Derek S. Kimmerly

Differing Effects of Obstructive and Central Sleep Apneas on Stroke Volume in Patients with Heart Failure

RATIONALE Obstructive sleep apnea and central sleep apnea increase risk of mortality in patients with heart failure (HF), possibly because of hemodynamic compromise during sleep. However, beat-to-beat stroke volume (SV) has not been assessed in response to obstructive and central events during sleep in patients with HF. Because obstructive events generate negative intrathoracic pressure that reduces left ventricular (LV) preload and increases afterload, but central events do not, obstructive events should lead to greater hemodynamic compromise than central events. OBJECTIVES To determine the effects of obstructive and central apneas and hypopneas during sleep on SV in patients with HF. METHODS Patients with systolic HF (LV ejection fraction ≤ 45%) and sleep apnea underwent beat-to-beat measurement of SV by digital photoplethysmography during polysomnography. Change in SV from before to the end of obstructive and central respiratory events was calculated and compared between these types of events. MEASUREMENTS AND MAIN RESULTS Changes in SV were assessed during 252 obstructive and 148 central respiratory events in 40 patients with HF. Whereas SV decreased by 6.8 (±8.7)% during obstructive events, it increased by 2.6 (±5.4)% during central events (P < 0.001 for difference). For obstructive events, reduction in SV was associated independently with LV ejection fraction, duration of respiratory events, and degree of oxygen desaturation. CONCLUSIONS In patients with HF, obstructive and central respiratory events have opposite hemodynamic effects: whereas obstructive sleep apnea appears to have an adverse effect on SV, central sleep apnea appears to have little or slightly positive effects on SV. These observations may have implications for therapeutic approaches to these two breathing disturbances.

Apnea-Induced Cortical BOLD-fMRI and Peripheral Sympathoneural Firing Response Patterns of Awake Healthy Humans

End-expiratory breath-holds (BH) and Mueller manoeuvres (MM) elicit large increases in muscle sympathetic nerve activity (MSNA). In 16 healthy humans (9♀, 35±4 years) we used functional magnetic resonance imaging with blood oxygen level-dependent (BOLD) contrast to determine the cortical network associated with such sympathoexcitation. We hypothesized that increases in MSNA evoked by these simulated apneas are accompanied by BOLD contrast changes in the insular cortex, thalamus and limbic cortex. A series of 150 whole-brain images were collected during 3 randomly performed 16-second end-expiratory BHs and MMs (-30 mmHg). The identical protocol was repeated separately with MSNA recorded from the fibular nerve. The time course of the sympathoexcitatory response to both breathing tasks were correlated with whole-brain BOLD signal changes. Brain sites demonstrating both positive (activation) and negative (deactivation) correlations with the MSNA time course were identified. Sympathetic burst incidence increased (p<0.001) from 29±6 (rest) to 49±6 (BH) and 47±6 bursts/100 heartbeats (MM). Increased neural activity (Z-scores) was identified in the right posterior and anterior insular cortices (3.74, 3.64), dorsal anterior cingulate (3.42), fastigial and dentate cerebellar nuclei (3.02, 3.34). Signal intensity decreased in the left posterior insula (3.28) and ventral anterior cingulate (3.01). Apnea both activates and inhibits elements of a cortical network involved in the generation of sympathetic outflow. These findings identify a neuroanatomical substrate to guide future investigations into central mechanisms contributing to disorders characterized by elevated basal MSNA and exaggerated sympathetic responses to simulated apneas such as sleep apnea and heart failure.

