Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.

Ischemic exercise and the muscle metaboreflex.

In exercising muscle, interstitial metabolites accumulate and stimulate muscle afferents. This evokes the muscle metaboreflex and raises arterial blood pressure (BP). In this report, we examined the effects of tension generation on muscle metabolites and BP during ischemic forearm exercise in humans. Heart rate (HR), BP, P(i), H(2)PO(4)(-), and pH ((31)P-NMR spectroscopy) data were collected in 10 normal healthy men (age 23 +/- 1 yr) during rhythmic handgrip exercise. After baseline measurements, the subjects performed rhythmic handgrip for 2 min. At 2 min, a 250-mmHg occlusion cuff was inflated, and ischemic handgrip exercise was continued until near fatigue (Borg 19). Measurements were continued for an additional 30 s of ischemia. This protocol was performed at 15, 30, 45, and 60% of the subjects' maximum voluntary contraction (MVC) in random order. As tension increased, the time to fatigue decreased. In addition, mean arterial pressure and HR were higher at 60% MVC than at any of the other lower tensions. The NMR data showed significantly greater increases in H(2)PO(4)(-), P(i), and H(+) at 60% than at 15 and 30% MVC. Therefore, despite the subjects working to the same perceived effort level, a greater reflex response (represented by BP and HR data) was elicited at 60% MVC than at any of the other ischemic tensions. These data are consistent with the hypothesis that, as tension increases, factors aside from insufficient blood flow contribute to the work effect on muscle metabolites and the magnitude of the reflex response.

Dissociation of muscle sympathetic nerve activity and leg vascular resistance in humans.

We examined the hypothesis that the increase in inactive leg vascular resistance during forearm metaboreflex activation is dissociated from muscle sympathetic nerve activity (MSNA). MSNA (microneurography), femoral artery mean blood velocity (FAMBV, Doppler), mean arterial pressure (MAP), and heart rate (HR) were assessed during fatiguing static handgrip exercise (SHG, 2 min) followed by posthandgrip ischemia (PHI, 2 min). Whereas both MAP and MSNA increase during SHG, the transition from SHG to PHI is characterized by a transient reduction in MAP but sustained elevation in MSNA, facilitating separation of these factors in vivo. Femoral artery vascular resistance (FAVR) was calculated (MAP/MBV). MSNA increased by 59 +/- 20% above baseline during SHG (P < 0.05) and was 58 +/- 18 and 78 +/- 18% above baseline at 10 and 20 s of PHI, respectively (P < 0.05 vs. baseline). Compared with baseline, FAVR increased 51 +/- 22% during SHG (P < 0.0001) but returned to baseline levels during the first 30 s of PHI, reflecting the changes in MAP (P < 0.005) and not MSNA. It was concluded that control of leg muscle vascular resistance is sensitive to changes in arterial pressure and can be dissociated from sympathetic factors.

Limb congestion enhances the synchronization of sympathetic outflow with muscle contraction.

In this report, we examined if the synchronization of muscle sympathetic nerve activity (MSNA) with muscle contraction is enhanced by limb congestion. To explore this relationship, we applied signal-averaging techniques to the MSNA signal obtained during short bouts of forearm contraction (2-s contraction/3-s rest cycle) at 40% maximal voluntary contraction for 5 min. We performed this analysis before and after forearm venous congestion; an intervention that augments the autonomic response to sustained static muscle contractions via a local effect on muscle afferents. There was an increased percentage of the MSNA noted during second 2 of the 5-s contraction/rest cycles. The percentage of total MSNA seen during this particular second increased from minute 1 to 5 of contraction and was increased further by limb congestion (control minute 1 = 25.6 +/- 2.0%, minute 5 = 32.8 +/- 2.2%; limb congestion minute 1 = 29.3 +/- 2.1%, minute 5 = 37.8 +/- 3.9%; exercise main effect <0.005; limb congestion main effect P = 0.054). These changes in the distribution of signal-averaged MSNA were seen despite the fact that the mean number of sympathetic discharges did not increase over baseline. We conclude that synchronization of contraction and MSNA is seen during short repetitive bouts of handgrip. The sensitizing effect of contraction time and limb congestion are apparently due to feedback from muscle afferents within the exercising muscle.

