of hypertension were found in 6.4% of patients. Age >50 years (odds ratio: 5.2 [95% CI: 1.9–14.2]; P<0.01), neck circumference ≥41 cm for women and ≥43 cm for men (odds ratio: 4.7 [95% CI: 1.3–16.9]; P=0.02), and presence of snoring (odds ratio: 3.7 [95% CI: 1.3–11]; P=0.02) were predictors of obstructive sleep apnea. In conclusion, obstructive sleep apnea appears to be the most common condition associated with resistant hypertension. Age >50 years, large neck circumference measurement, and snoring are good predictors of obstructive sleep apnea in this population.

Effects of Continuous Positive Airway Pressure on Obstructive Sleep Apnea and Left Ventricular Afterload in Patients With Heart Failure

BACKGROUND The objectives of this study were to determine the effects of continuous positive airway pressure (CPAP) on blood pressure (BP) and systolic left ventricular transmural pressure (LVPtm) during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA). In CHF patients with OSA, chronic nightly CPAP treatment abolishes OSA and improves left ventricular (LV) ejection fraction. We hypothesized that one mechanism whereby CPAP improves cardiac function in CHF patients with OSA is by lowering LV afterload during sleep. METHODS AND RESULTS Eight pharmacologically treated CHF patients with OSA were studied during overnight polysomnography. BP and esophageal pressure (Pes) (ie, intrathoracic pressure) were recorded before the onset of sleep and during stage 2 non-rapid eye movement sleep before, during, and after CPAP application. OSA was associated with an increase in systolic BP (from 120.4+/-7.8 to 131.8+/-10.6 mm Hg, P<0.05) and systolic LVPtm (from 124.4+/-7.7 to 137.2+/-10.8 mm Hg, P<0.05) from wakefulness to stage 2 sleep. CPAP alleviated OSA, improved oxyhemoglobin saturation, and reduced systolic BP in stage 2 sleep to 115.4+/-8.5 mm Hg (P<0.01), systolic LVPtm to 117.4+/-8.5 mm Hg (P<0.01), heart rate, Pes amplitude, and respiratory rate. CONCLUSIONS In CHF patients with OSA, LV afterload increases from wakefulness to stage 2 sleep. By alleviating OSA, CPAP reduces LV afterload and heart rate, unloads inspiratory muscles, and improves arterial oxygenation during stage 2 sleep. CPAP is a nonpharmacological means of further reducing afterload and heart rate during sleep in pharmacologically treated CHF patients with OSA.

Pharyngeal Size in Snorers, Nonsnorers, and Patients with Obstructive Sleep Apnea

We measured pharyngeal cross-sectional area and its change with alterations in lung volume in 10 subjects who snored and had obstructive sleep apnea, 6 subjects who snored and did not have obstructive sleep apnea, and 9 subjects who did not snore. Pharyngeal area was measured with use of an acoustic-reflection technique. We found that snorers with and without sleep apnea had a significantly smaller mean (+/- SE) pharyngeal cross-sectional area (4.1 +/- 0.2 and 3.7 +/- 0.9 cm2, respectively) at functional residual capacity than nonsnorers (5.4 +/- 0.5 cm2, P less than 0.025). When lung volume decreased from functional residual capacity to residual volume, both nonsnorers and snorers with sleep apnea had a decrease in pharyngeal area (from 5.4 +/- 0.5 to 4.5 +/- 0.4 cm2 and 4.1 +/- 0.2 to 3.4 +/- 0.2 cm2, respectively), whereas snorers without sleep apnea had no such decrease, suggesting that their pharynxes were less collapsible at low lung volumes. We conclude that snorers with and without sleep apnea have smaller pharyngeal cross-sectional areas than nonsnorers and that snorers with sleep apnea have a further decrease as lung volume falls.

Nocturnal Rostral Fluid Shift A Unifying Concept for the Pathogenesis of Obstructive and Central Sleep Apnea in Men With Heart Failure

Background— Obstructive sleep apnea (OSA) and central sleep apnea are common in patients with heart failure. We hypothesized that in such patients, severity of OSA is related to overnight rostral leg fluid displacement and increase in neck circumference, severity of central sleep apnea is related to overnight rostral fluid displacement and to sleep Pco2, and continuous positive airway pressure alleviates OSA in association with prevention of fluid accumulation in the neck. Methods and Results— In 57 patients with heart failure (ejection fraction ≤45%), we measured change in leg fluid volume and neck circumference before and after polysomnography, and we measured transcutaneous Pco2 during polysomnography. Patients were divided into an obstructive-dominant group (≥50% of apneas and hypopneas obstructive) and a central-dominant group (>50% of events central). Patients with OSA received continuous positive airway pressure. In obstructive-dominant patients, there were inverse relationships between overnight change in leg fluid volume and both the overnight change in neck circumference (r=−0.780, P<0.001) and the apnea-hypopnea index (r=−0.881, P<0.001) but not transcutaneous Pco2. In central-dominant patients, the overnight reduction in leg fluid volume correlated inversely with the apnea-hypopnea index (r=−0.919, P<0.001) and the overnight change in neck circumference (r=−0.568, P=0.013) and directly with transcutaneous Pco2 (r=0.569, P=0.009). Continuous positive airway pressure alleviated OSA in association with prevention of the overnight increase in neck circumference (P<0.001). Conclusions— Our findings suggest that nocturnal rostral fluid shift is a unifying concept contributing to the pathogenesis of both OSA and central sleep apnea in patients with heart failure.