Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans.

In humans, cerebrovascular responses to alterations in arterial Pco(2) and Po(2) are well documented. However, few studies have investigated human coronary vascular responses to alterations in blood gases. This study investigated the extent to which the cerebral and coronary vasculatures differ in their responses to euoxic hypercapnia and isocapnic hypoxia in healthy volunteers. Participants (n = 15) were tested at rest on two occasions. On the first visit, middle cerebral artery blood velocity (V(P)) was assessed using transcranial Doppler ultrasound. On the second visit, coronary sinus blood flow (CSBF) was measured using cardiac MRI. For comparison with V(P), CSBF was normalized to the rate pressure product [an index of myocardial oxygen consumption; normalized (n)CSBF]. Both testing sessions began with 5 min of euoxic [end-tidal Po(2) (Pet(O(2))) = 88 Torr] isocapnia [end-tidal Pco(2) (Pet(CO(2))) = +1 Torr above resting values]. Pet(O(2)) was next held at 88 Torr, and Pet(CO(2)) was increased to 40 and 45 Torr in 5-min increments. Participants were then returned to euoxic isocapnia for 5 min, after which Pet(O(2)) was decreased from 88 to 60, 52 and 45 Torr in 5-min decrements. Changes in V(P) and nCSBF were normalized to isocapnic euoxic conditions and indexed against Pet(CO(2)) and arterial oxyhemoglobin saturation. The V(P) gain for euoxic hypercapnia (%/Torr) was significantly higher than nCSBF (P = 0.030). Conversely, the V(P) gain for isocapnic hypoxia (%/%desaturation) was not different from nCSBF (P = 0.518). These findings demonstrate, compared with coronary circulation, that the cerebral circulation is more sensitive to hypercapnia but similarly sensitive to hypoxia.

Related papers:

title: Differential sensitivities of cerebral and brachial blood flow to hypercapnia in humans.
abstract: Although it is known that the vasculatures of the brain and the forearm are sensitive to changes in arterial Pco(2), previous investigations have not made direct comparisons of the sensitivities of cerebral blood flow (CBF) (middle cerebral artery blood velocity associated with maximum frequency of Doppler shift; Vp) and brachial blood flow (BBF) to hypercapnia. We compared the sensitivities of Vp and BBF to hypercapnia in humans. On the basis of the critical importance of the brain for the survival of the organism, we hypothesized that Vp would be more sensitive than BBF to hypercapnia. Nine healthy males (30.1 +/- 5.2 yr, mean +/- SD) participated. Euoxic hypercapnia (end-tidal Po(2) = 88 Torr, end-tidal Pco(2) = 9 Torr above resting) was achieved by using the technique of dynamic end-tidal forcing. Vp was measured by transcranial Doppler ultrasound as an index of CBF, whereas BBF was measured in the brachial artery by echo Doppler. Vp and BBF were measured during two 60-min trials of hypercapnia, each trial separated by 60 min. Since no differences in the responses were found between trials, data from both trials were averaged to make comparisons between Vp and BBF. During hypercapnia, Vp and BBF increased by 34 +/- 8 and 14 +/- 8%, respectively. Vp remained elevated throughout the hypercapnic period, but BBF returned to baseline levels by 60 min. The Vp CO(2) sensitivity was greater than BBF (4 +/- 1 vs. 2 +/- 1%/Torr; P < 0.05). Our findings confirm that Vp has a greater sensitivity than BBF in response to hypercapnia and show an adaptive response of BBF that is not evident in Vp.

title: THE BLOOD FLOW IN THE BRAIN AND THE LEG OF MAN, AND THE CHANGES INDUCED BY ALTERATION OF BLOOD GASES.
abstract: The solution of various neurological problems awaits an increase in our knowledge of the circulation of blood within the brain. Much has been gained by the demonstration of Forbes (1) and his co-workers that the pial vessels of the cat are under both vasomotor and chemical control. These experiments consisted of actual inspection and measurement of pial vessels viewed through a window screwed in the skull, the pressure of the cerebrospinal fluid and of the blood being measured simultaneously. In particular, Wolff and Lennox (2) showed that changes in the gaseous content of the blood had a prompt and clear cut effect on the diameter of pial vessels, an effect which was independent of the systemic blood pressure. These authors observed that an increase in the carbon dioxide content of the blood was attended by an extreme dilatation of pial vessels whereas a decrease was followed by a constriction. Variations in oxygen content resulted in relatively small changes. An increase in oxygen tension produced a slight constriction and a decrease in tension a slight dilatation of the observed vessels. There are two difficulties in the way of accepting these observations as significant of cerebral circulatory changes in man. First, experiments were conducted on cats under amytal anesthesia. Second, the vessels lying in the pial covering of the brain may act differently from vessels lying within the brain. Intracranial circulation is of such great importance to the organism and is so modified by the closed box arrangement of the skull that there is need for specific experimentation in man. Observations concerning blood ffow through the brain of unanesthetized persons seemed impossible until Myerson, Halloran and Hirsch (3) demonstrated the feasibility of obtaining blood from the internal jugular vein. By means of this procedure, we have repeated the experimental observations of Wolff and Lennox (2), using patients and judging

title: Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans
abstract: The relative importance of CO2 and sympathetic stimulation in the regulation of cerebral and peripheral vasculatures has not been previously studied in humans. We investigated the effect of sympathetic activation, produced by isometric handgrip (HG) exercise, on cerebral and femoral vasculatures during periods of isocapnia and hypercapnia. In 14 healthy males (28.1 ± 3.7 (mean ±s.d.) years), we measured flow velocity (; transcranial Doppler ultrasound) in the middle cerebral artery during euoxic isocapnia (ISO, +1 mmHg above rest) and two levels of euoxic hypercapnia (HC5, end‐tidal PCO2, P  ET,CO 2 , =+5 mmHg above ISO; HC10, P  ET,CO 2 =+10 above ISO). Each PET,CO2 level was maintained for 10 min using the dynamic end‐tidal forcing technique, during which increases in sympathetic activity were elicited by a 2‐min HG at 30% of maximal voluntary contraction. Femoral blood flow (FBF; Doppler ultrasound), muscle sympathetic nerve activity (MSNA; microneurography) and mean arterial pressure (MAP; Portapres) were also measured. Hypercapnia increased and FBF by 5.0 and 0.6% mmHg−1, respectively, and MSNA by 20–220%. Isometric HG increased MSNA by 50% and MAP by 20%, with no differences between ISO, HC5 and HC10. During the ISO HG there was an increase in cerebral vascular resistance (CVR; 20 ± 11%), while remained unchanged. During HC5 and HC10 HG, increased (13% and 14%, respectively), but CVR was unchanged. In contrast, HG‐induced sympathetic stimulation increased femoral vascular resistance (FVR) during ISO, HC5 and HC10 (17–41%), while there was a general decrease in FBF below ISO. The HG‐induced increases in MSNA were associated with increases in FVR in all conditions (r= 0.76–0.87), whereas increases in MSNA were associated with increases in CVR only during ISO (r= 0.91). In summary, in the absence of hypercapnia, HG exercise caused cerebral vasoconstriction, myogenically and/or neurally, which was reflected by increases in CVR and a maintained . In contrast, HG increased FVR during conditions of ISO, HC5 and HC10. Therefore, the cerebral circulation is more responsive to alterations in PCO2, and less responsive to sympathetic stimulation than the femoral circulation.

title: Relationship between middle cerebral artery blood velocity and end-tidal PCO2 in the hypocapnic-hypercapnic range in humans.
abstract: This study examined the relationship between cerebral blood flow (CBF) and end-tidal PCO2 (PETCO2) in humans. We used transcranial Doppler ultrasound to determine middle cerebral artery peak blood velocity responses to 14 levels of PETCO2 in a range of 22 to 50 Torr with a constant end-tidal PO2 (100 Torr) in eight subjects. PETCO2 and end-tidal PO2 were controlled by using the technique of dynamic end-tidal forcing combined with controlled hyperventilation. Two protocols were conducted in which PETCO2 was changed by 2 Torr every 2 min from hypocapnia to hypercapnia (protocol I) and vice-versa (protocol D). Over the range of PETCO2 studied, the sensitivity of peak blood velocity to changes in PETCO2 (CBF-PETCO2 sensitivity) was nonlinear with a greater sensitivity in hypercapnia (4.7 and 4.0%/Torr, protocols I and D, respectively) compared with hypocapnia (2.5 and 2.2%/Torr). Furthermore, there was evidence of hysteresis in the CBF-PETCO2 sensitivity; for a given PETCO2, there was greater sensitivity during protocol I compared with protocol D. In conclusion, CBF-PETCO2 sensitivity varies depending on the level of PETCO2 and the protocol that is used. The mechanisms underlying these responses require further investigation.