Adenosine contributes to hypoxia-induced forearm vasodilation in humans.

In humans, hypoxia leads to increased sympathetic neural outflow to skeletal muscle. However, blood flow increases in the forearm. The mechanism of hypoxia-induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is cholinergically mediated or is due to local release of adenosine, normal subjects were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately 20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm tissue(-1)) was infused into the brachial artery to block adenosine receptors (n = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg over 4 min) infused into the brachial artery (n = 8). The responses of forearm blood flow (plethysmography) and forearm vascular resistance to hypoxia in the infused and opposite (control) forearms were compared. During hypoxia (arterial O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P < 0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P < 0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data suggest that adenosine contributes to hypoxia-induced vasodilation, whereas cholinergic vasodilation does not play a role.

Characteristics of the muscle mechanoreflex during quadriceps contractions in humans.

We examined muscle sympathetic nerve activity (MSNA) in the nonexercising lower limb during repetitive static quadriceps contraction paradigm at 25% maximal voluntary contraction in eight men. Subjects performed 20-s contractions with 5-s rest periods for up to 12 contractions. Although the workload was constant, we found that MSNA amplitude rose as a function of contraction number [0.6 ln (amplitude/min)/contraction]; this suggests chemical sensitization of the muscle reflex response. We employed signal-averaging techniques and then integrated the data to examine the onset latency of the MSNA response as a function of the 25-s contraction-rest period. We observed an onset latency of approximately 4-6 s. Moreover, although the onset latency did not appear to vary as a function of contraction number, the rate of MSNA increase took approximately four contractions to reach a steady-state rate of rise; this suggests contraction-induced sensitization. The onset latency reported here is similar to findings in recent animal studies, but it is at odds with latencies determined in prior human handgrip contraction studies. We believe our data suggest that 1) mechanically sensitive afferents contribute importantly to the MSNA response to the paradigm employed and 2) these afferents may be sensitized by the chemical products of muscle contraction.

Sympathetic discharge and vascular resistance after bed rest.

The effect of -6 degrees head-down-tilt bed rest (HDBR) for 14 days on supine sympathetic discharge and cardiovascular hemodynamics at rest was assessed. Mean arterial pressure, heart rate (n = 25), muscle sympathetic nerve activity (MSNA; n = 16) burst frequency, and forearm blood flow (n = 14) were measured, and forearm vascular resistance (FVR) was calculated. Stroke distance, our index of stroke volume, was derived from measurements of aortic mean blood velocity (Doppler) and R-R interval (n = 7). With these data, an index of total peripheral resistance was determined. Heart rate at rest was greater in the post (71 +/- 2 beats/min)- compared with the pre-HDBR test (66 +/- 2 beats/min; P < 0.003), but mean arterial pressure was unchanged. Aortic stroke distance during post-HDBR (15.5 +/- 1.1 cm/beat) was reduced from pre-HDBR levels (20.0 +/- 1.5 cm/beat) (P < 0.03). Also, MSNA burst frequency was reduced in the post (16.7 +/- 2.8 beats/min)- compared with the pre (25.2 +/- 2.6 beats/min)-HDBR condition (P < 0.01). Bed rest did not alter forearm blood flow, FVR, or total peripheral resistance. Thus reductions in MSNA with HDBR were not associated with a decrease in FVR.

The use of left ventricular epicardial surface velocity patterns as a marker of pacing site.

Ectopic ventricular foci were simulated at selected endocardial sites in 15 closed-chest canines using ventricular pacing. During this pacing, a noninvasive x-ray backscatter imaging technique was used to measure epicardial LV displacements at 5-ms intervals during the cardiac cycle. These displacement measurements were used to calculate epicardial surface velocities in each study and were presented as a time sequence of color coded velocity maps. Characteristic patterns in the timing and spatial propagation of LV surface velocities were noted for each pacing site, particularly during the expansion of the LV during isovolumic contraction and the inward motion of the LV during ejection. Average surface velocity maps for the 15 canines were computed for each pacing site. These average maps were used as standards for comparison with individual pacing studies to determine the probable site of pacing. Comparisons were made using a computer algorithm, based upon auto- and cross-correlation techniques in the time domain. This algorithm correctly identified pacing sites with sensitivities of RA 74%, LV 76%, RV 79%, and RVOT 77% and specificities of RA 98%, LV 96%, RV 90%, and RVOT 93%. The results show that this noninvasive mapping procedure has potential for identifying the location of an ectopic ventricular focus.