Association between Resting State Brain Functional Connectivity and Muscle Sympathetic Burst Incidence

The insula (IC) and cingulate are key components of the central autonomic network and central nodes of the salience network (SN), a set of spatially distinct but temporally correlated brain regions identified with resting-state (task free) functional MRI (rsMRI). To examine the SNs involvement in sympathetic outflow, we tested the hypothesis that individual differences in intrinsic connectivity of the SN correlate positively with resting postganglionic muscle sympathetic nerve activity (MSNA) burst incidence (BI) in subjects without and with obstructive sleep apnea (OSA). Overnight polysomnography, 5-min rsMRI, and fibular MSNA recording were performed in 36 subjects (mean age 57 yr; 10 women, 26 men). Independent component analysis (ICA) of the entire cohort identified the SN as including bilateral IC, pregenual anterior cingulate cortex (pgACC), midcingulate cortex (MCC), and the temporoparietal junction (TPJ). There was a positive correlation between BI and the apnea-hypopnea index (AHI) (P < 0.001), but dual-regression analysis identified no differences in SN functional connectivity between subjects with no or mild OSA (n = 17) and moderate or severe (n = 19) OSA. Correlation analysis relating BI to the strength of connectivity within the SN revealed large (i.e., spatial extent) and strong correlations for the left IC (P < 0.001), right pgACC/MCC (P < 0.006), left TPJ (P < 0.004), thalamus (P < 0.035), and cerebellum (P < 0.013). Indexes of sleep apnea were unrelated to BI and the strength of SN connectivity. There were no relationships between BI and default or sensorimotor network connectivity. This study links connectivity within the SN to MSNA, demonstrating several of its nodes to be key sympathoexcitatory regions.

The Influence of Oral L-Glutamine Supplementation on Muscle Strength Recovery and Soreness Following Unilateral Knee Extension Eccentric Exercise.

The study aimed to examine the effects that L-glutamine supplementation has on quadriceps muscle strength and soreness ratings following eccentric exercise. It was hypothesized that glutamine ingestion would quicken the recovery rate of peak force production and decrease muscle soreness ratings over a 72-hr recovery period. Sixteen healthy participants (8♀/8♂; 22 ± 4 years) volunteered in a double-blind, randomized, placebo-controlled crossover study. Supplement conditions consisted of isoenergetic placebo (maltodextrin, 0.6 g·kg-1·day-1) and L-glutamine (0.3 g·kg-1·day-1 + 0.3 g·kg-1·day-1 maltodextrin) ingestion once per day over 72 hr. Knee extensor peak torque at 0°, 30°, and 180° per second and muscle soreness were measured before, immediately following, 24, 48, and 72 hr posteccentric exercise. Eccentric exercise consisted of 8 sets (10 repetitions/set) of unilateral knee extension at 125% maximum concentric force with 2-min rest intervals. L-glutamine resulted in greater relative peak torque at 180°/sec both immediately after (71 ± 8% vs. 66 ± 9%), and 72 hr (91 ± 8% vs. 86 ± 7%) postexercise (all, p < .01). In men, L-glutamine produced greater (p < .01) peak torques at 30°/ sec postexercise. Men also produced greater normalized peak torques at 30°/sec (Nm/kg) in the L-glutamine condition than women (all, p < .05). In the entire sample, L-glutamine resulted in lower soreness ratings at 24 (2.8 ± 1.2 vs. 3.4 ± 1.2), 48 (2.6 ± 1.4 vs. 3.9 ± 1.2), and 72 (1.7 ± 1.2 vs. 2.9 ± 1.3) hr postexercise (p < .01). The L-glutamine supplementation resulted in faster recovery of peak torque and diminished muscle soreness following eccentric exercise. The effect of L-glutamine on muscle force recovery may be greater in men than women.

A review of human neuroimaging investigations involved with central autonomic regulation of baroreflex-mediated cardiovascular control

Effective regulation of central blood volume and arterial pressure is critical for optimal cardiovascular homeostasis. Inadequate regulation of mean arterial pressure has important pathophysiological implications including syncope, end organ damage, and stroke. Such regulation requires appropriate central integration of barosensory afferents and reflex autonomic control of the heart and blood vessels. The neural pathways involved with the baroreflex include brainstem nuclei that receive modulatory input from higher brain centres. Studies in anesthetized animals have highlighted the role of a central autonomic network involved with baroreflex control. The refinement of functional neuroimaging techniques has provided the opportunity to confirm and extend these findings in awake humans. Such methods have provided information about the temporal and spatial neural patterns associated with changes in barosensory afferent activity and reflex autonomic and cardiovascular responses. This review focuses on human neuroimaging investigations that utilized volitional (e.g., respiratory challenges) and/or non-volitional (e.g. lower body suction) methods to study baroreflex control. The cumulative evidence points to the importance of a baroreflex autonomic network that includes the insular cortex, anterior cingulate cortex, medial prefrontal cortex, amygdala and cerebellum. Future work is required to further delineate the brain regions involved specifically with sensing barosensory afferents versus reflex efferent responses. The use of functional electrophysiological imaging techniques (e.g. MEG) may provide an opportunity to: 1) expand the methods and physiologic measures used to study central baroreflex function in humans, and 2) enhance the temporal precision required to delineate the order of activation within higher brain regions involved with baroreflex control.

