Urs A. Leuenberger

Hemodynamic effects of supplemental oxygen administration in congestive heart failure

OBJECTIVES This study sought to determine the hemodynamic effects of oxygen therapy in heart failure. BACKGROUND High dose oxygen has detrimental hemodynamic effects in normal subjects, yet oxygen is a common therapy for heart failure. Whether oxygen alters hemodynamic variables in heart failure is unknown. METHODS We studied 10 patients with New York Heart Association functional class III and IV congestive heart failure who inhaled room air and 100% oxygen for 20 min. Variables measured included cardiac output, stroke volume, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance, mean arterial pressure and heart rate. Graded oxygen concentrations were also studied (room air, 24%, 40% and 100% oxygen, respectively; n = 7). In five separate patients, muscle sympathetic nerve activity and ventilation were measured during 100% oxygen. RESULTS The 100% oxygen reduced cardiac output (from 3.7 +/- 0.3 to 3.1 +/- 0.4 liters/min [mean +/- SE], p < 0.01) and stroke volume (from 46 +/- 4 to 38 +/- 5 ml/beat per min, p < 0.01) and increased pulmonary capillary wedge pressure (from 25 +/- 2 to 29 +/- 3 mm Hg, p < 0.05) and systemic vascular resistance (from 1,628 +/- 154 to 2,203 +/- 199 dynes.s/cm5, p < 0.01). Graded oxygen led to a progressive decline in cardiac output (one-way analysis of variance, p < 0.0001) and stroke volume (p < 0.017) and an increase in systemic vascular resistance (p < 0.005). The 100% oxygen did not alter sympathetic activity or ventilation. CONCLUSIONS In heart failure, oxygen has a detrimental effect on cardiac output, stroke volume, pulmonary capillary wedge pressure and systemic vascular resistance. These changes are independent of sympathetic activity and ventilation.

Different vasodilator responses of human arms and legs

Forearm vascular responses to intra‐arterial infusions of endothelium‐dependent and ‐independent vasodilators have been thoroughly characterized in humans. While the forearm is a well‐established experimental model for studying human vascular function, it is of limited consequence to systemic cardiovascular control owing to its small muscle mass and blood flow requirements. In the present study we determined whether these responses could be generalized to the leg. Based upon blood pressure differences between the leg and arm during upright posture, we hypothesized that the responsiveness to endothelium‐dependent vasodilators would be greater in the forearm than the leg. Brachial and femoral artery blood flow (Q, ultrasound Doppler) at rest and during intra‐arterial infusions of endothelium‐dependent (acetylcholine and substance P) and ‐independent (sodium nitroprusside) vasodilators were measured in eight healthy men (22–27 years old). Resting blood flows in the forearm before infusion of acetylcholine, substance P or sodium nitroprusside were 25 ± 4, 30 ± 7 and 29 ± 5 ml min−1, respectively, and in the leg were 370 ± 32, 409 ± 62 and 330 ± 30 ml min−1, respectively. At the highest infusion rate of acetylcholine (16 μg (100 ml tissue)−1 min−1) there was a greater (P < 0.05) increase in Q to the forearm (1864 ± 476%) than to the leg (569 ± 86%). Similarly, at the highest infusion rate of substance P (125 pg (100 ml tissue)−1 min−1) there was a greater (P < 0.05) increase in Q to the forearm (911 ± 286%) than to the leg (243 ± 58%). The responses to sodium nitroprusside (1 μg (100 ml tissue)−1 min−1) were also greater (P < 0.05) in the forearm (925 ± 164%) than in the leg (326 ± 65%). These data indicate that vascular responses to both endothelium‐dependent and ‐independent vasodilator agents are blunted in the leg compared to the forearm.

Effects of intermittent hypoxia on sympathetic activity and blood pressure in humans

Sympathetic nerve activity and arterial pressure are frequently elevated in patients with obstructive sleep apnea (OSA). The mechanisms responsible for chronic sympathetic activation and hypertension in OSA are unknown. To determine whether repetitive apneas raise sympathetic nerve activity and/or arterial pressure, awake and healthy young subjects performed voluntary end-expiratory apneas for 20 s per min for 30 min (room air apneas). To accentuate intermittent hypoxia, in a separate group of subjects, hypoxic gas (inspired O2 10%) was added to the inspiratory port for 20 s before each apnea (hypoxic apneas). Mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA, peroneal microneurography) were determined before and up to 30 min following the repetitive apneas. Following 30 hypoxic apneas (O2 saturation nadir 83.1+/-1.2%), MSNA increased from 17.4+/-2.7 to 23.4+/-2.5 bursts/min and from 164+/-28 to 240+/-35 arbitrary units respectively (P<0.01 for both; n=10) and remained elevated while MAP increased transiently from 80.5+/-3.7 to 83.1+/-3.9 mm Hg (P<0.05; n=11). In contrast, in the subjects who performed repetitive apneas during room air exposure (O2 saturation nadir 95.1+/-0.8%), MAP and MSNA did not change (n=8). End-tidal CO2 post-apnea, an index of apnea-induced hypercapnia, was similar in the 2 groups. In a separate control group, no effect of time on MAP or MSNA was noted (n=7). Thus, repetitive hypoxic apneas result in sustained sympathetic activation and a transient elevation of blood pressure. These effects appear to be due to intermittent hypoxia and may play a role in the sympathetic activation and hypertension in OSA.