title: Augmented hypoxic cerebral vasodilation in men during 5 days at 3,810 m altitude.
abstract: The fractional increase in cerebral blood flow (CBF) velocity (VCBF) from the control value with 5-min steps of isocapnic hypoxia and hyperoxic hypercapnia was measured by transcranial Doppler in six sea-level native men before and during a 5-day sojourn at 3,810 m altitude to determine whether cerebral vasoreactivity to low arterial O2 saturation (SaO2) gradually increased [as does the hypoxic ventilatory response (HVR)] or diminished (adapted, in concert with known slow fall of CBF) at altitude. A control resting PCO2 value was chosen each day during preliminary hyperoxia to set ventilation at 140 ml.kg-1.min-1 for this and the parallel HVR study, attempting to establish control cerebrospinal fluid (CSF) and brain extracellular fluid pH values unaltered by acclimatization. The relationship of CBF to SaO2 was nonlinear, steepening at a lower SaO2. A hyperbolic equation was used to describe hypoxic cerebrovascular reactivity: fractional VCBF = x[60/ (SaO2-40)-1], where X is the fractional increase of VCBF at 70%.X rose from 0.346 +/- 0.104 (SD) at sea level to 0.463 +/- 0.084 on altitude day 5 (P < 0.05 by paired t-test, justified by the a priori experimental plan). For comparison with CO2 sensitivity, from these X values, we estimate the rise in CBF in response to a 1% fall in SaO2 at 80% to be 1.30% at sea level and 1.74% after 5 days at altitude. CBF sensitivity to increased end-tidal PCO2 rose from 4.01 +/- 0.62%/Torr at sea level to 5.12 +/- 0.79%/Torr on day 5 (P < 0.05), as expected, at the lower PCO2 due to the logarithmic relationship of PCO2 to CSF pH. This change was not significant after correction to log PCO2. We conclude that the cerebral vascular response to acute isocapnic hypoxia may increase during acclimatization at high altitude. The mechanism is unknown but is presumably unrelated to the parallel carotid chemosensitization that, in these subjects, increased the HVR by 60% in the same 5-day period from 0.91 +/- 0.38 to 1.46 +/- 0.59 l.min-1.% fall in SaO2-1).

title: Dynamics of the cerebral blood flow response to step changes in end-tidal PCO2 and PO2 in humans.
abstract: This study examined the dynamics of the cerebral blood flow response to hypoxia and hypercapnia in humans. Middle cerebral artery blood flow (MCAF) was assessed continuously using transcranial Doppler ultrasound. MCAF was calculated on a beat-by-beat basis as the product of the intensity-weighted mean velocity and the total power of the reflected signal. End-tidal PCO2 (PETCO2) and PO2 (PETO2) were controlled using a dynamic end-tidal forcing system. Six repeats of each of four protocols were administered to six subjects. The first was a control protocol with PETO2 held at 100 Torr and PETCO2 held 1-2 Torr above eucapnia throughout. The second was a hypoxic step protocol with PETO2 lowered from control values to 50 Torr for 20 min. The third was a hypercapnic step protocol with PETCO2 elevated from control by 7.5 Torr for 20 min. The fourth was a hypoxic-and-hypercapnic step protocol lasting 20 min. The total power of the Doppler signal remained relatively constant, suggesting that the cross-sectional area of the vessel changed little. After the initial transient in MCAF at the onset of the stimulus, no adaptation or progressive increase was observed over the remaining 20 min. A simple model consisting of a single pure delay, gain terms, time constants, and offsets for the on and off transients was fitted to the hypoxic and hypercapnic protocols. For hypercapnia, all the parameters for the onset were significantly different from the relief of the stimulus. The asymmetry was characterized by a slower on transient than off transient and also by a degree of undershoot after the relief of hypercapnia. Finally, the results from this study show that the cerebral blood flow response to hypoxia and hypercapnia in humans is much faster than has previously been thought.

title: Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans.
abstract: Hypoxia increases cerebral blood flow (CBF), but it is unknown whether this increase is uniform across all brain regions. We used H(2)(15)O positron emission tomography imaging to measure absolute blood flow in 50 regions of interest across the human brain (n = 5) during normoxia and moderate hypoxia. Pco(2) was kept constant ( approximately 44 Torr) throughout the study to avoid decreases in CBF associated with the hypocapnia that normally occurs with hypoxia. Breathing was controlled by mechanical ventilation. During hypoxia (inspired Po(2) = 70 Torr), mean end-tidal Po(2) fell to 45 +/- 6.3 Torr (means +/- SD). Mean global CBF increased from normoxic levels of 0.39 +/- 0.13 to 0.45 +/- 0.13 ml/g during hypoxia. Increases in regional CBF were not uniform and ranged from 9.9 +/- 8.6% in the occipital lobe to 28.9 +/- 10.3% in the nucleus accumbens. Regions of interest that were better perfused during normoxia generally showed a greater regional CBF response. Phylogenetically older regions of the brain tended to show larger vascular responses to hypoxia than evolutionary younger regions, e.g., the putamen, brain stem, thalamus, caudate nucleus, nucleus accumbens, and pallidum received greater than average increases in blood flow, while cortical regions generally received below average increases. The heterogeneous blood flow distribution during hypoxia may serve to protect regions of the brain with essential homeostatic roles. This may be relevant to conditions such as altitude, breath-hold diving, and obstructive sleep apnea, and may have implications for functional brain imaging studies that involve hypoxia.

title: Effect of hypercapnia and hypocapnia on myocardial blood flow and performance in anaesthetized dogs.
abstract: The effects of hypercapnia and hypocapnia on haemodynamics, coronary blood flow, and lactate metabolism were evaluated in anaesthetized closed chest dogs. Coronary flow increased with increased pCO2 and oxygen consumption and left ventricular performance were well maintained. Hypocapnia reduced coronary flow, oxygen consumption, and left ventricular functional performance.

title: Brain Compared to Heart Tissue Oxygen Pressure During Changes in Arterial Carbon Dioxide in the Dog
abstract: Myocardial tissue oxygen pressure (PmO2) and left anterior descending (LAD) artery blood flow were measured in dogs anesthetized with 1.5% isoflurane, and were then compared to brain tissue oxygen pressure (PbO2) and middle cerebral artery (MCA) blood flow during normocapnia, hypocapnia, and hypercapnia. A craniotomy was performed and a tissue probe (Codman, Inc.) that measures PO2, PCO2, and pH was inserted into the brain cortex in the MCA region (n = 8). Separately, after a thoracotomy, a probe was inserted into the middle myocardium of the left ventricle, within the distribution of the LAD, in eight dogs. Blood flow probes were placed on the LAD or MCA. Blood flow and tissue gases were measured during normocapnia (PaCO2 = 38 mm Hg), hypocapnia (PaCO2 = 26 mm Hg), and hypercapnia (PaCO2 = 53 mm Hg). Mean arterial pressure, heart rate, arterial gases, and pH were not different between brain and heart measurements. PbO2 was 21 ± 9 mm Hg (mean ± SD ), 40 ± 16 mm Hg, and 47 ± 11 mm Hg. PmO2 was 35 ± 12 mm Hg, 40 ± 14 mm Hg, and 48 ± 15 mm Hg during hypocapnia, normocapnia, and hypercapnia respectively. During hypercapnia, LAD and MCA flow increased 50% and tissue oxygenation increased 20% (P < .05). During hypocapnia, MCA flow and PbO2 decreased 50% (P < .05), but LAD flow and PmO2 did not significantly change. These results indicated that LAD flow and myocardial PO2 were less responsive to hypocapnia than MCA flow and PbO2.

