The hypoxic ventilatory response and hypoxic burden are predictors of the magnitude of ventilatory long-term facilitation in humans.

Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. The magnitude of these forms of plasticity might be influenced by anthropometric and physiological variables, as well as protocol elements. However, the impact of many of these variables on the magnitude of respiratory plasticity has not been established in humans. A meta-analysis was completed using anthropometric and physiological variables obtained from 124 participants that completed one of three intermittent hypoxia protocols. Simple correlations between the aggregate variables and the magnitude of PA and vLTF standardized to baseline was completed. Thereafter, the variables correlated to PA or vLTF were input into a multilinear regression equation. Baseline measures of the hypoxic ventilatory response was the sole predictor of PA (R = 0.370, P = 0.012). Similarly, this variable along with the hypoxic burden predicted the magnitude of vLTF (R = 0.546, P < 0.006 for both variables). In addition, the magnitude of PA was strongly correlated to vLTF (R = 0.617, P < 0.001). Anthropometric measures do not predict the magnitude of PA and vLTF in humans. Alternatively, the hypoxic ventilatory response was the sole predictor of PA, and in combination with the hypoxic burden, predicted the magnitude of vLTF. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity. KEY POINTS: Mild intermittent hypoxia initiates progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) in humans. Many of the anthropometric and physiological variables that could impact the magnitude of these forms of plasticity are unknown. Anthropometric and physiological variables were measured from a total of 124 participants that completed one of three distinct intermittent hypoxia protocols. The variables correlated to PA or vLTF were input into a multilinear regression analysis. The hypoxic ventilatory response was the sole predictor of PA, while this variable in addition to the average hypoxic burden predicted the magnitude of vLTF. A strong correlation between PA and vLTF was also revealed. These influences should be considered in the design of mild intermittent hypoxia protocol studies in humans. Moreover, the strong correlation between PA and vLTF suggests that a common mechanistic pathway may have a role in the initiation of these forms of plasticity.

Racial differences in upper airway collapsibility and loop gain in young adult males.

STUDY OBJECTIVES: Previous studies reported that the apnea-hypopnea index was similar in young adult Black and White participants. However, whether this similarity reflects an analogous combination of apneas and hypopneas is unknown. Likewise, the physiological mechanisms underlying this similarity has not been explored. METHODS: 60 Black and 48 White males completed the study. After matching for age and body mass index, 41 participants remained in each group. All participants completed a sleep study. Subsequently, standard sleep indices along with loop gain and the arousal threshold were determined. In addition, airway collapsibility (24 of 60 and 14 of 48 participants) and the hypoxic ventilatory response during wakefulness (30 of 60 and 25 of 48 participants) was measured. RESULTS: The apnea-hypopnea index was similar in Blacks and Whites (p = .140). However, the index was comprised of more apneas (p = .014) and fewer hypopneas (p = .025) in Black males. These modifications were coupled to a reduced loop gain (p = .0002) and a more collapsible airway (p = .030). These differences were independent of whether or not the groups were matched. For a given hypoxic response, loop gain was reduced in Black compared to White males (p = .023). CONCLUSIONS: Despite a similar apnea-hypopnea index, more apneas and fewer hypopneas were evident in young adult Black compared to White males. The physiological mechanisms that contribute to these events were also different between groups. Addressing these differences may be important when considering novel therapeutic approaches to eliminate apnea in Black and White participants.

Divergent Ventilatory and Blood Pressure Responses are Evident Following Repeated Daily Exposure to Mild Intermittent Hypoxia in Males with OSA and Hypertension.

