Ian Wilcox

Obstructive Sleep Apnea and Cardiovascular Disease

Obstructive sleep apnea (OSA) is a common disorder associated with an increased risk of cardiovascular disease and stroke. As it is strongly associated with known cardiovascular risk factors, including obesity, insulin resistance, and dyslipidemia, OSA is an independent risk factor for hypertension and has also been implicated in the pathogenesis of congestive cardiac failure, pulmonary hypertension, arrhythmias, and atherosclerosis. Obesity is strongly linked to an increased risk of OSA, and weight loss can reduce the severity of OSA. The current standard treatment for OSA-nasal continuous positive airway pressure (CPAP)-eliminates apnea and the ensuing acute hemodynamic changes during sleep. Long-term CPAP treatment studies have shown a reduction in nocturnal cardiac ischemic episodes and improvements in daytime blood pressure levels and left ventricular function. Despite the availability of effective therapy, OSA remains an underdiagnosed and undertreated condition. A lack of physician awareness is one of the primary reasons for this deficit in diagnosis and treatment.

“Syndrome Z”: the interaction of sleep apnoea, vascular risk factors and heart disease

Obstructive sleep apnoea (OSA) has been linked to increased cardiovascular morbidity and mortality from both coronary heart disease and stroke,1-3 but whether this risk is due to coexistent known cardiovascular risk factors or specific effects of OSA remains to be established. In populations at risk of vascular disease, many patients who experience a cardiovascular event either do not have identifiable risk factors or have disease severity which appears to be out of proportion to their known risk factors. A lot of the variance in the incidence of vascular disease is therefore not explained by known risk factors. It is possible that OSA is a cardiovascular risk factor, previously largely unrecognised, which may account for some of the apparently unexplained variance in vascular risk. Data from the Framingham and other studies have clearly shown that at any level of systolic blood pressure there is a substantial increase in cardiovascular risk with increasing levels of plasma cholesterol, and the presence of glucose intolerance (insulin resistance) further increases this risk.4 Although obesity is a well recognised cardiovascular risk factor, the distribution of body fat is an independent risk factor with central or visceral obesity increasing cardiovascular risk. In the study by Larsen and co-workers5 increasing waist circumference (an index of central obesity) increased the risk of both coronary heart disease and stroke at all tertiles of body mass index. Since these risk factors have been shown to be independent predictors of adverse events, they will show at least additive effects in combination and possibly potentiate each other. Epidemiological and other studies have identified clustering of multiple vascular risk factors. One such cluster is a quartet of risk factors which includes systemic hypertension, insulin resistance, hyperlipidaemia, and central obesity which been defined as “syndrome X”.6 In this cluster there are …

Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation

Background: Obstructive sleep apnoea (OSA) is a common and potentially reversible cause of systemic hypertension. The mechanisms whereby OSA leads to hypertension and the effects of treatment on arterial function, however, are not well established. Microvascular arterial endothelial and smooth muscle function was assessed in subjects with OSA before and after treatment with continuous positive airways pressure (CPAP). Methods: Ten subjects of mean (SE) age 49 (8) years with at least moderately severe OSA had detailed forearm vascular reactivity studies before and after 3 months of CPAP treatment. The systemic circulation was assessed by measuring brachial artery pressure, flow and resistance responses to intra-arterial infusions of acetylcholine (ACh; an endothelium dependent vasodilator), sodium nitroprusside (SNP; an endothelium independent vasodilator), l-NMMA (a nitric oxide (NO) antagonist), and l-arginine (the substrate for NO). Results: Before CPAP, ACh and SNP infusions increased forearm blood flow in a dose dependent manner (p<0.01). After CPAP, endothelium dependent dilation to ACh was significantly increased (434 (23)% of baseline after CPAP v 278 (20)% before CPAP, p<0.001), whereas SNP induced dilation was unchanged. Resting NO production was higher after CPAP, evidenced by a significantly greater reduction in basal flow by l-NMMA (p = 0.05). l-Arginine reversed the effect of l-NMMA in all cases. Conclusion: In patients with OSA, treatment with CPAP improves baseline endothelial NO release and stimulates endothelium dependent vasorelaxation in the systemic circulation. This is a potential mechanism for improving systemic and vascular function in patients with OSA treated with CPAP.