title: Effects of Altered Pao2 and Paco2 on Left Ventricular Function and Coronary Hemodynamics in Sheep
abstract: The effects of acute changes in arterial carbon dioxide and oxygen tension, produced by altering the inspired gas mixtures while maintaining constant-volume intermittent positive pressure ventilation, on global function, regional left ventricular function, and coronary hemodynamics were studied in eight sheep during halothane anesthesia. Hyper-capnia (Paco2, 73.5 ± 2.3 mm Hg, mean ± SD) increased heart rate, stroke volume, and cardiac output but decreased systolic shortening in the base of the left ventricle. Hypocapnia (Pao2, 24 ± 1.5 mm Hg) decreased cardiac output and coronary flow below levels seen with hypercapnia but not below levels seen with normocapnia. Systolic shortening decreased in both apical and basal regions, and left ventricular relaxation was impaired as evidenced by a reduction of the nadir of LV dP/dt. Hypoxemia (Pao2, 39 ± 1.5mmHg) elicited a hyperdynamic response of the circulation, increased coronary blood flow, and exhausted the coronary flow reserve. Neither changes in Paco2 nor changes in Pao2 caused postsystolic shortening, although hypercapnia caused nonuniformity of contraction in the left ventricle. Thus, marked alterations in oxygen and carbon dioxide tensions do not cause left ventricular dysfunction, even though moderate hypoxia reduces the coronary flow reserve.

title: Coronary flow velocity changes in response to hypercapnia: assessment by transthoracic Doppler echocardiography.
abstract: The effects of hypercapnia on coronary arteries in human beings are not known. We used transthoracic Doppler echocardiography to evaluate coronary blood flow velocity (CFV) changes in response to hypercapnia in healthy adults.



Twenty adults underwent transthoracic Doppler echocardiography of the left anterior descending coronary artery while breathing room air, 40% fraction of inspired oxygen, and 40% fraction of inspired oxygen with carbon dioxide supplemented to end-tidal tensions of +5, +7.5, and +10 mm Hg above baseline.



Mean (SD) diastolic peak CFV values for these conditions were 23.1 (9.1), 23.0 (9.0), 25.5 (9.3), 27.9 (11.5), and 31.5 (13.0) cm/s, respectively. Significant overall differences between conditions (P < .001) and progressive levels of hypercapnia (P < or = .01) were observed. CFV increases remained significant after adjusting for increases in cardiac output (P = .038).



CFV increases with hypercapnia. This is the first report of human coronary artery flow responses to hypercapnia. Transthoracic Doppler echocardiography methodology is feasible for measuring CFV and the effects of hypercapnia on the coronary circulation.

title: Heart and brain circulation and CO2 in healthy men
abstract: To compare blood flow response to arterial carbon dioxide tension change in the heart and brain of normal elderly men.

title: Simple, accurate equations for human blood O2 dissociation computations.
abstract: Hill's equation can be slightly modified to fit the standard human blood O2 dissociation curve to within plus or minus 0.0055 fractional saturation (S) from O less than S less than 1. Other modifications of Hill's equation may be used to compute Po2 (Torr) from S (Eq. 2), and the temperature coefficient of Po2 (Eq. 3). Variations of the Bohr coefficient with Po2 are given by Eq. 4. S = (((Po2(3) + 150 Po2)(-1) x 23,400) + 1)(-1) (1) In Po2 = 0.385 In (S-1 - 1)(-1) + 3.32 - (72 S)(-1) - 0.17(S6) (2) DELTA In Po2/delta T = 0.058 ((0.243 X Po2/100)(3.88) + 1)(-1) + 0.013 (3) delta In Po2/delta pH = (Po2/26.6)(0.184) - 2.2 (4) Procedures are described to determine Po2 and S of blood iteratively after extraction or addition of a defined amount of O2 and to compute P50 of blood from a single sample after measuring Po2, pH, and S.

title: Coronary blood flow responses to physiological stress in humans.
abstract: 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.

title: The influence of chemical factors on the coronary circulation
abstract: THE previous experiments made in this laboratory(, 2) and elsewhere, led to the conclusion that, in the heart isolated from the rest of the body, one of the main factors influencing the coronary circulation was the formation of metabolites by the heart muscle itself. Nakagawa found that the coronary flow is practically uninfluenced by fairly wide ranges of temperature, by alterations in the rate of the heart-beat brought about by excitation of the sino-auricular node, by stimulation of the vagus nerve, or by alterations in the inflow and consequent output of the heart. In all these cases large variations are produced in the metabolism of the heart as measured by its oxygen consumption (Evans (3)). If the products of the metabolism of the heart muscle played an important part in adjusting the calibre of the blood vessels to the needs of the heart for oxygen, we would expect that in all these cases of increased metabolism there would also be increased production of metabolites and dilatation of the coronary vessels, which is not the case. In fact, under these conditions there is a lack of adaptation of the blood supply of the heart to its needs, a condition which we can hardly expect to hold in the intact animal, where we may expect further research to reveal other means of adapting the coronary flow to the needs of the heart. The chief evidence for the importance of metabolites in regulating the blood flow through the organ was from the perfusion experiments of Barcroft and DiXon(4), also the observation of Morawitz on the whole animal, that the flow increased on injecting into the circulation blood which had already flowed out from the coronary sinus, and the observation of Markwalder and Starling, that the maximum flow through the coronary vessels occurred in asphyxia just before the heart failed altogether'.

title: Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide.
abstract: This study examined the effect of high, normal, and uncontrolled end-tidal Pco(2) (Pet(CO(2))) on the ventilatory, peak cerebral blood flow velocity (V(p)), and mean arterial blood pressure (MAP) responses to acute hypoxia. Nine healthy subjects undertook, in random order, three hypoxic protocols (end-tidal Po(2) was held at eight steps between 300 and 45 Torr) in conditions of hypercapnia, isocapnia, or poikilocapnia (Pet(CO(2)) +7.5 Torr, +1.0 Torr, or uncontrolled, respectively). Transcranial Doppler ultrasound was used to measure V(p) in the middle cerebral artery. The slopes of the linear regressions of ventilation, V(p), and MAP with arterial O(2) saturation were significantly greater in hypercapnia than in both isocapnia and poikilocapnia (P < 0.05). Strong, significant correlations were observed between ventilation, V(p), and MAP with each Pet(CO(2)) condition. These data suggest that 1). a high acute hypoxic ventilatory response (AHVR) decreases the acute hypoxic cerebral blood flow responses during poikilocapnia hypoxia, due to hypocapnic-induced cerebral vasoconstriction; and 2). in hypercapnic hypoxia, a high AHVR is associated with a high acute hypoxic cerebral blood flow response, demonstrating a linkage of individual sensitivities of ventilation and cerebral blood flow to the interaction of Pet(CO(2)) and hypoxia. In summary, the between-individual variability in AHVR is shown to be firmly linked to the variability in V(p) and MAP responses to hypoxia. Individuals with a high AHVR are found also to have high V(p) and MAP responses to hypoxia.

title: Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study.
abstract: Measurement of intracranial arterial blood flow velocity is a new technique with potentially a number of very useful applications. This study validates the technique by comparing it to cerebral blood flow (CBF) measured using intravenous Xenon133 and extracranial clearance recording. We have measured the middle cerebral artery (MCA) blood flow velocity in 17 symptomatic patients with the EME TC 264 transcranial Doppler velocimeter and compared these measurements to the ipsilateral hemispheric cerebral blood flow measured with an intravenous Xenon133 technique (Novo Cerebrograph 10A). Measurements were made at rest and during hypercapnia. The absolute measurement of MCA velocity and hemispheric CBF showed a poor correlation (r = 0.424, p less than 0.01) due to wide between-patient variations at rest but the blood flow response to hypercapnia, expressed as a reactivity index, showed a good correlation (r = 0.849, p less than 0.001). Thus changes in MCA velocity reliably correlate with changes in cerebral blood flow but the absolute velocity cannot be used as an indicator of CBF.