Introduction: Resting minute ventilation and ventilation during and following hypoxia may be enhanced following daily exposure to mild intermittent hypoxia (MIH). In contrast, resting systolic blood pressure (SBP) is reduced following daily exposure to MIH. However, it is presently unknown if the reduction in resting SBP following daily exposure, is coupled with reduced SBP responses during and after acute exposure to MIH. Methods: Participants with obstructive sleep apnea (OSA) and hypertension (n = 10) were exposed to twelve 2-min bouts of MIH (oxygen saturation-87%)/day for 15 days. A control group (n = 6) was exposed to a sham protocol during which compressed air (i.e., FIO2 = 0.21) was inspired in place of MIH. Results: The hypoxic ventilatory response (HVR) and hypoxic systolic blood pressure response (HSBP) increased from the first to the last hypoxic episode on the initial (HVR: 0.08 ± 0.02 vs. 0.13 ± 0.02 L/min/mmHg, p = 0.03; HSBP: 0.13 ± 0.04 vs. 0.37 ± 0.06 mmHg/mmHg, p < 0.001) and final (HVR: 0.10 ± 0.01 vs. 0.15 ± 0.03 L/min/mmHg, p = 0.03; HSBP: 0.16 ± 0.03 vs. 0.41 ± 0.34 mmHg/mmHg, p < 0.001) day. The magnitude of the increase was not different between days (p ≥ 0.83). Following exposure to MIH, minute ventilation and SBP was elevated compared to baseline on the initial (MV: 16.70 ± 1.10 vs. 14.20 ± 0.28 L/min, p = 0.01; SBP: 167.26 ± 4.43 vs. 151.13 ± 4.56 mmHg, p < 0.001) and final (MV: 17.90 ± 1.25 vs. 15.40 ± 0.77 L/min, p = 0.01; SBP: 156.24 ± 3.42 vs. 137.18 ± 4.17 mmHg, p < 0.001) day. The magnitude of the increases was similar on both days (MV: 3.68 ± 1.69 vs. 3.22 ± 1.27 L/min, SBP: 14.83 ± 2.64 vs. 14.28 ± 1.66 mmHg, p ≥ 0.414). Despite these similarities, blood pressure at baseline and at other time points during the MIH protocol was reduced on the final compared to the initial day (p ≤ 0.005). Conclusion: The ventilatory and blood pressure responses during and following acute MIH were similar on the initial and final day of exposure. Alternatively, blood pressure was down regulated, while ventilation was similar at all time points (i.e., baseline, during and following MIH) after daily exposure to MIH.

Daily Exposure to Mild Intermittent Hypoxia Reduces Blood Pressure in Male Patients with Obstructive Sleep Apnea and Hypertension.

Rationale: Daily exposure to mild intermittent hypoxia (MIH) may elicit beneficial cardiovascular outcomes. Objectives: To determine the effect of 15 days of MIH and in-home continuous positive airway pressure treatment on blood pressure in participants with obstructive sleep apnea and hypertension. Methods: We administered MIH during wakefulness 5 days/week for 3 weeks. The protocol consisted of twelve 2-minute bouts of hypoxia interspersed with 2 minutes of normoxia. End-tidal carbon dioxide was maintained 2 mm Hg above baseline values throughout the protocol. Control participants were exposed to a sham protocol (i.e., compressed air). All participants were treated with continuous positive airway pressure over the 3-week period. Results are mean ± SD. Measurements and Main Results: Sixteen male participants completed the study (experimental n = 10; control n = 6). Systolic blood pressure at rest during wakefulness over 24 hours was reduced after 15 days of MIH (142.9 ± 8.6 vs. 132.0 ± 10.7 mm Hg; P < 0.001), but not following the sham protocol (149.9 ± 8.6 vs. 149.7 ± 10.8 mm Hg; P = 0.915). Thus, the reduction in blood pressure from baseline was greater in the experimental group compared with control (-10.91 ± 4.1 vs. -0.17 ± 3.6 mm Hg; P = 0.003). Modifications in blood pressure were accompanied by increased parasympathetic and reduced sympathetic activity in the experimental group, as estimated by blood pressure and heart rate variability analysis. No detrimental neurocognitive and metabolic outcomes were evident following MIH. Conclusions: MIH elicits beneficial cardiovascular and autonomic outcomes in males with OSA and concurrent hypertension. Clinical trial registered with www.clinicaltrials.gov (NCT03736382).

A comprehensive review of respiratory, autonomic and cardiovascular responses to intermittent hypoxia in humans.

This review explores forms of respiratory and autonomic plasticity, and associated outcome measures, that are initiated by exposure to intermittent hypoxia. The review focuses primarily on studies that have been completed in humans and primarily explores the impact of mild intermittent hypoxia on outcome measures. Studies that have explored two forms of respiratory plasticity, progressive augmentation of the hypoxic ventilatory response and long-term facilitation of ventilation and upper airway muscle activity, are initially reviewed. The role these forms of plasticity might have in sleep disordered breathing are also explored. Thereafter, the role of intermittent hypoxia in the initiation of autonomic plasticity is reviewed and the role this form of plasticity has in cardiovascular and hemodynamic responses during and following intermittent hypoxia is addressed. The role of these responses in individuals with sleep disordered breathing and spinal cord injury are subsequently addressed. Ultimately an integrated picture of the respiratory, autonomic and cardiovascular responses to intermittent hypoxia is presented. The goal of the integrated picture is to address the types of responses that one might expect in humans exposed to one-time and repeated daily exposure to mild intermittent hypoxia. This form of intermittent hypoxia is highlighted because of its potential therapeutic impact in promoting functional improvement and recovery in several physiological systems.