Augmented leg vasoconstriction in dynamically exercising older men during acute sympathetic stimulation

Vasoconstrictor responsiveness to acute sympathetic stimulation declines with advancing age in resting skeletal muscle. The purpose of the present study was to determine if age‐related reductions in sympathetic vasoconstrictor responsiveness also occur in exercising skeletal muscle. Thirteen younger (20–30 years) and seven older (62–74 years) healthy non‐endurance‐trained men performed cycle ergometer exercise at ∼60 % of peak oxygen uptake while leg blood flow (femoral vein thermodilution), mean arterial blood pressure (radial artery catheter), and plasma adrenaline and noradrenaline concentrations were measured. After steady state was reached (i.e. ∼4 min), acute sympathetic stimulation was achieved by immersing a hand in ice water for 2–4 min (cold pressor test, CPT). CPT tended to cause a larger increase in mean arterial blood pressure in older men (older (O): 16 ± 3 mmHg; younger (Y): 10 ± 2 mmHg) during exercise, but increases in arterial noradrenaline were similar (O: 2.56 ± 0.96 nM; Y: 1.98 ± 0.40 nM). However, the older men demonstrated a larger percentage reduction in exercising leg vascular conductance (leg blood flow/mean arterial pressure) during CPT compared to younger men (O: ‐13.6 ± 3.1%; Y: ‐1.5 ± 4.3%; P= 0.04). Leg blood flow tended to increase in the younger men, but not in the older men (P= 0.10). These results suggest, in contrast to what has been observed in resting skeletal muscle, that vasoconstrictor responsiveness to sympathetic stimulation is not reduced, but may be augmented in exercising muscle of healthy older humans. This could reflect a reduced ability of local substances (e.g. nitric oxide) to impair vasoconstriction in response to sympathetic stimulation during exercise in older humans.

Systemic Hypoxia Elevates Skeletal Muscle Interstitial Adenosine Levels in Humans

BACKGROUND Adenosine is a potent vasodilator that has been shown to increase in cardiac tissue in response to hypoxia. However, peripheral vasodilatation also occurs during hypoxia, and the vasoactive substance(s) responsible for skeletal muscle vasodilation have not yet been completely identified. Therefore, the purpose of this study was to measure and quantify skeletal muscle interstitial adenosine during acute systemic hypoxia. METHODS AND RESULTS Skeletal muscle interstitial adenosine concentrations were determined by the microdialysis technique, in which 4 semipermeable microdialysis probes were inserted into the vastus lateralis muscle of 6 healthy male subjects and perfused at a rate of 5 microL/min with Ringers solution. Sixty minutes after the insertion of the microdialysis probes, systemic hypoxia was induced for 30 minutes by having the subjects breathe a mixture of 10.5% O2 in N2. Arterial oxygen saturation (fingertip oximeter) was lowered (P<0.05) from 96+/-0.7% to 74.9+/-1.4%, and forearm blood flow was increased 28%. During normoxia, the interstitial adenosine concentration was 0. 44+/-0.08 micromol/L, and it was increased to 1.03+/-0.15 (P<0.05) and 0.85+/-0.09 (P<0.05) after 15 and 30 minutes of hypoxia, respectively. CONCLUSIONS These data are consistent with the concept that during acute systemic hypoxia, interstitial adenosine plays a key role in stimulating peripheral vasodilation.

An episode of ventricular tachycardia during long-duration spaceflight

An episode of nonsustained ventricular tachycardia was recorded from a crew member during the second month aboard the MIR space station. Although asymptomatic, this cardiac event increases the concern that serious cardiac dysrhythmias may be a limiting factor during long-duration spaceflight.