title: A Comparison of Transcranial Doppler and Cerebral Blood Flow Studies to Assess Cerebral Vasoreactivity
abstract: The aim of this study was to determine the ability of transcranial Doppler ultrasonography when used to assess cerebral vasoreactivity. The results of this method were compared with regional cerebral blood flow measurements.  Forty-three patients with symptoms suggesting cerebrovascular disease took part Transcranial Doppler findings in the middle cerebral arteries were compared with regional cerebral blood flow in the corresponding perfusion territories before and after acetazolamide administration.  There was a significant positive correlation between the absolute increase in cerebral blood flow in milliliters per 100 g per minute and the percent increase in velocity (r=0.63). The right-left, side-to-side difference of the acetazolamide response obtained by the two methods also showed a positive correlation (r=0.80). Control limits obtained from healthy subjects were used for both the blood flow increase (absolute values and asymmetry in absolute values) and the velocity increase (percent increase and asymmetry in percent increase). The two methods then agreed in their evaluation of vasoreactivity in 74 (86%) of the 86 middle cerebral artery perfusion territories; 20 (23%) were assessed by both methods as having a reduced vasodilatory reserve. Eleven hemispheres with a slightly reduced regional cerebral blood flow response to acetazolamide were not detected by transcranial Doppler, whereas all territories with a marked reduction were identified by Doppler. Only one hemisphere with a normal cerebral blood flow increase after acetazolamide administration was assessed by Doppler as having reduced vasoreactivity.  Transcranial Doppler and the acetazolamide test may be used in clinical situations to assess cerebral vasoreactivity.

title: Mapping of the cerebral vascular response to hypoxia and hypercapnia using quantitative perfusion MRI at 3 T
abstract: Changes in breathing change the concentration of oxygen and carbon dioxide in arterial blood resulting in changes in cerebral blood flow (CBF). This mechanism can be described by the cerebral vascular response (CVR), which has been shown to be altered in different physiological and pathophysiological states. CBF maps of grey matter (GM) were determined with a pulsed arterial spin labelling technique at 3 T in a group of 19 subjects under baseline conditions, hypoxia, and hypercapnia. Experimental conditions allowed a change in either arterial oxygen (hypoxia) or carbon dioxide (hypercapnia) concentration compared with the baseline, leaving the other variable constant, in order to separate the effects of these two variables. From these results, maps were calculated showing the regional distribution of the CVR to hypoxia and hypercapnia in GM. Maps of CVR to hypoxia showed very high intra‐subject variations, with some GM regions exhibiting a positive response and others a negative response. Per 10% decrease in arterial oxygen saturation, there was a statistically significant 7.0 ± 2.9% (mean ± SEM) increase in GM‐CBF for the group. However, 70% of subjects showed an overall positive CVR (positive responders), and the remaining 30% an overall negative CVR (negative responders). Maps of CVR to hypercapnia showed less intra‐subject variation. Per 1 mm Hg increase in partial pressure of end‐tidal carbon dioxide, there was a statistically significant 5.8 ± 0.9% increase in GM‐CBF, all subjects showing an overall positive CVR. As the brain is particularly vulnerable to hypoxia, a condition associated with cardiorespiratory diseases, CVR maps may help in the clinic to identify the areas most prone to damage because of a reduced CVR.

title: Synergistic action of myocardial oxygen and carbon dioxide in controlling coronary blood flow.
abstract: A two-part experiment was designed to test the hypothesis that myocardial oxygen and carbon dioxide tensions, as measured by coronary venous oxygen and carbon dioxide tensions, determine coronary blood flow during increases in myocardial oxygen consumption. The left main coronary artery was pump-perfused at constant pressure in closed-chest, anesthetized dogs. Oxygenators in the perfusion circuit permitted control of coronary arterial gas tensions. The steady-state relation between coronary venous oxygen and carbon dioxide tensions and coronary flow at a constant myocardial oxygen consumption was determined by locally altering coronary arterial oxygen and carbon dioxide tensions. Values of coronary venous oxygen and carbon dioxide tensions and coronary flow were also obtained at normal coronary arterial gas tensions during pacing-induced increases in myocardial oxygen consumption. The data yielded a hyperbolic relation among coronary venous oxygen and carbon dioxide tension and coronary flow during constant myocardial metabolism, suggesting a synergistic interaction between myocardial oxygen and carbon dioxide tensions in determining coronary flow. This relation was then used to predict the coronary flow change during pacing-induced increases in myocardial metabolism. Approximately 40% of the flow response during pacing-induced increases in myocardial oxygen consumption was predicted. In conclusion, coronary venous oxygen and carbon dioxide tensions synergistically interact to produce steady-state changes in coronary flow at a constant myocardial oxygen consumption. Changes in myocardial oxygen and carbon dioxide tensions can account for about 40% of the change in coronary flow during moderate changes in myocardial oxygen consumption.

title: Indexes of flow and cross-sectional area of the middle cerebral artery using doppler ultrasound during hypoxia and hypercapnia in humans.
abstract: This study examined changes in cross-sectional area of the middle cerebral artery as assessed by changes in Doppler signal power during hypoxia and hypercapnia. In addition, it examined the degree of consistency among three indexes of cerebral blood flow and velocity: the velocity spectral outline (VP), the intensity-weighted mean velocity (VIWM), and an index of middle cerebral artery flow (P. VIWM). P. VIWM was calculated as the product of VIWM multiplied by the total power signal. Power is proportional to cross-sectional area of the vessel; this calculation therefore allows for any changes in this variable.



Four protocols were used, each repeated six times for six healthy adults aged 20.8 +/- 1.7 years (mean +/- SD). The first was a control protocol (A) with end-tidal PO2 (ETPO2) maintained at 100 mm Hg and ETPCO2 at 1 to 2 mm Hg above eucapnia throughout. The second was a hypoxic step protocol (B) with ETPO2 lowered from control values to 50 mm Hg for 20 minutes. The third was a hypercapnic step protocol (C) with ETPCO2 elevated from control by 7.5 mm Hg for 20 minutes. The fourth was a combined hypoxic and hypercapnic step protocol (D) lasting 20 minutes. A dynamic end-tidal forcing system was used to control ETPCO2 and ETPO2. Doppler data were collected and stored every 10 milliseconds, and mean values were determined later on a beat-by-beat basis. VP, VIWM, power, and P.VIWM were expressed as a percentage of the average value over a 3-minute period before the step.



In protocols A and B, there were no changes in power and there were no differences between VP, VIWM, and P.VIWM. In C, at the relief from hypercapnia, there was a transient nonsignificant increase in power and a transient nonsignificant decrease in both VP and VIWM compared with P.VIWM. In D, during the stimulus period, VP was significantly higher than VIWM (paired t test, P < .05), but both indexes were not different from P.VIWM. In the period that followed relief from hypoxia and hypercapnia, the Doppler power signal was significantly increased by 3.8%. During this period, VP and VIWM were significantly lower than P.VIWM.