Variations in loop gain and arousal threshold during NREM sleep are affected by time of day over a 24-hour period in participants with obstructive sleep apnea.

We investigated whether time of day affects loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Eleven men with obstructive sleep apnea (apnea-hypopnea index > 5 events/h) completed a constant-routine protocol that comprised 3-h sleep sessions in the evening [10 PM (1) to 1 AM], morning (6 AM to 9 AM), afternoon (2 PM to 5 PM), and subsequent evening [10 PM (2) to 1 AM]. During each sleep session LG and the AT were measured during NREM sleep with a model-based approach. Our results showed the presence of a rhythmicity in both LG (P < 0.0001) and the AT (P < 0.001) over a 24-h period. In addition, LG and the AT were greater in the morning compared with both evening sessions [6 AM vs. 10 PM (1) vs. 10 PM (2): LG (1 cycle/min): 0.71 ± 0.23 vs. 0.60 ± 0.22 (P = 0.01) vs. 0.56 ± 0.10 (P < 0.001), AT (fraction of eupneic breathing): 1.45 ± 0.47 vs. 1.28 ± 0.36 (P = 0.02) vs. 1.20 ± 0.18 (P = 0.001)]. No difference in LG and the AT existed between the evening sessions (LG: P = 0.27; AT: P = 0.24). LG was correlated to measures of the hypocapnic ventilatory response (i.e., a measure of chemoreflex sensitivity) (r = 0.72 and P = 0.045) and the critical closing pressure (i.e., a measure of airway collapsibility) (r = 0.77 and P = 0.02) that we previously published. We conclude that time of day, independent of hallmarks of sleep apnea, affects LG and the AT during NREM sleep. These modifications may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with obstructive sleep apnea. In addition, efficaciousness of treatments for obstructive sleep apnea that target LG and the AT may be modified by a rhythmicity in these variables.NEW & NOTEWORTHY Loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep are greater in the morning compared with the afternoon and evening. Loop gain measures are correlated to chemoreflex sensitivity and the critical closing pressure measured during NREM sleep in the evening, morning, and afternoon. Breathing (in)stability and efficaciousness of treatments for obstructive sleep apnea may be modulated by a circadian rhythmicity in loop gain and the arousal threshold.

Imatinib modulates pro-inflammatory microenvironment with angiostatic effects in experimental lung carcinogenesis.

Lung cancer has second highest rate of incidence and mortality around the world. Smoking cigarettes is the main stream cause of lung carcinogenesis along with other factors such as spontaneous mutations, inactivation of tumor suppressor genes. The present study was aimed to identify the mechanistic role of Imatinib in the chemoprevention of experimental lung carcinogenesis in rat model. Gross morphological observations for tumor formation, histological examinations, RT-PCR, Western blotting, fluorescence spectroscopy and molecular docking studies were performed to elucidate the chemopreventive effects of Imatinib and support our hypothesis by various experiments. It is evident that immuno-compromised microenvironment inside solid tumors is responsible for tumor progression and drug resistance. Therefore, it is inevitable to modulate the pro-inflammatory signaling inside solid tumors to restrict neoangiogenesis. In the present study, we observed that Imatinib could downregulate the inflammatory signaling and also attributed angiostatic effects. Moreover, Imatinib also altered the biophysical properties of BAL cells such as plasma membrane potential, fluidity and microviscosity to restrict their infiltration and thereby accumulation to mount immuno-compromised environment inside the solid tumors during angiogenesis. Our molecular docking studies suggest that immunomodulatory and angiostatic properties of Imatinib could be either independent of each other or just a case of synergistic pleiotropy. Imatinib was observed to activate the intrinsic or mitochondrial pathway of apoptosis to achieve desired effects in cancer cell killings. Interestingly, binding of Imatinib inside the catalytic domain of PARP-1 also suggests that it has caspase-independent properties in promoting cancer cell deaths.