Cortical autonomic network gray matter and sympathetic nerve activity in obstructive sleep apnea

The sympathetic excitation elicited acutely by obstructive apnea during sleep (OSA) carries over into wakefulness. We hypothesized that OSA induces structural changes in the insula and cingulate, key central autonomic network (CAN) elements with projections to brainstem sympathetic premotor regions. The aims of this study were to: 1) apply two distinct but complementary methods (cortical thickness analysis [CTA] and voxel based morphometry [VBM]) to compare insula and cingulate grey matter thickness in subjects without and with OSA; 2) determine if oxygen desaturation index (ODI) relates to cortical thickness; and 3) determine if cortical thickness or volume in these regions predicts muscle sympathetic nerve (MSNA) burst incidence (BI). Overnight polysomnography, anatomical MRI and MSNA data were acquired in 41 subjects with no or mild OSA (n=19; 59±2 yrs [Mean±SE]; 6 female; apnea-hypopnea index [AHI] 7±1 events/hour) or moderate to severe OSA (n=22; 59±2 yrs; 5 female; AHI 31±4 events/hour). Between group CTA analyses identified cortical thinning within the left dorsal posterior insula (LdpIC) and thickening within the left mid-cingulate (LMCC) cortex, while VBM identified thickening within bilateral thalami (all, (P<0.05)). CTA revealed inverse relationships between ODI and bilateral dpIC and left posterior cingulate (LPCC)/precuneus thickness. Positive correlations between BI and LMCC grey matter thickness/volume were evident with both methods and between BI and left posterior thalamus volume using VBM. In OSA the magnitude of insular thinning, although a function of hypoxia severity, does not influence MSNA whereas cingulate and thalamic thickening relate directly to the intensity of sympathetic discharge during wakefulness.

Long-duration bed rest modifies sympathetic neural recruitment strategies in males and females

To understand the impact of physical deconditioning with head-down tilt bed rest (HDBR) on the malleability of sympathetic discharge patterns, we studied 1) baseline integrated muscle sympathetic nerve activity (MSNA; microneurography) from 13 female participants in the WISE-2005 60-day HDBR study (retrospective analysis), 2) integrated MSNA and multiunit action potential (AP) analysis in 13 male participants performed on data collected at baseline and during physiological stress imposed by end-inspiratory apnea in a new 60-day HDBR study, and 3) a repeatability study (control; n = 6, retrospective analysis, 4 wk between tests). Neither baseline integrated burst frequency nor incidence were altered with HDBR (both P > 0.35). However, baseline integrated burst latency increased in both HDBR studies (male: 1.35 ± 0.02 to 1.39 ± 0.02 s, P < 0.01; female: 1.23 ± 0.02 to 1.29 ± 0.02 s, P < 0.01), whereas controls exhibited no change across two visits (1.25 ± 0.02 to 1.25 ± 0.02 s, group-by-time interaction, P = 0.02). With the exception of increased AP latency ( P = 0.03), male baseline AP data did not change with HDBR (all P > 0.19). The change in AP frequency on going from baseline to apnea (∆94 ± 25 to ∆317 ± 55 AP/min, P < 0.01) and the number of active sympathetic clusters per burst (∆0 ± 0.2 to ∆1 ± 0.2 clusters/burst, P = 0.02) were greater post- compared with pre-HDBR. The change in total clusters with apnea was ∆0 ± 0.5 clusters pre- and ∆2 ± 0.7 clusters post-HDBR ( P = 0.07). These data indicate that 60-day HDBR modified discharge characteristics in baseline burst latency and sympathetic neural recruitment during apneic stress. NEW & NOTEWORTHY Long-duration bed rest did not modify baseline sympathetic burst frequency in male and female participants, but examination of additional features of the multiunit signal provided novel evidence to suggest augmented synaptic delays or processing times at baseline for all sympathetic action potentials. Furthermore, long-duration bed rest increased reflex-sympathetic arousal to apneic stress in male participants primarily by mechanisms involving an augmented firing rate of action potential clusters active at baseline.