Augmented sympathetic tone alters muscle metabolism with exercise: lack of evidence for functional sympatholysis.

It is unclear whether sympathetic tone opposes dilator influences in exercising skeletal muscle. We examined high levels of sympathetic tone, evoked by lower body negative pressure (LBNP, -60 mmHg) on intramuscular pH and phosphocreatine (PCr) levels (31P-nuclear magnetic resonance spectroscopy) during graded rhythmic handgrip (30 contractions/min; approximately 17, 34, 52 and 69% maximal voluntary contraction). Exercise was performed with LBNP and without LBNP (Control). At the end of exercise, LBNP caused lower levels of muscle pH (6.59 +/- 0.09) compared with Control (6.78 +/- 0.05; P < 0.05). PCr recovery, an index of mitochondrial respiration, was less during the recovery phase of the LBNP trial. Exercise mean arterial pressure was not altered by LBNP. The protocols were repeated with measurements of forearm blood flow velocity and deep venous samples (active forearm) of hemoglobin (Hb) saturation, pH, and lactate. With LBNP, mean blood velocity was reduced at rest, during exercise, and during recovery compared with Control (P < 0.05). Also, venous Hb saturation and pH levels during exercise and recovery were lower with LBNP and lactate was higher compared with Control (P < 0.05). We conclude that LBNP enhanced sympathetic tone and reduced oxygen transport. At high workloads, there was a greater reliance on nonoxidative metabolism. In other words, sympatholysis did not occur.

Epicardial surface dynamics in the closed-chest normal canine.

Past studies of the changing three-dimensional shape of the heart in the closed chest during the cardiac cycle have been restricted to the measurement of local deformations at a relatively few specific locations, and often have required surgical procedures that alter the measurements obtained. In the study reported here, high precision displacement and velocity measurements were obtained at the epicardial interface using a Compton backscatter imaging technique that does not require a surgical intervention or contrast injections. Displacement and velocity measurements were obtained at more than 200 locations at the epicardial interface at 13 ms intervals throughout the cardiac cycle. Measurements of the changing shape of the heart during the cardiac cycle with this technique are precise to 0.1 mm (S.D.). Displacement and velocity patterns recorded in this study confirm and integrate the studies of many others and also add new information. An unexpected vigorous inward motion of both the LV (39 mm s-1) and RV (26 mm s-1) surfaces during isovolumic relaxation and early rapid refill is demonstrated. Velocities during this period equal or exceed those that occur during ejection. During ejection, inward LV motion at the base of the heart precedes that at the apex by 80-90 ms. Posterior LV displacements and velocities during ejection are 4-6 times greater than those at the anterior and apex. The Compton backscatter imaging technique for obtaining undisturbed measurements of cardiac dynamics in the closed chest has potential as a non-invasive clinical tool for serial studies of cardiac surface motion abnormalities. The data presented can also be used to set surface boundary conditions for biomechanical models of heart deformation.

Inward diastolic motion: a normal component of isovolumic relaxation and rapid refill.

Many reports note expansive events occurring in the left ventricle during isovolumic relaxation. Expansions during isovolumic relaxation require compensatory inward displacements elsewhere in the ventricle. The location and character of such compensatory displacements have been a continuing source of speculation. Using a high-precision Compton backscatter imaging (CBI) technique, we have detected an early diastolic inward motion that initiates during isovolumic relaxation on the right and left epicardial free walls of the heart in 100% of the 14 normal canines we have studied. This inward motion is first detected 20-30 ms after left ventricular maximal rate of pressure decrease over time (-dP/dtmax), lasts into the early rapid filling phase with a mean duration of 92 +/- 5 (SE) ms, and ends approximately 30 ms after opening of the mitral valve. Maximum wall velocities during this time period (approximately 20 mm/s) exceed those occurring in the same regions during systole. Inward surface displacements in the areas undergoing inward motion average 1.1 +/- 0.2 and 0.9 +/- 0.2 mm on the left and right side of the heart, respectively.