At the levels of either hypoxia or hypercapnia used in this study, there were no changes in cross-sectional area of the middle cerebral artery, and changes in both VP and VIWM accurately reflect changes in P.VIWM. With combined hypoxia and hypercapnia, however, at the relief from the stimuli when there is a very large and rapid decrease in P.VIWM, power is increased, suggesting an increase in the cross-sectional area. During this period, changes in VP and VIWM underestimate the changes in P.VIWM.

title: Assessments of flow by transcranial Doppler ultrasound in the middle cerebral artery during exercise in humans.
abstract: This study examined the consistency between three indexes of cerebral blood flow (CBF) obtained by using transcranial Doppler ultrasound in eight human volunteers. Each subject undertook three sessions of graded exercise, consisting of 6 min of rest, 6 min at 20% of maximal oxygen uptake (VO2 max), 6 min at 40% VO2 max, and 6 min of recovery. Values were obtained every 10 ms for the velocity associated with the maximal frequency of the Doppler shift (VP), the intensity-weighted mean velocity (VIWM), and total signal power (P). Beat-by-beat averages for three indexes (P, IWM, provided significantly different results for the percent changes in CBF with exercise. At 20% of VO2 max, P and IWM showed significant (P < 0.05) increases of 8 and 6%, respectively, whereas showed a nonsignificant increase of 3%. At 40% of VO2 max, P and IWM showed significant (P < 0.05) increases of 14 and 8%, respectively, whereas showed a nonsignificant increase of 4%. Our results suggest that the increase in CBF with exercise that has been reported with transcranial Doppler ultrasound needs to be treated with caution, as much of the response could arise as an artifact from the increase in amplitude and frequency of the arterial pressure waveform.

title: Accuracy of segmented MR velocity mapping to measure small vessel pulsatile flow in a phantom simulating cardiac motion
abstract: The purpose of this study was to investigate the accuracy of conventional, segmented, and echo‐shared MR velocity mapping sequences to measure pulsatile flow in small moving vessels using a phantom with simulated cardiac motion. The phantom moved either cyclically in‐plane, through‐plane, in‐ and through‐plane, or was stationary. The mean error in average flow was –2% ± 3% (mean ± SD) for all sequences under all conditions, with or without background correction, as long as the region of interest (ROI) size was equal to the vessel cross‐sectional size. Overestimation of flow as a result of an oversized ROI was less than 20%, and independent of field of view (FOV) and matrix, as long as the offset in angle between the imaging plane and flow direction was less than 10 degrees. Segmented velocity mapping sequences are surprisingly accurate in measuring average flow and render flow profiles in small moving vessels despite the blurring in the images due to vessel motion.  Imaging 2001;13:722–728.

title: Global left ventricular perfusion: noninvasive measurement with cine MR imaging and phase velocity mapping of coronary venous outflow.
abstract: Velocity and volumetric flow of left ventricular venous outflow in the distal coronary sinus were measured with magnetic resonance (MR) velocity mapping techniques in 24 healthy men. A total of 16-21 velocity maps were acquired throughout the cardiac cycle. To determine the accuracy of the MR velocity-mapping pulse sequence, measurements were obtained with a flow phantom. Mean blood flow was 144 mL/min +/- 62 (standard deviation); mean velocity, 2.1 cm/sec +/- 1.0; and mean cross-sectional area, 1.2 cm2. Phasic measurements revealed a biphasic flow pattern in the coronary sinus, with a first peak in systole (257 mL/min +/- 174) and a second peak in early diastole (1,090 mL/min +/- 487). The cross-sectional area varied between 0.5 cm2 +/- 0.2 at end diastole and 1.9 cm2 +/- 0.6 in systole, a finding that suggests a capacitance function for venous outflow. Mean blood flow measurements were in agreement with measurements obtained invasively in previous studies. It is concluded that MR velocity mapping can enable noninvasive measurement of coronary venous outflow and global left ventricular perfusion and may become clinically useful in assessment of coronary blood flow reserve.

title: THE EFFECTS OF ALTERED ARTERIAL TENSIONS OF CARBON DIOXIDE AND OXYGEN ON CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN CONSUMPTION OF NORMAL YOUNG MEN.
abstract: A method for measuring quantitatively the volume of cerebral blood flow in man by inhalation of nitrous oxide (1) found its first application in a study of the cerebral circulatory effects of low CO2 tension achieved by hyperventilation; of high CO2 tension, and of high and low 02 tensions obtained by inhalation of appropriate gas mixtures (2). Only the first part of this study, the effects of active and passive hyperventilation, has been published in detail (3). The purpose of the present paper is to present the remainder of these findings and to derive from them, together with those of the hyperventilation experiments, evidence bearing on the intrinsic control of the human cerebral circulation as revealed by quantitative measurements.

title: Independent role of arterial O2 tension in local control of coronary blood flow.
abstract: The aim of this study of a blood-perfused isolated rabbit heart preparation was to differentiate the effects on coronary resistance of large changes in arterial O2 tension (arterial PO2 = 45-400 Torr) from the effects of variations in arterial O2 content or myocardial O2 delivery. Standard stored human blood was resuspended in Krebs-Henseleit buffer and was oxygenated to obtain normal PO2, high PO2, and low PO2. Hemoglobin concentrations were adjusted to obtain the same arterial O2 content (CaO2) for the three PO2s. In a first set of experiments, in which coronary blood flow (CBF) was free and adapted to a constant perfusion pressure, switching from control [138 +/- 17 (SE) Torr] to high PO2 blood (380 +/- 27 Torr) induced a significant decrease in CBF and myocardial O2 consumption (MVO2). Switching from control (125 +/- 3 Torr) to low PO2 blood (49 +/- 5 Torr) induced a significant increase in CBF and MVO2. In a second set of experiments, the switch from control (159 +/- 5 Torr) to high PO2 (389 +/- 32 Torr) was performed in a preparation in which CBF and consequently O2 delivery were constant. Under these conditions, the increase in perfusion pressure demonstrated that PO2 affected coronary resistance, even though the O2 delivery was constant. No significant change in myocardial performance was observed in any of these experimental procedures. These results show that arterial PO2 may affect coronary blood flow regulation independently of any mediation by the autonomic nervous system and of any associated changes in O2 content or O2 delivery.

title: Transient responses of coronary flow in the blood‐perfused isolated rat heart submitted to changes in oxygen content.
abstract: This study examines the transient response of coronary blood flow to acute changes in O2 content at normal and high arterial PO2 (Pa, O2) in the blood‐perfused, working isolated rat heart. The perfusion system used in this study presents the following advantages: it eliminates the gas/blood interface, includes a peripheral circulation for control of pre‐load and after‐load, and allows for rapid change of perfusates and continuous recording of aortic and coronary blood flow. With this system the isolated rat heart is capable of stable haemodynamic performance for periods in excess of 4 h. A sudden decrease in O2 content from 0.147 to 0.067 11(‐11) at constant Pa,O2 (133 mmHg; n = 15) was associated with a marked increase in coronary blood flow (QCOR). This increase showed two phases: a rapid phase which reached 200% of the control value in 20 s, followed by a slow phase (235% in 90 s). When the same decrease in O2 content (0.135 to 0.057 11(‐1] was associated with an increase in Pa, O2 (n = 22; 143 to 412 mmHg), the response of QCOR was limited both in amplitude (175% rather than 235%) and in rate of onset (response time of 15.6 instead of 9.2 s). These results are consistent with the majority of currently popular hypotheses regarding control of QCOR including the adenosine hypothesis and that of vessel wall PO2 being a direct mediator. The time course of changes in coronary vascular resistance, with a Pa, O2‐dependent rapid phase, suggests the simultaneous function of the two mechanisms.

title: Age and sex differences in cerebral hemodynamics: a transcranial Doppler study.
abstract: Hemodynamic factors seem to play an important role in the pathogenesis of cerebral ischemic events. The aim of this study was to evaluate whether changes in cerebrovascular reactivity occur in women after menopause.



Using transcranial Doppler ultrasonography, we studied the changes of flow velocity after hypercapnia in the middle cerebral arteries of 45 healthy premenopausal women (mean age, 32.3 years; range, 20 to 47 years) and 40 postmenopausal women (mean age, 54.4 years; range, 48 to 64 years). The same measurements were recorded in two groups of healthy male subjects age matched with premenopausal (45 subjects) and postmenopausal women (40 subjects). Moreover, a subgroup of postmenopausal women aged 48 to 53 years (15 subjects) were compared with a group of 15 premenopausal women of the same age. We obtained hypercapnia with breath holding and evaluated cerebrovascular reactivity with the breath-holding index (BHI).



BHI was significantly lower in postmenopausal women (0.89+/-0.3) than in premenopausal women (1.59+/-0.3; P<0.0001) and in young (1.34+/-0.5; P<0.001) and old men (1.20+/-0.4; P<0.04). In the latter group, BHI was significantly lower than in premenopausal women (P<.0001). BHI values were also significantly lower in postmenopausal than in premenopausal women of the same age (0.81+/-0.1 versus 1.34+/-0.1; P<0.0001).



