Citations

The ability to work efficiently at altitude is impaired by the reduced arterial oxygen tension. Acetazolamide may improve systemic saturation (SaO 2 ) by stimulating ventilation but increases the work of breathing. Efforts have focused on the potential role of sildenafil in improving exercise performance in high altitude environment. The purpose of this study was to determine the effects of acetazolamide and sildenafil on oxygen uptake (VO 2 ) and breathing efficiency during submaximal hypoxic exercise. Sixteen volunteers received sildenafil 40 mg (S), acetazolamide 125 mg (A) or matching placebo (P) tid × four doses in double‐blind fashion starting 8 hours prior to hypoxic exposure over 3 separate overnight stays in an altitude tent with an O 2 concentration of 12.5%, and then performed hypoxic submaximal exercise on a stationary bicycle for 10 min at a workload of 40% of VO 2 peak. SaO 2 decreased with exercise but there was no difference in exercising SaO 2 or VO 2 between conditions. As expected, acetazolamide increased ventilation compared to placebo and sildenafil. Breathing efficiency as measured by Ve/VCO 2 decreased with acetazolamide in comparison to placebo and sildenafil (P: 42.6±1.2, S: 41.9±1.6, A: 46.7±1.1, p<0.01). Sildenafil did not change breathing efficiency while acetazolamide reduced breathing efficiency during hypoxic exercise. This study was funded by Mayo Foundation and NIH Grant No. HL71478.

Reduced partial pressures of inspired O 2 may influence the bronchial circulation through a number of mechanisms (e.g. altered pulmonary and systemic vascular pressures, lung fluid regulation, airway cooling & drying from increased ventilation). The present study examined the impact of acute, graded hypoxia on bronchial blood flow (Q aw ) in eight healthy adults (28 ± 9 years). Subjects were exposed to inspired O 2 levels resulting in arterial O 2 saturation (SaO 2 ) values of 90% and 80% for 15 min each. To control for the mild hyperventilation that accompanies hypoxia, subjects then mimicked the 80% SaO 2 ventilation (V E ) rate with 21% FIO 2 and again with CO 2 added to the inspirate to maintain normocapnia. Q aw and cardiac output (CO) were measured using soluble gas techniques. Also measured were alveolar‐capillary conductance (D m , index of lung fluid balance), pulmonary capillary blood volume (V c ), and systemic mean (MAP) and pulmonary arterial pressures (PAP). Hypoxia resulted in minimal change in MAP, a small rise in PAP, minimal change in CO and V c , and a rise in D m . There was also a non significant decrease in Q aw with hypoxia. Mild hyperventilation resulted in a significant fall in Q aw , but when normocapnia was maintained, Q aw returned to baseline values. These data suggest that acute, graded hypoxic exposure does not significantly impact Q aw , however, the hypocapnia associated with mild hyperventilation reduces Q aw .

We recently reported altered cardiovascular structure and function in heart failure (HF) patients based on the Arg16/Gly and Gln27/Glu beta‐2 adrenergic receptor (ADRB2) polymorphisms. The purpose of this study was to extend the echocardiographic analysis based on haplotype combination of ADRB2 at nucleotides −654, 46 79, 252, 491, 523, in a larger database of HF patients (n=126, age 56±1yr, LV ejection fraction, LVEF 29±1%, BMI 28±0.4kg/m 2 , mean±SEM) and healthy controls (n=100, age 50±2yr, LVEF 63±0.7%, BMI 25±0.3kg/m 2 ). The most common haplotypes in both HF and control were 2, 8, and 12 (2=AACGCC, 8=GGCACA, and 12=GGGGCC, for nucleotides −654, 46, 79, 252, 491, and 523). Cardiac function did not differ according to haplotype pairs in the control subjects. In HF, the widest discrepancies were between haplotype pair 2/2 (which includes the Arg16+Gln27 homozygotes) and haplotype pair 12/12 (which includes the Gly16+Glu27 homozygotes), respectively: 2/2 displayed lower cardiac index (2.3±0.1 v 2.7±0.1 l/min/m 2 ), greater left atrial diameter (53±2 v 47±2 mm), shorter LV decel time (185±11 v 224±14 msec), and greater right ventricular pressure (44±2 v 33±2 mmHg) p<0.05 for all). These data suggest that in HF, haplotype variation of the ADRB2 is associated with differences in cardiac function, and SNP positions 16 and 27 remain major loci of interest. Support: K23RR‐17520, HL‐71478.