The unstable ST segment early after thrombolysis for acute infarction and its usefulness as a marker of recurrent coronary occlusion

To investigate the incidence of early recurrent ST elevation after intravenous thrombolytic therapy for acute myocardial infarction, 12-lead electrocardiograms were continuously monitored for 571 +/- 326 minutes in 31 patients presenting within 4 hours of symptom onset. The study group comprised 9 women and 22 men (mean age +/- standard deviation 53 +/- 12 years), with ST elevation (anterior in 15, inferior in 16) on the initial electrocardiogram, who were given either tissue plasminogen activator (22 patients) or streptokinase (9 patients). Angiography was performed in 30 of 31 patients at 7 to 10 days. Early (less than 3 hours) resolution of ST elevation occurred in 19 patients (61%) at a median of 94 minutes (interquartile range 57 to 113) after thrombolysis, whereas 12 (39%) had no or late (greater than 6 hours) resolution. Eleven of the 19 with early resolution (58%) had either transient (5 patients) or sustained (6 patients) recurrences of ST elevation. Recurrent ST elevation was equal to or more than the initial peak elevation in 9 of 11 patients, and greater than 75% of initial peak in 2. A total of 25 episodes of recurrent ST elevation were observed in the 11 patients (19 transient and 6 sustained episodes), of which 8 (32%) were silent. The proportion of silent episodes was similar for transient (35%) and sustained (33%) recurrences. All patients with sustained recurrent ST elevation had at least 1 preceding transient recurrence. The median duration of transient recurrent ST elevation was 43 minutes (28 to 63).(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic significance of a predischarge exercise test in risk stratification after unstable angina pectoris

The prognostic significance of exercise testing was compared with clinical and electrocardiographic (ECG) variables in a prospective study of 107 patients with unstable angina discharged from the hospital on medical therapy. During a follow-up period of 12.8 +/- 1.4 months, 10 patients (9%) had a nonfatal myocardial infarction (n = 8) or died (n = 2) and 22 (20%) were readmitted with recurrent unstable angina. The relation between 20 clinical, ECG and exercise test variables and the risk of adverse outcome (death, nonfatal myocardial infarction or recurrent unstable angina) was analyzed using both univariate and multivariate (logistic regression) analysis. Univariate predictors of adverse outcome included diabetes mellitus, evolutionary T wave changes, T wave changes on the preexercise ECG and low maximal rate-pressure product during exercise. Independent predictors of adverse outcome in multivariate analysis included diabetes mellitus, evolutionary T wave changes after admission, rest pain during hospitalization, ST depression during exercise and low maximal rate-pressure product. A predictive model constructed using the regression equation and all independent predictors stratified patients into high and low risk groups (41% and 5% risk of adverse outcome, respectively). The result of a predischarge exercise test adds independent prognostic information to clinical and ECG data in medically treated patients with unstable angina and could be used in combination with clinical and ECG data to identify patients at risk of adverse events.

Ventilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea

Sleep apnoea is common in patients with heart failure. While most patients have central sleep apnoea (CSA), a minority have obstructive sleep apnoea (OSA). The pathophysiology of CSA is not well understood. We hypothesized that central chemosensitivity would be an important pathophysiological factor in patients with CSA, and not in OSA. The aim of this study was to compare ventilatory responses between patients with CSA and those with OSA. Acute ventilatory responses to eucapnic hypoxia and hyperoxic hypercapnia were measured during wakefulness in 34 patients (33 males and one female, aged 59±8 yrs (mean±sd)), with stable medically-treated left ventricular dysfunction (LVD) and sleep apnoea (18 OSA and 16 CSA). Patients with CSA had a decreased awake end-tidal carbon dioxide tension (4.1± 0.5 kPa), increased ventilatory response to carbon dioxide (0.65±0.43 L·min-1·kPa PCO2-1), and eucapnic hypoxic responses in the normal range (0.6±0.4 L·min-1/% fall in arterial oxygen saturation (Sa,O2)). In contrast, patients with OSA had normal endtidal carbon dioxide tension (4.9±0.5 kPa), and normal ventilatory responses to hypercapnia (0.29±0.16 L·min-1·kPa PCO2-1) and hypoxia (0.5±0.5 L·min-1/% fall in Sa,O2). These findings suggest that augmented chemosensitivity to hypercapnia may be an important factor in the pathophysiology of central sleep apnoea in patients with heart failure.

Prognosis and sleep disordered breathing in heart failure

Abnormal breathing in heart failure as originally described by Cheyne1 and subsequently by Stokes2 was observed in apparently awake patients as an agonal breathing pattern. “. . . The only peculiarity in the last period of his illness was in the state of the respiration. For several days his breathing was irregular, then it would become perceptible, though very low, then by degrees it became heaving and quick, and then it would cease again: this revolution in the state of his breathing occupied about a minute, during which there were about 30 acts of respiration (Cheyne, 1818) . . .” The patient described in this report was an obese, elderly, alcoholic who had suffered a substantial, and ultimately, fatal stroke. He probably had obstructive sleep apnoea prior to the stroke and developed central apnoea subsequently. In the literature subsequent to these reports periodic respiration associated with central apnoeas was believed to be a terminal consequence of end stage heart failure.3-5 More recently it has been recognised that central apnoeas occur commonly in heart failure, especially during sleep, being reported in 40–50% of patients, predominantly men, with stable, medically treated congestive heart failure.6 This sleep breathing abnormality leads to sleep fragmentation, alterations in sleep architecture—with relative increases in stage 1 and 2 sleep and reduction in REM sleep—and a clinical sleep disorder with symptoms of tiredness and sleepiness in some patients.7 The sleep disorder in central sleep apnoea is a consequence of the development of congestive heart failure. Although the pathophysiology is not completely understood, hyperventilation,8 increased chemoreceptor drive,9 and increased circulation time4 10 11 are all believed to be important factors promoting this sleep disorder. Identification of obstructive sleep apnoea (OSA) in patients with primarily left ventricular (LV) dysfunction and clinical heart …