These findings suggest that the large reduction of cerebrovascular reactivity in postmenopausal women cannot be considered a simple factor related to aging but is probably influenced by hormonal changes. The alteration in cerebrovascular regulation could be involved in the increase of cerebrovascular disease in postmenopausal women.

title: Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans.
abstract: We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 +/- 4.2 yr, mean +/- SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (Vp) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH (P < 0.01) and PH (P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, Vp was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of approximately 0.34 cm x s(-1).%desaturation(-1) (P < 0.05). The Vp response to PH was biphasic with an initial decrease from baseline occurring at 79 +/- 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of -0.24 cm x s(-1) x % desaturation(-1). When expressed in relation to end-tidal Pco2, a sensitivity of -1.08 cm x s(-1).Torr(-1) was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.

title: Cerebrovascular responses to altitude
abstract: The regulation of cerebral blood flow (CBF) is a complex process that is altered significantly with altitude exposure. Acute exposure produces a marked increase in CBF, in proportion to the severity of the hypoxia and mitigated by hyperventilation-induced hypocapnia when CO(2) is uncontrolled. A number of mediators contribute to the hypoxia-induced cerebral vasodilation, including adenosine, potassium channels, substance P, prostaglandins, and NO. Upon acclimatization to altitude, CBF returns towards normal sea-level values in subsequent days and weeks, mediated by a progressive increase in PO2, first through hyperventilation followed by erythropoiesis. With long-term altitude exposure, a number of mechanisms play a role in regulating CBF, including acid-base balance, hematological modifications, and angiogenesis. Finally, several cerebrovascular disorders are associated with altitude exposure. Existing gaps in our knowledge of CBF and altitude, and areas of future investigation include effects of longer exposures, intermittent hypoxia, and gender differences in the CBF responses to altitude.

title: Influence of Altitude Exposure on Coronary Flow Reserve
abstract: Although no data exist on the effect of altitude exposure on coronary flow reserve (CFR), patients with coronary artery disease (CAD) are advised not to exceed moderate altitudes of ≈2500 m above sea level. We studied the influence of altitude on myocardial blood flow (MBF) in controls and CAD patients. In 10 healthy controls and 8 patients with CAD, MBF was measured by positron emission tomography and 15O-labeled water at rest, during adenosine stress, and after supine bicycle exercise. This protocol was repeated during inhalation of a hypoxic gas mixture corresponding to an altitude of 4500 m (controls) and 2500 m (CAD). Workload was targeted to comparable heart rate–blood pressure products at normoxia and hypoxia. Resting MBF increased significantly in controls at 4500 m (+24%, P <0.01) and in CAD patients at 2500 m (+24%, P <0.05). Altitude had no influence on adenosine-induced hyperemia and CFR. Exercise-induced hyperemia increased significantly in controls (+38%, P <0.01) at 4500 m (despite a reduction in workload, −28%, P <0.0001) but not in CAD patients at 2500 m (moderate decrease in workload, −11%, P <0.05). Exercise-induced reserve was preserved in controls (+10%, P =NS) but decreased in CAD patients (−18%, P <0.005). At 2500 m altitude, there is a significant decrease in exercise-induced reserve in CAD patients, indicating that compensatory mechanisms might be exhausted even at moderate altitudes, whereas healthy controls have preserved reserve up to 4500 m. Thus, patients with CAD and impaired CFR should be cautious when performing physical exercise even at moderate altitude.

title: Cerebral Formation of Free Radicals during Hypoxia Does Not Cause Structural Damage and is Associated with a Reduction in Mitochondrial PO2; Evidence of O2-Sensing in Humans?
abstract: Cellular hypoxia triggers a homeostatic increase in mitochondrial free radical signaling. In this study, blood was obtained from the radial artery and jugular venous bulb in 10 men during normoxia and 9 hours hypoxia (12.9% O2). Mitochondrial oxygen tension ( ( P ˉ O 2 mit ) ) was derived from cerebral blood flow and blood gases. The ascorbate radical (A•−) was detected by electron paramagnetic resonance spectroscopy and neuron-specific enolase (NSE), a biomarker of neuronal injury, by enzyme-linked immunosorbent assay. Hypoxia increased the cerebral output of A•− in proportion to the reduction in P ˉ O 2 mit , but did not affect NSE exchange. These findings suggest that neuro-oxidative stress may constitute an adaptive response.

title: Global Cerebral Oxidative Metabolism during Hypercapnia and Hypocapnia in Humans: Implications for BOLD fMRI
abstract: The effect of carbon dioxide (CO2) on cerebral metabolism is of tremendous interest to functional imaging. In particular, mild-to-moderate hypercapnia is routinely used in calibrated blood oxygen-level dependent (BOLD)-functional magnetic resonance imaging (fMRI)-based quantification of cerebral oxidative metabolism changes (ΔCMRO2), and relies on the assumption of a stable CMRO2 during CO2 challenges. However, this assumption has been challenged by certain animal studies, necessitating its verification in humans and under conditions customary to fMRI. We report, for the first time, on global ΔCMRO2 measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO2 modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO2 is expected at the levels of end-tidal CO2 changes customary to calibrated BOLD.

title: Cerebral blood flow and BOLD fMRI responses to hypoxia in awake and anesthetized rats
abstract: This study investigated the functional MRI responses to graded hypoxia in awake/restrained and anesthetized animals by measuring cerebral blood flow (CBF) and blood oxygenation (BOLD) changes and estimating changes in cerebral metabolic rate of oxygen (CMRO2). Hypoxia in isoflurane anesthetized rats reduced blood pressure but did not change heart rate and respiration rate. In contrast, hypoxia in awake animals showed compensatory responses by sustaining blood pressure, increasing heart rate and respiration rate. Basal CBF was higher under isoflurane anesthesia than awake state because isoflurane is a vasodilator. Graded hypoxia decreased BOLD signals. Surprisingly, hypoxia also decreased CBF likely because hypoxia induced hypocapnia. Hypoxia-induced CBF and BOLD decreases were smaller in awake, relative to anesthetized, rats at low pO2, but similar at high pO2. CBF leveled off with decreasing hypoxia-induced pCO2 in awake rats, but monotonically decreased in anesthetized rats. CMRO2 estimated using a biophysical BOLD model did not change under mild hypoxia but was reduced under severe hypoxia relative to baseline. These results showed that isoflurane attenuated autonomic responses to hypoxia, hypoxia-induced hypocapnia dominated CBF changes, tissues in awake conditions appeared better oxygenated, and severe hypoxia reduced oxygen metabolism. This study underscored the marked differences in BOLD and CBF MRI responses to hypoxia in vivo between awake and anesthetized conditions and has implications for functional MRI studies of hypoxia in anesthetized animal models.

title: Rapid magnetic resonance measurement of global cerebral metabolic rate of oxygen consumption in humans during rest and hypercapnia
abstract: The effect of hypercapnia on cerebral metabolic rate of oxygen consumption (CMRO2) has been a subject of intensive investigation and debate. Most applications of hypercapnia are based on the assumption that a mild increase in partial pressure of carbon dioxide has negligible effect on cerebral metabolism. In this study, we sought to further investigate the vascular and metabolic effects of hypercapnia by simultaneously measuring global venous oxygen saturation (SvO2) and total cerebral blood flow (tCBF), with a temporal resolution of 30 seconds using magnetic resonance susceptometry and phase-contrast techniques in 10 healthy awake adults. While significant increases in SvO2 and tCBF were observed during hypercapnia (P < 0.005), no change in CMRO2 was noted (P > 0.05). Additionally, fractional changes in tCBF and end-tidal carbon dioxide (R2 = 0.72, P < 0.005), as well as baseline SvO2 and tCBF (R2 = 0.72, P < 0.005), were found to be correlated. The data also suggested a correlation between cerebral vascular reactivity (CVR) and baseline tCBF (R2 = 0.44, P = 0.052). A CVR value of 6.1% ± 1.6%/mm Hg was determined using a linear-fit model. Additionally, an average undershoot of 6.7% ± 4% and 17.1% ± 7% was observed in SvO2 and tCBF upon recovery from hypercapnia in six subjects.