Background Fluid flux in the lungs is influenced by factors altering accumulation or removal (e.g., stimulation of epithelium sodium channels, ENaC). Purpose To determine if ENaC are necessary in the normal fluid regulation with simulated altitude exposure. Methods/Results On separate occasions, 19 healthy subjects (27 ± 5 y) received either nebulized amiloride (ENaC antagonist) or placebo (nebulized saline) during 17 h normobaric hypoxia (FIO2 = 12.5%) in a randomized, double‐blind fashion. Lung diffusing capacity for carbon monoxide (DLCO), alveolar‐capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were measured via a rebreathe method before and after hypoxic exposure. DLCO was not different at baseline for the amiloride vs. placebo treatments (19 ± 5 vs. 21 ± 8 mL/min/mmHg). Hypoxic exposure increased Vc but did not change Dm in both treatments (Placebo: Vc = 43 ± 22 vs. 59±23 mL p=0.011, Dm = 35 ± 10 vs. 37 ± 12 mL/min/mmHg p=0.312; Amiloride: Vc = 38 ± 17 vs. 57 ± 22 mL p<0.01, Dm = 31 ± 8 vs. 34 ± 10 mL/min/mmHg p= 0.206). Conclusion Normobaric hypoxia did not differentially affect alveolar‐capillary conductance in amiloride and placebo conditions, suggesting that ENaC do not have a role in normal lung fluid regulation during acute hypoxic exposure. HL71478

Background Patients with heart failure (HF) often develop pulmonary system abnormalities. Specifically, an abnormal ventilation relative to metabolic demand (V E /VCO 2 , ventilatory efficiency) during exercise has been shown to be an important marker of disease severity and prognosis. The purpose of this investigation was to focus on the factors that underlie the abnormal breathing efficiency in this population. Methods 14 controls (10 male) and 40 (36 male) mod‐severe HF patients, age 52±12 and 56±8 yrs, respectively, performed graded exercise on a cycle ergometer. Gas exchange and blood gas measurements were made during submaximal exercise (~65% peak VO 2 ) and used to quantify the influence of hyperventilation (PaCO 2 ) and dead space ventilation (V D ) on V E /VCO 2 . Results The V E /VCO 2 ratio was lower in controls (30±4) than in HF (45±9, p<0.001) due to a lower PaCO 2 and higher V D /V T that contributed an estimated 29% and 71%, respectively, to the increased V E /VCO 2 (p<0.05). The elevated V D /V T in HF was in turn the result of a tachypneic breathing pattern (lower V T , 877±306 vs 2003±504ml, p<0.01) in the presence of a relatively normal V D (9.6±3.8 vs 11.9±5.7 L/min, p=0.094). Conclusion The abnormal ventilation in relation to metabolic demand in HF during exercise is predominantly due to alterations in breathing pattern, rather than hyperventilation or changes in ventilation/perfusion relationships. HL71478

Pulse Decomposition Analysis (PDA) offers new insights into factors altering the arterial pressure pulse contour. PDA premise is that peripheral arterial pressure pulse envelope consists of distinct component pressure pulses, a left ventricular ejection and its reflections. Two PDA parameters appear to be particularly useful in quantifying the pulse contour. P2P1 is the ratio of second component pulse and primary ejection pulse amplitudes. T13 is the temporal delay between the third component pulse and the primary ejection pulse. P2P1 and T13 parameters were used to examine pressure pulse contour changes in 81 healthy subjects (18–27 yrs; BMI 27.5 ± 2.6) undergoing a Stroop mental stress test, cycle ergometer stress tests (3 min; 50W and 100W), and post‐exercise recovery. Digital pressure pulse contours were recorded/quantified using PDA formalism. Relative to baseline, P2P1 increased 8% post‐Stroop (individual variation 0% to 15%), T13 increased 4%, (individual variation 0% to 8%). Exercise decreased P2P1 21 ± 14%, while the T13 change was 19 ± 15%. PDA‐based pulse propagation model quantifies physical changes that arterial pulse reflection sites undergo. Peripheral arterial pressure pulse appears to be due to the primary ejection pulse and two major reflections. Two reflection sites in the central arteries appear to be responsible for the “reflected” wave part of the pulse contour.