A line-focus collimator with a field of view of uniform thickness.

A new line-focus x-ray collimator features a field of view (FOV) with uniform thickness in the near field between the collimator and focal line. General design equations were developed and then constrained to define such a uniform FOV. A prototype collimator was experimentally evaluated using a Compton backscatter imaging technique. The full-width-tenth-max (FWTM) thickness, measured at 420 locations in the near field, showed good uniformity (1.51 +/- 0.06 cm) and closely approximated the nominal design thickness (1.8 cm).

The effects of pacing site on left ventricular epicardial surface velocity patterns during systole.

Changes in epicardial LV velocity patterns during isovolumic contraction and ejection as induced by ventricular pacing were studied in 15 canines. A noninvasive imaging technique that provided high temporal resolution was used to study the timing of an outward expansion of the LV during isovolumic contraction and the propagation pattern of an inward LV velocity wavefront during ejection. With this technique, surface displacements were measured (+/- 0.1 mm SD) at 50-70 locations on the LV free wall at 5-msec intervals. Velocities were calculated by differentiating the surface displacement waveforms and an interpolation procedure was used to provide detailed color coded velocity maps of the LV surface. LV surface velocities were determined from data obtained during closed-chest endocardial pacing from each of four sites: right atrium, right ventricular apex, left ventricular apex, and right ventricular outflow tract. These surface velocities showed a distinct spatial and temporal pattern for each pacing site. The results show that this noninvasive mapping procedure has potential for determining the location of an ectopic ventricular focus.

Real-time volume measurements in the isolated beating rat heart.

A new technique, utilizing scattered X-rays, has been developed that is capable of measuring isolated working rat heart left ventricular (LV) volumes continuously throughout the cardiac cycle. The technique was validated by comparing cardiac outputs measured via fluid collections (r = 0.959, n = 10). The new methodology will permit real-time measurements of pressure-volume relationships, stroke work, and indexes of diastolic function in the isolated working rat heart.

Analysis of edge-tracking errors inherent in fluoroscopic images of the beating heart.

RATIONALE AND OBJECTIVES: Because of the complex relationships between the dynamic three-dimensional cardiac surface shape and its projected image, errors arise with the use of two-dimensional silhouettes to measure displacements of the heart. The character and frequency of such errors are examined. METHODS: A high-precision x-ray scatter imaging technique was used to reconstruct the three-dimensional shape of the left ventricular free wall throughout the cardiac cycle. Displacements of the three-dimensional surface were then compared with those on the two-dimensional projected silhouette. Silhouette displacement errors were determined as a function of time during the cardiac cycle and variability between hearts. RESULTS: Differences between silhouette measurements and those on the cardiac surface range from 0% to 125% of peak-to-peak displacements occur, along 33% to 75% of the silhouette contours and cover 66% of the cardiac cycle. CONCLUSION: Two-dimensional silhouette displacements provide inconsistent measurements of motion patterns on the three-dimensional cardiac surface.

Real-time ventricular volumes and cardiac function in the working rat heart.

The measurement of instantaneous left ventricular volumes throughout the cardiac cycle in a rat heart beating at rates of 300 to 600 min-1 with a chamber volume of only a few tenths of a milliliter is difficult. Combining an x-ray scatter detection system with a small x-ray source collimated to scatter low energy x-rays off a working rat heart, measurements of real-time changes in ventricular volumes can be determined. The x-ray scatter signal is proportional to the volume and can be calibrated to measure the actual volume. Using this system, changes in ventricular function can readily be detected. An example of data obtained from increasing preload with a fixed afterload is shown. This technique not only distinguishes an increasing stroke volume, but also more rapid early diastolic filling and systolic ejection rates with increasing preload. This new x-ray scatter technique appears to be a promising way to measure rapidly changing left ventricular volumes and function in the working rat heart. This could significantly enhance the scientific use of the rat model.