Achieving Canadian physical activity guidelines is associated with better vascular function independent of aerobic fitness and sedentary time in older adults

Canadian physical activity guidelines recommend older adults accumulate 150 min of weekly moderate to vigorous physical activity (MVPA). Older adults who are insufficiently active may have reduced blood vessel health and an increased risk of cardiovascular disease. We tested this hypothesis in 11 older adults who did (7 female; age, 65 ± 5 years; MVPA, = 239 ± 81 min/week) and 10 older adults who did not (7 female; age, 68 ± 9 years; MVPA, 95 ± 33 min/week) meet MVPA guidelines. Flow-mediated dilation (FMD) in the brachial (BA) and popliteal (POP) arteries, as well as nitroglycerin-mediated dilation (NMD; endothelial-independent dilation) in the POP were assessed via ultrasonography. Aerobic fitness (peak oxygen uptake) was determined using a graded, maximal cycle ergometry test via indirect calorimetry. MVPA and sedentary time were assessed over 5 days using the PiezoRx and activPAL, respectively. There were no differences in peak oxygen uptake (26 ± 10 vs. 22 ± 10 mL O2/(kg·min); p = 0.26) or sedentary time (512 ± 64 vs. 517 ± 76 min/day; p = 0.87) between groups; however, those who achieved the MVPA guidelines had a higher BA-FMD (5.1% ± 1.3% vs. 3.6% ± 1.7%; p = 0.03), POP-FMD (2.6% ± 1.1% vs. 1.3% ± 0.8%; p = 0.006), and POP-NMD (5.1% ± 1.7% vs. 3.3% ± 2.1%; p = 0.04). In the pooled sample, MVPA was moderately correlated to both BA-FMD (r = 0.53; p = 0.01) and POP-NMD (r = 0.59; p = 0.005), and strongly correlated to POP-FMD (r = 0.85; p < 0.001). Collectively, our results provide supporting evidence that meeting MVPA guidelines is associated with better vascular function and may reduce the risk of developing cardiovascular disease in older adults. Furthermore, these data suggest that weekly MVPA time may have a greater impact on blood vessel function than aerobic fitness and weekly sedentary time.

Using the Portapres® for the measurement of toe arterial blood pressure during movement: is it valid and reliable?

The aim of the study was to assess the validity and reliability of using the Portapres® to measure toe blood pressure during rest and exercise. Construct validity, concurrent validity, and interday reliability were assessed by measuring toe (Portapres®)) and brachial blood pressure in 16 nondisabled participants on consecutive days. Construct validity was assessed by pedaling on a cycle ergometer (6 revolutions per minute) and comparing the measured toe blood pressure to an estimated value based on orthostatic factors. Concurrent validity was assessed by comparing toe and brachial blood pressure during supine rest and following 10 min of cycling exercise. Interday reliability was assessed by recording toe and brachial blood pressure during supine rest on a second day. Construct validity analysis shows that the toe blood pressure signal was moderately correlated with the changes in heart–toe distance and that changes in toe blood pressure during slow cycling were similar to the estimated value. Resting toe and brachial mean arterial blood pressure showed concurrent validity with only a fixed bias explained by the change in orthostatic pressure and the toe–brachial index. Furthermore, cycling exercise was associated with an increase in brachial and a decrease in toe mean blood pressure. The interday reliability analysis showed no proportional or fixed bias for mean arterial blood pressure. Our study showed the feasibility of using the Portapres® to measure toe blood pressure during movement and can be used to study the effect of movement‐related forces during cycling on toe blood pressure.