Clinical significance of silent ischemia in unstable angina pectoris

In a prospective study the significance of silent ischemia was evaluated in 66 patients with a clinical diagnosis of unstable angina (no requirement for reversible ST-T changes during pain on 12-lead electrocardiograms before entry), and the results of continuous 2-channel electrocardiographic (ECG) recordings, begun within 24 hours of admission, were compared with other clinical and ECG predictors of adverse outcome. Ischemic changes were detected in 7 patients (11%) during a mean of 41 hours of recording. There were 37 episodes of transient ST-segment change (16 ST elevation, 21 ST depression) of which 11 (30%) were symptomatic and 26 (70%) were silent. All 7 patients had at least 1 silent episode and 5 also had symptomatic episodes during the recording but only 2 patients had exclusively silent episodes. During a mean follow-up of 13.3 months, 3 patients died, 5 had a nonfatal myocardial infarction and 32 required revascularization. Although transient myocardial ischemia during the continuous ECG recording, whether silent or symptomatic, was a specific predictor of subsequent nonfatal myocardial infarction or death (specificity 92%), its sensitivity for these events was low (25%). In contrast, recurrent rest pain (greater than or equal to 1 episode) occurred in all patients with these serious adverse events (sensitivity 100%, specificity 49%). Transient ischemia occurs infrequently during continuous ECG recordings in patients with unstable angina not selected by reversible ST-T changes on a 12-lead electrocardiogram at entry. Recurrent rest pain after hospital admission is a more sensitive predictor of serious events in this group.

Noninvasive pressure preset ventilation for the treatment of Cheyne-Stokes respiration during sleep

Cheyne-Stokes respiration (CSR) during sleep is common in patients with congestive heart failure (CHF). This pattern of breathing fragments sleep, leading to daytime symptoms of sleepiness and fatigue. It was hypothesized that by controlling CSR with noninvasive pressure preset ventilation (NPPV), there would be a decrease in sleep fragmentation and an improvement in sleep quality. Nine patients (eight males, one female; mean +/- SD 65 +/- 11 yrs) with symptomatic CSR diagnosed on overnight polysomnography (apnoea/hypopnoea index (AHI) 49 +/- 10 x h(-1), minimum arterial oxygen saturation (Sa,O2, 77 +/- 7%) and CHF (left ventricular ejection fraction 25 +/- 8%) were studied. After a period of acclimatization to NPPV (variable positive airway pressure (VPAP) II ST, Sydney, NSW, Australia and bilevel positive airway pressure (BiPAP), Murraysville, PA, USA), sleep studies were repeated on therapy. NPPV almost completely abolished CSR in all patients with a reduction in AHI from 49 +/- 10 to 6 +/- 5 x h(-1) (p<0.001). Residual respiratory events were primarily due to upper airway obstruction at sleep on-set. Arousal index was markedly decreased from 42 +/- 6 to 17 +/- 7 x h(-1) (p <0.001). Sleep architecture showed a trend toward improvement with a reduction in stage 1 and 2 (79 +/- 7% during the diagnostic night versus 72 +/- 10% during NPPV, (p=0.057)), whilst sleep efficiency, slow-wave sleep (SWS), and rapid eye movement (REM) were not altered. Controlling Cheyne-Stokes respiration with noninvasive pressure preset ventilation resulted in reduced arousal and improved sleep quality in the patients with congestive heart failure. Noninvasive pressure preset ventilation should be considered a potential therapy for Cheyne-Stokes respiration in congestive heart failure in those patients who do not respond or fail to tolerate nasal continuous positive airway pressure therapy.

6 Sleep-disordered breathing and obesity

Summary Recent epidemiological data indicate that obstructive sleep apnoea (OSA) and related conditions are extremely common in the middle-aged population. Obesity is an important aetiological factor in sleep-disordered breathing with a multifactorial role in the pathogenesis of upper airway occlusion. One extreme of the spectrum of sleep-disordered breathing is obesity-hypoventilation syndrome (one type of OSA with awake respiratory failure). Sleep-disordered breathing has a number of clinical consequences, including excess cardiovascular morbidity. Obesity is an important confounder of this association. Treatment of these disorders has been revolutionized by the use of nasal continuous positive airway pressure (CPAP). Weight reduction reduces apnoea severity but is not curative in most obese patients with sleep apnoea.