A flying spot X-ray system for Compton backscatter imaging.

A Compton X-ray backscatter imaging (CBI) system using a single detector and a mechanically rastered "flying spot" X-ray beam has been designed, built, and tested. While retaining the essential noninvasive imaging capability of previous multiple detector CBI devices, this single detector system incorporates several advances over earlier CBI devices: more efficient detection of scattered X-rays, reduced X-ray exposure, and a simplified scan protocol more suitable for use with humans. This new CBI system also has specific design features to permit automating data acquisition from multiple two-dimensional image planes for integration into a 3D dynamic surface image. A simulated multislice scan study of a human thorax phantom provided X-ray dosimetry data verifying a very low X-ray dose (~50 mrem) delivered by this imaging device. Validation experiments with mechanical models show that surface displacement at typical heart beat frequencies can be measured to the nearest 0.1 mm (SD).

A device for a noninvasive evaluation of coronary bypass grafts.

A new device is presented for evaluating the patency of coronary bypass grafts. Bypass grafts are located within the chest cavity using a Compton backscatter imaging (CBI) technique that creates frontal plane tomographic images. The tomographic image pixels are mapped into computer memory and displayed. A display pointer is used to mark the position of the bypass graft. The computer uses that information to subsequently position a radiation detector, such that it "looks" at the location of the bypass graft within the closed chest. The patency of the graft is then evaluated by monitoring an X-ray induced iodine fluorescence transient in the graft, subsequent to a peripheral intravenous contrast injection. This imaging and graft evaluation device is relatively inexpensive and its application does not require cutdowns or catheterization. The associated radiation dose is 1/10 to 1/50 of that associated with alternative X-ray graft patency evaluation techniques. Preliminary testing has been performed on mechanical and animal models.

High precision Compton backscatter maps of myocardial wall dynamics. Theory and applications.

Compton backscatter imaging (CBI) is a technique that uses x-rays scattered from the closed-chest surface of the heart to obtain high frequency (5 msec) and high precision (+/- 0.1 mm SD) measurements of regional surface displacements and velocities. These measurements are acquired in a three-dimensional format that allows the reconstruction of the epicardial surface and the creation of color coded displacement and velocity maps at many time points during the cardiac cycle. Applications of the technique are shown to characterize detailed regional normal wall displacement and velocity patterns, and the significant alteration of those patterns after coronary embolization. The technique is also applied to the characterization of early diastolic wall dynamics. CBI measurements show that a brief and somewhat paradoxical inward displacement of the anterior ventricular wall occurs during early diastole in normal canines. The wall dynamics associated with this inward displacement suggest a brief collapse of the ventricle subsequent to aortic valve closure. Diastolic collapse velocities and displacements are significantly altered subsequent to coronary occlusion with mean and maximum collapse velocities decreasing by 50% and concomitant inward displacements decreasing by 40%. Data acquisition with CBI is non-invasive, does not require contrast agents or radioisotopes, and uses low irradiation levels (125 kVp, 3-5 ma). The average radiation dose to the heart for a typical study is 250 mrem, significantly lower than that of other radiation based imaging techniques.

Coronary artery embolization in closed-chest canines using flexible radiopaque plugs.

A new technique induces localized myocardial infarction in closed-chest dogs by placing discrete plugs in coronary arteries without using cumbersome coaxial catheters or guide wires. Flexible plugs, essential to this method, are formed by extruding a dental impression polymer, rendered radiopaque with sodium iodide, into spaghetti-like strands. Segments of these strands can be injected through a catheter into a selected coronary artery. Contact with blood or saline causes plugs to swell. The mean increase in plug diameter due to swelling was 27 +/- 20%. Eight anesthetized dogs were embolized via carotid approach [6 left anterior descending (LAD), 1 left circumflex (LCX), and 1 LAD and LCX]. Plug positions were monitored fluoroscopically. One animal died at 2 days postembolization. The remaining seven dogs were killed after 14-37 days. Autopsies showed complete vessel occlusion and localized infarction. Infarcts resulting from coronary artery occlusion with one, two, or three plugs involved 2-26% of the left ventricular mass.