Coronary blood flow responses to physiological stress in humans

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at -10 and -30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O(2)), hyperoxia (100% O(2)), and hypercapnia (5% CO(2)) for 5 min each. At the higher level of handgrip, mean blood pressure increased (P < 0.001), whereas CBV did not change [P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased (P < 0.02; and P < 0.01, for -10 and -30 mmHg, respectively), whereas blood pressure did not change (P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased (P < 0.02) and decreased during hyperoxia (P < 0.01), although blood pressure did not change (P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.

Effect of repetitive hypoxic apnoeas on baroreflex function in humans

Baroreflex function is impaired in patients with obstructive sleep apnoea. We tested the hypothesis that short‐term exposure to repetitive hypoxic apnoeas (RHA) produces prolonged impairment in baroreflex function. Baroreflex function was determined using the modified Oxford technique in 14 subjects (26 ± 1 years). Baroreflex sensitivity (BRS) was quantified from the R‐R interval–systolic blood pressure (BP; cardiovagal BRS), heart rate–systolic BP (HR BRS) and muscle sympathetic nerve activity (MSNA)–diastolic BP (sympathetic BRS) relations. RHA involved subjects performing repetitive end‐expiratory apnoeas (20 s) every minute for 30 min during intermittent hypoxia to accentuate oxygen desaturation. After RHA, BP and MSNA at rest were elevated. BRS was measured ∼7 (Post 1), ∼30 (Post 2) and ∼50 min (Post 3) after RHA to provide insight into the temporal pattern of responses. Cardiovagal BRS (16.8 ± 1.3, 16.5 ± 1.6, 17.6 ± 2.0 and 17.4 ± 1.5 ms mmHg−1 for Pre, Post 1, Post 2 and Post 3, respectively), HR BRS (−1.1 ± 0.1, −1.1 ± 0.1, −1.3 ± 0.1 and −1.4 ± 0.1 beats min−1 mmHg−1) and sympathetic BRS (−4.5 ± 0.6, −4.4 ± 0.7, −3.7 ± 0.5 and −4.7 ± 1.0 arbitrary units (au) beat−1 mmHg−1) were unchanged by RHA. In contrast, the operating points of the baroreflexes were shifted rightward (to higher levels of BP) and upward (to higher levels of heart rate and MSNA) after RHA (P < 0.05). Time control studies performed in five additional subjects showed no change in any of the measured variables over time. Collectively, these data indicate that short‐term exposure to RHA shifts (‘resets’) the baroreflex stimulus–response curve to higher levels of BP without influencing BRS for extended periods of time.

A real-time device for converting Doppler ultrasound audio signals into fluid flow velocity

A Doppler signal converter has been developed to facilitate cardiovascular and exercise physiology research. This device directly converts audio signals from a clinical Doppler ultrasound imaging system into a real-time analog signal that accurately represents blood flow velocity and is easily recorded by any standard data acquisition system. This real-time flow velocity signal, when simultaneously recorded with other physiological signals of interest, permits the observation of transient flow response to experimental interventions in a manner not possible when using standard Doppler imaging devices. This converted flow velocity signal also permits a more robust and less subjective analysis of data in a fraction of the time required by previous analytic methods. This signal converter provides this capability inexpensively and requires no modification of either the imaging or data acquisition system.

Changes of central haemodynamic parameters during mental stress and acute bouts of static and dynamic exercise

Chronic dynamic (aerobic) exercise decreases central arterial stiffness, whereas chronic resistance exercise evokes the opposite effect. Nevertheless, there is little information available on the effects of acute bouts of exercise. Also, there is limited data showing an increase of central arterial stiffness during acute mental stress. This study aimed to determine the effect of acute mental and physical (static and dynamic exercise) stress on indices of central arterial stiffness. Fifteen young healthy volunteers were studied. The following paradigms were performed: (1) 2 min of mental arithmetic, (2) short bouts (20 s) of static handgrip at 20 and 70% of maximal voluntary contraction (MVC), (3) fatiguing handgrip at 40% MVC and (4) incremental dynamic knee extensor exercise. Central aortic waveforms were assessed using SphygmoCor software. As compared to baseline, pulse wave transit time decreased significantly for all four interventions indicating that central arterial stiffness increased. During fatiguing handgrip there was a fall in the ratio of peripheral to central pulse pressure from 1.69±0.02 at baseline to 1.56±0.05 (P<0.05). In the knee extensor protocol a non-significant trend for the opposite effect was noted. The augmentation index increased significantly during the arithmetic, short static and fatiguing handgrip protocols, whereas there was no change in the knee extensor protocol. We conclude that (1) during all types of acute stress tested in this study (including dynamic exercise) estimated central stiffness increased, (2) during static exercise the workload posed on the left ventricle (expressed as change in central pulse pressure) is relatively higher than that posed during dynamic exercise (given the same pulse pressure change in the periphery).