Respiration, R-R interval, blood pressure, and other polysomnographic variables were recorded in eight normal subjects and nine patients with untreated obstructive sleep apnea syndrome in wakefulness and sleep. To increase respiratory and cardiovascular variability, a computer-controlled ventilator delivered randomly modulated inspiratory pressures that were superimposed on a baseline continuous positive airway pressure. A mathematical model allowed heart rate variability to be partitioned into a component mediated by respiratory-cardiac coupling and one mediated by the baroreflexes. Respiratory-cardiac coupling gain was lower in patients versus normal subjects (36.9 +/- 3.3 versus 66.1 +/- 5.6 milliseconds L-1, p < 0.03). Baroreflex gain in patients was also depressed relative to normal subjects (2.3 +/- 0.4 versus 4.9 +/- 0.7 milliseconds mm Hg-1; p < 0.02). Baroreflex gain increased two- to threefold from wakefulness to sleep in normal subjects, but was relatively unaffected by state change in patients. Along with results derived from spectral analysis of cardiovascular variability, these findings confirm previous reports that obstructive sleep apnea syndrome is associated with reduced parasympathetic and elevated sympathetic activity. The model-based approach provides a more precise characterization of heart rate variability that can be employed in conjunction with spectral analysis for the noninvasive detection and assessment of autonomic cardiovascular abnormality in obstructive sleep apnea syndrome.

Heart rate variability (HRV) is mediated by at least three primary mechanisms: 1) vagal feedback from pulmonary stretch receptors (PSR), 2) central medullary coupling between respiratory and cardiovagal neurons (RCC), and 3) arterial baroreflex (ABR)-induced fluctuations. We employed a noninvasive experimental protocol in conjunction with a minimal model to determine how these sources of HRV are altered in obstructive sleep apnea syndrome (OSAS). Respiration, heart rate, and blood pressure were monitored in eight normal subjects and nine untreated OSAS patients in relaxed wakefulness and stage 2 and rapid eye movement sleep. A computer-controlled ventilator delivered inspiratory pressures that varied randomly from breath to breath. Application of the model to the corresponding subject responses allowed the delineation of the three components of HRV. In all states, RCC gain was lower in OSAS patients than in normal subjects (P < 0.04). ABR gain was also reduced in OSAS patients (P < 0.03). RCC and ABR gains increased from wakefulness to sleep (P < 0.04). However, there was no difference in PSR gain between subject groups or across states. The findings of this study suggest that the adverse autonomic effects of OSAS include impairment of baroreflex gain and central respiratory-cardiovascular coupling, but the component of respiratory sinus arrhythmia that is mediated by lung vagal feedback remains intact.

We used genetically engineered D(2) receptor-deficient [D(2)-(-/-)] and wild-type [D(2)-(+/+)] mice to test the hypothesis that dopamine D(2) receptors modulate the ventilatory response to acute hypoxia [hypoxic ventilatory response (HVR)] and hypercapnia [hypercapnic ventilatory response (HCVR)] and time-dependent changes in ventilation during chronic hypoxia. HVR was independent of gender in D(2)-(+/+) mice and significantly greater in D(2)-(-/-) than in D(2)-(+/+) female mice. HCVR was significantly greater in female D(2)-(+/+) mice than in male D(2)-(+/+) and was greater in D(2)-(-/-) male mice than in D(2)-(+/+) male mice. Exposure to hypoxia for 2-8 days was studied in male mice only. D(2)-(+/+) mice showed time-dependent increases in "baseline" ventilation (inspired PO(2) = 214 Torr) and hypoxic stimulated ventilation (inspired PO(2) = 70 Torr) after 8 days of acclimatization to hypoxia, but D(2)-(-/-) mice did not. Hence, dopamine D(2) receptors modulate the acute HVR and HCVR in mice in a gender-specific manner and contribute to time-dependent changes in ventilation and the acute HVR during acclimatization to hypoxia.

Using the Volterra-Wiener approach, we employed a minimal model to quantitatively characterize the linear and nonlinear effects of respiration (RCC) and arterial blood pressure (ABR) on heart rate variability (HRV) in normal controls and subjects with moderate-to-severe obstructive sleep apnea syndrome (OSAS). Respiration, R-R interval (RRI), blood pressure (BP) and other polysomnographic variables were recorded in eight normal controls and nine OSAS subjects in wakefulness, Stage 2 and rapid eye-movement sleep. To increase respiratory and cardiovascular variability, a preprogrammed ventilator delivered randomly timed inspiratory pressures that were superimposed on a baseline continuous positive airway pressure. Except for lower resting RRI in OSAS subjects, summary statistical measures of RRI and BP and their variabilities were similar in controls and OSAS. In contrast, RCC and ABR gains were significantly lower in OSAS. Nonlinear ABR gain and the interaction between respiration and blood pressure in modulating RRI were substantially reduced in OSAS. ABR gain increased during sleep in controls but remained unchanged in OSAS. These findings suggest that normotensive OSAS subjects have impaired daytime parasympathetic and sympathetic function. Nonlinear minimal modeling of HRV provides a useful, insightful, and comprehensive approach for the detection and assessment of abnormal autonomic function in OSAS.

Recent studies suggest that exposure to repetitive episodes of hypoxia and transient arousal can lead to increased risk for cardiovascular disease in patients with obstructive sleep apnea syndrome (OSAS). To obtain an improved understanding of and to quantitatively characterize the autonomic effects of arousal from sleep, a time-varying closed-loop model was used to determine the interrelationships among respiration, heart rate and blood pressure in 8 normal adults. A recursive least squares algorithm was used in combination with the Laguerre expansion technique to estimate the time-varying impulse responses of the 4 model components. We found that during arousal: 1) respiratory-cardiac coupling gain increases in nonrapid-eye movement (NREM) but not in REM sleep; 2) in both NREM and REM sleep, baroreflex gain shows an initial increase, but this is followed by a more sustained decrease below pre-arousal baseline levels, allowing sympathetic tone to be elevated over a relatively long duration; 3) the gains of other model components show increases with arousal that are consistent with the increased sympathetic modulation of systemic vascular resistance and contractility of the heart. These findings establish a normative database against which further measurements of cardiovascular arousal responses in OSAS may be compared.