Resistance training does not alter same-day sleep architecture in institutionalized older adults.

Sleep disturbance is a common symptom in institutionalized older adults that reduces their quality of life and may contribute to progression of cognitive impairment. While we found that a 7-week combination of resistance training, walking and social activity significantly improved sleep in institutionalized older adults compared with a usual care control group, no one to our knowledge has determined the acute effects of resistance training on same-day sleep in this population. Given the effort required to promote exercise adherence in institutionalized older adults and to obtain a positive training effect, understanding of the acute effects of resistance training on same-day sleep architecture should be elucidated, especially with respect to unintended consequences. This secondary data analysis assessed if resistance training altered the same-day sleep architecture in institutionalized older adults. Forty-three participants (age 81.5 ± 8.1 years, male = 17, female = 26) had two attended overnight polysomnography tests in their rooms for sleep architecture analysis; one polysomnography with same-day resistance training, one without any resistance training. Resistance training consisted of chest and leg press exercises (three sets, eight repetitions, 80% predicted one-repetition maximum). There were no significant changes in sleep architecture between either polysomnography nights; sleep efficiency (P = 0.71), time in non-rapid eye movement stages (P = 0.50), time in rapid eye movement stages (P = 0.14), time awake (P = 0.56), time until sleep onset (P = 0.47), total sleep stage shifts (P = 0.65) or rapid eye movement sleep stage latency (P = 0.57). Our results show no acute same-day effects of resistance training on sleep architecture in institutionalized older adults. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00888706.

Strength training and light physical activity reduces the apnea-hypopnea index in institutionalized older adults.

OBJECTIVES: To determine the effect of 7 weeks of resistance training and walking on the apnea-hypopnea index (AHI) in institutionalized older adults compared with a usual care control group. DESIGN: Secondary analysis of data from a randomized controlled trial. SETTING: Ten nursing and 3 assisted living facilities in Arkansas. PARTICIPANTS: Institutionalized older adults. INTERVENTIONS: Exercise group (EG) performed supervised resistance training to arm and hip extensors on 3 days a week with additional 2 days a week of light walking. Usual care group (UC) participated in the usual activities provided within their living facility. MEASUREMENTS: Two nights of polysomnography before and following 7-week intervention. RESULTS: Adjusted means in the EG group showed a decrease in AHI from 20.2 (SD ±1.3) at baseline to 16.7 (SD ±0.9) at 7 weeks. Absolute strength gains were not associated with improved AHI. CONCLUSION: Supervised resistance training and light walking reduced the severity of obstructive sleep apnea in institutionalized older adults.

Correlation of early functional capacity with biventricular function and residual pulmonary artery hypertension following mitral valve replacement surgery.

PURPOSE: To evaluate the functional capacity following mitral valve replacement in the early postoperative period and to determine the correlation of biventricular function and residual pulmonary artery hypertension (PAH) to the functional capacity. METHODS: On the seventh postoperative day, 53 patients who underwent mitral valve replacement with preoperative diagnosis of PAH underwent a 2-dimensional echocardiographic and Doppler examination for the assessment of right ventricular systolic pressure, along with right ventricular (RV) and left ventricular (LV) myocardial performance indices (MPIs). These assessments were followed by a 6-Minute Walk Test. Five patients were eventually withdrawn from the study. RESULTS: The diminished functional capacity (51.6% ± 4.1% of predicted 6-Minute Walk Test distance for age, gender, weight, and height) significantly correlated with biventricular dysfunction evident from elevated RVMPI (0.35 ± 0.09) and LVMPI (0.52 ± 0.11) (for both Ps ≤ .001). Furthermore, the residual PAH, with mean right ventricular systolic pressure of 37 ± 11 mm Hg, showed negative correlation with the functional capacity (P ≤ .001). In addition, LVMPI had strong association with RVMPI (P ≤ .001). Linear regression analysis demonstrated that LVMPI and right ventricular systolic pressure were independent predictors of functional capacity. CONCLUSIONS: The RV and LV function, as quantified by MPI, and the degree of residual PAH are associated with functional capacity impairment after mitral valve replacement, with LVMPI and residual PAH as the independent predictorsqbetween RV and LV performance indices indicate that ventricular interactions contribute to the functional capacity impairment in these patients.