title: Human Cerebrovascular Response to Combined Hypoxia and Hypercapnia
abstract: The N2O technique was used in 6 human subjects to measure cerebral blood flow and metabolism during hypoxia and hypercapnia induced by the inhalation of 10% O2-5% CO2. Ventilation increased from 7.7 to 46.3 liters/min; Pao2 decreased from 88 to 62 mm Hg; Paco2 increased from 38 to 45 mm Hg (for each P <.01). Mean cerebral blood flow increased from 56 to 97 ml/100 g/min (P <.01). Because cerebral O2 consumption was unchanged, the technique of estimating changes in cerebral flow from arterial-jugular venous O2 differences was used to follow changes during the first 10 min of inhalation of 10% O2-5% CO2 in 6 additional subjects. The rapidity of cerebral vasodilatation was increased by this combination of stimuli. The enhanced respiratory response produced by breathing 10% O2-5% CO2 appeared responsible for the more rapid cerebrovascular response and may offer some protective benefits. Comparisons of the present data with previous studies lead to the conclusion that simultaneous hypoxia and hypercapnia have additive dilator effects on the cerebral vasculature. Thus, the observed increases in cerebral flow were the sum of their individual effects.

title: Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals
abstract: Functional magnetic resonance imaging (fMRI) was used to investigate the effects of inspired hypoxic, hyperoxic, and hypercapnic gases on baseline and stimulus-evoked changes in blood oxygenation level-dependent (BOLD) signals, cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen (CMRO2) in spontaneously breathing rats under isoflurane anesthesia. Each animal was subjected to a baseline period of six inspired gas conditions (9% O2, 12% O2, 21% O2, 100% O2, 5% CO2, and 10% CO2) followed by a superimposed period of forepaw stimulation. Significant stimulus-evoked fMRI responses were found in the primary somatosensory cortices. Relative fMRI responses to forepaw stimulation varied across gas conditions and were dependent on baseline physiology, whereas absolute fMRI responses were similar across moderate gas conditions (12% O2, 21% O2 100% O2, and 5% CO2) and were relatively independent of baseline physiology. Consistent with data obtained using well-established techniques, baseline and stimulus-evoked CMRO2 were invariant across moderate physiological perturbations thereby supporting a CMRO2-fMRI technique for non-invasive CMRO2 measurement. However, under 9% O2 and 10% CO2, stimulus-evoked CBF and BOLD were substantially reduced and the CMRO2 formalism appeared invalid, likely due to attenuated neurovascular coupling and/or a failure of the model under extreme physiological perturbations. These findings demonstrate that absolute fMRI measurements help distinguish neural from non-neural contributions to the fMRI signals and may lend a more accurate measure of brain activity during states of altered basal physiology. Moreover, since numerous pharmacologic agents, pathophysiological states, and psychiatric conditions alter baseline physiology independent of neural activity, these results have implications for neuroimaging studies using relative fMRI changes to map brain activity.

title: The Influence of Carbon Dioxide on Brain Activity and Metabolism in Conscious Humans
abstract: A better understanding of carbon dioxide (CO2) effect on brain activity may have a profound impact on clinical studies using CO2 manipulation to assess cerebrovascular reserve and on the use of hypercapnia as a means to calibrate functional magnetic resonance imaging (fMRI) signal. This study investigates how an increase in blood CO2, via inhalation of 5% CO2, may alter brain activity in humans. Dynamic measurement of brain metabolism revealed that mild hypercapnia resulted in a suppression of cerebral metabolic rate of oxygen (CMRO 2 ) by 13.4%±2.3% (N=14) and, furthermore, the CMRO 2 change was proportional to the subject's end-tidal CO2 (Et-CO2) change. When using functional connectivity MRI (fcMRI) to assess the changes in resting-state neural activity, it was found that hypercapnia resulted in a reduction in all fcMRI indices assessed including cluster volume, cross-correlation coefficient, and amplitude of the fcMRI signal in the default-mode network (DMN). The extent of the reduction was more pronounced than similar indices obtained in visual-evoked fMRI, suggesting a selective suppression effect on resting-state neural activity. Scalp electroencephalogram (EEG) studies comparing hypercapnia with normocapnia conditions showed a relative increase in low frequency power in the EEG spectra, suggesting that the brain is entering a low arousal state on CO2 inhalation.

title: Hypoxia and hyperoxia alter brain metabolism in awake human
abstract: The interaction between neural activity and brain vasculature forms the basis of brain mapping techniques such as functional MRI, PET and optical imaging. Up until now, the interaction has primarily been considered as unidirectional. That is, neural activity can change the vascular parameters (e.g. blood oxygenation), but little attention was received as to whether gas content changes in the blood would reversely alter neural activity. The present study will investigate whether physiologic manipulation of O2 content in the arterial blood will change brain activity and metabolism. We used a recently developed MRI technique (1,2) to monitor the subject’s cerebral metabolic rate of oxygen (CMRO2) while increasing or decreasing the O2 content in the inspired air. Our data suggest that hypoxia enhanced oxygen metabolism and hyperoxia suppressed it. Furthermore, the modulation effect appears to be proportional to the O2 content in the arterial blood, rather than to the O2 content in the inhaled air. The characterization of the reverse effect between neural activity and vasculature can provide a new perspective to brain metabolism and its regulation, as well as a potential non-invasive, convenient and cost-effective means to modulate brain activity in certain conditions such as neurodegenerative diseases.  Twelve healthy subjects were studied on a 3T Philips System, six of which were studied with hypoxia (13.5% O2, 3 F and 3 M, age 19-31) and the other six with hyperoxia (98% O2, 4 F and 2 M, age 23-27). Quantification of CMRO2 was based on a recently reported MRI technique (1, 2). Briefly, this technique uses the Fick principle of arteriovenous difference to estimate the rate of oxygen consumption, CMRO2=CBFx[(Ya-Yv)xCa+(PaO2PvO2)xCd] , where CBF is cerebral blood flow, Ya and Yv are arterial and venous oxygenations (in %) respectively, Ca and Cd are constants associated with hemoglobin’s oxygen-carrying capacity and plasma’s oxygen-dissolving capacity, respectively. PaO2 and PvO2 are O2 tensions in artery and vein, respectively. We should note that usually the oxygen dissolved in plasma is negligible (<2%) compared to the hemoglobin-bound oxygen. However, in the special case of hyperoxia, the dissolved amount is no longer negligible (>10%), which is why we included O2 tension terms in the equation. For this study, the values of Ca and Cd were based on physiology literature. The other parameters were measured on a subject-specific and condition-specific basis as follows: Ya was measured with Pulse Oximeter, Yv was measured by TRUST MRI at the sagittal sinus (1), PvO2 was estimated from Yv using the oxygen dissociation curve, CBF was measured with the phase-contrast quantitative flow technique at the sagittal sinus, PaO2 was approximated with alveolar O2 level as measured from the exhaled air with an oxygen sensor. Note that the CMRO2 measured with the above method is a whole-brain measure with no spatial information. However, the O2 effect, if any, is expected to be global since the entire brain will see a change in O2 tension. The sequence parameters were: for TRUST MRI, voxel size 3.44x3.44x5mm, TR=8000ms, TI=1200ms, four TEs: 0ms, 40ms, 80ms and 160ms, duration 3.5 min; for PC MRI, voxel size 0.45x0.45x5 mm, maximum velocity 80cm/s, duration 30 sec. Experiments started with room-air, then the breathing air was switched to 13.5% O2 or 98% O2 filled in a Douglas bag. Finally, the air was switched back to room air for another CMRO2 measurement.  Physiologic parameters during the normoxia, hypoxia and hyperoxia periods are summarized in Table 1. Hypoxia decreased arterial oxygenation as expected. Venous oxygenation level also reduced. Interestingly, the amount of decrease for both parameters appears to be similar, suggesting that the extraction fraction (Ya-Yv) did not change much (p>0.05). CBF increased considerably (by 21±5%, p=0.01) when switching from normoxia to hypoxia, and can be visualized in the phase-contrast velocity map (Figs. 1c and d). Based on these experimental measures, CMRO2 calculated from the equation above showed an increase of 25±6% (n=6, p=0.007). Comparing the two normoxia periods before and after the hypoxia block, the physiologic parameters are not different (p>0.05) and the CMRO2 values were also similar. For the hyperoxia manipulation (Table 1), the arterial oxygenation level did not change much as virtually all the hemoglobin is already saturated with O2 at normoxia. However, because the oxygen tension (shown as end-tidal O2 in Table 1) increased by approximately five times, the amount of oxygen dissolved in the plasma increased dramatically. Venous oxygenation increased significantly (p<0.001) upon hyperoxia challenge. Earlier we noted that hypoxia did not change the oxygen extraction fraction, thus we also investigated whether the extraction fraction changed with hyperoxia. At the face, it seems that (Ya-Yv) is reduced in this case. However, if we were to also account for the dissolved oxygen in the arterial blood, our calculation showed that the extraction fraction is again unchanged (p>0.05). That is, for each ml of blood passing through the capillary bed, the amount of oxygen that the tissue extracted is approximately the same for normoxia, hypoxia and hyperoxia conditions. CBF is reduced during hyperoxia compared to normoxia (14±2%, also see Figs. 1e and f). The calculation of CMRO2 then showed that the CMRO2 decreased by 10±1% when switching from normoxia to hyperoxia. Comparing the two normoxia periods, the parameters were unchanged. Figure 2 summarizes the percentage changes in CMRO2 as well as the two multipliers used to calculate it, i.e. CBF and oxygen extraction fraction (OEF=(Ya-Yv)xCa+(PaO2-PvO2)xCd). We have also tested to see if the CMRO2 modulation has a linear dependence on the oxygen metrics. We found that the CMRO2 change is not linear to the inhaled CO2 fraction (e.g. PaO2) nor to the arterial oxygenation level (e.g. Ya), but it appears to be linearly correlated with the total O2 content in the arterial blood (R=0.85; p<0.001), i.e. YaxCa+PaO2xCd. Our data suggest that a change in arterial oxygen content can modulate brain metabolism in a dose-dependent manner, with hypoxia increasing metabolic rate of oxygen and hyperoxia decreasing it. Therefore, in addition to the well-known “forward” neurovascular coupling (3) (i.e. neural activity can alter vascular parameters), the “reverse” coupling may also be important in the regulation of brain function.

title: Dependence of pial arteriolar response to hypercapnia on vessel size.
abstract: The responses of pial arterioles to changes in PaCO2 were studied in anesthetized cats equipped with cranial windows for the observation of the pial microcirculation. The percentile increase in vessel caliber induced by hypercapnia was size dependent, with the smaller vessels responding more vigorously than the larger ones. In contrast, the vasoconstrictor responses to arterial hypocapnia were size independent. Following topical application of phentolamine (10(-5) M), or after ipsilateral extirpation of the superior cervical ganglion, the increase in arteriolar caliber caused by moderate hypercapnia (5% CO2 inhalation) in the larger arterioles (greater than 100 micron in diameter) increased and became equal to that of the smaller arterioles (less than 100 micron in diameter). The response to hypocapnia was not affected by phentolamine. The results indicate that a major reason for the greater responsiveness of smaller vessels to moderate hypercapnia is the fact that the response of the larger vessels is limited by neurogenic vasoconstriction resulting from increased activity of adrenergic nerves originating from the cervical sympathetic chain. The absence of an influence of the sympathetic nervous system on the responses to hypocapnia is explained by the lack of significant resting neurogenic vasoconstrictor tone in pial arterioles of anesthetized cats.

title: Rapid and local autoregulation of cerebrovascular blood flow: a deep‐brain imaging study in the mouse
abstract: The brain obtains energy by keeping the cerebral blood flow constant against unexpected changes in systemic blood pressure. Although this homeostatic mechanism is widely known as cerebrovascular autoregulation, it is not understood how widely and how robustly it works in the brain. Using a needle‐like objective lens designed for deep‐tissue imaging, we quantified the degree of autoregulation in the mouse hippocampus with single‐capillary resolution. On average, hippocampal blood flow exhibited autoregulation over a comparatively broad range of arterial blood pressure and did not significantly respond to pressure changes induced by the pharmacological activation of autonomic nervous system receptors, whereas peripheral tissues showed linear blood flow changes. At the level of individual capillaries, however, about 40% of hippocampal capillaries did not undergo rapid autoregulation. This heterogeneity suggests the presence of a local baroreflex system to implement cerebral autoregulation.

title: Heterogeneous control of blood flow amongst different vascular beds
abstract: The control and maintenance of vascular tone is due to a balance between vasoconstrictor and vasodilator pathways. Vasomotor responses to neural, metabolic and physical factors vary between vessels in different vascular beds, as well as along the same bed, particularly as vessels become smaller. These differences result from variation in the composition of neurotransmitters released by perivascular nerves, variation in the array and activation of receptor subtypes expressed in different vascular beds and variation in the signal transduction pathways activated in either the vascular smooth muscle or endothelial cells. As the study of vasomotor responses often requires pre‐existing tone, some of the reported heterogeneity in the relative contributions of different vasodilator mechanisms may be compounded by different experimental conditions. Biochemical variations, such as the expression of ion channels, connexin subtypes and other important components of second messenger cascades, have been documented in the smooth muscle and endothelial cells in different parts of the body. Anatomical variations, in the presence and prevalence of gap junctions between smooth muscle cells, between endothelial cells and at myoendothelial gap junctions, between the two cell layers, have also been described. These factors will contribute further to the heterogeneity in local and conducted responses.

title: Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy.
abstract: Forty-five measurements of diameters of 12 human cerebral arteries were performed during 10 craniotomies under moderate changes in mean blood pressure and end tidal CO2. The mean change in blood pressure was 30 +/- 16 mm Hg (standard deviation) and that of end tidal CO2 was 14 +/- 6 mm Hg (standard deviation). These changes were induced with nitroprusside, phenylephrine, and adjustment of ventilator rate. Measurements were made through the operating microscope focused at the highest power, with meticulous attention to constant angle and distance from the artery. The mean diameter change in the large cerebral arteries (carotid, middle cerebral artery, vertebral artery) was less than 4%, but the smaller arteries (anterior cerebral artery, M2 segment of middle cerebral artery) showed diameter changes as large as 29% and 21% to end tidal CO2 and blood pressure changes, respectively. These data suggest that at the time of craniotomy, diameters of the large cerebral vessels do not significantly change during moderate variations in blood pressure and CO2, but that larger changes may occur in smaller vessels. This constancy of diameter suggests that the transcranial Doppler velocities obtained during intraoperative monitoring of craniotomies may closely reflect blood flow through the insonated artery.

title: MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis.
abstract: The relationship between middle cerebral artery (MCA) flow velocity (CFV) and cerebral blood flow (CBF) is uncertain because of unknown vessel diameter response to physiological stimuli. The purpose of this study was to directly examine the effect of a simulated orthostatic stress (lower body negative pressure [LBNP]) as well as increased or decreased end-tidal carbon dioxide partial pressure (P(ET)CO(2)) on MCA diameter and CFV.



Twelve subjects participated in a CO(2) manipulation protocol and/or an LBNP protocol. In the CO(2) manipulation protocol, subjects breathed room air (normocapnia) or 6% inspired CO(2) (hypercapnia), or they hyperventilated to approximately 25 mm Hg P(ET)CO(2) (hypocapnia). In the LBNP protocol, subjects experienced 10 minutes each of -20 and -40 mm Hg lower body suction. CFV and diameter of the MCA were measured by transcranial Doppler and MRI, respectively, during the experimental protocols.



Compared with normocapnia, hypercapnia produced increases in both P(ET)CO(2) (from 36+/-3 to 40+/-4 mm Hg, P<0.05) and CFV (from 63+/-4 to 80+/-6 cm/s, P<0.001) but did not change MCA diameters (from 2.9+/-0.3 to 2.8+/-0.3 mm). Hypocapnia produced decreases in both P(ET)CO(2) (24+/-2 mm Hg, P<0.005) and CFV (43+/-7 cm/s, P<0.001) compared with normocapnia, with no change in MCA diameters (from 2.9+/-0.3 to 2.9+/-0.4 mm). During -40 mm Hg LBNP, P(ET)CO(2) was not changed, but CFV (55+/-4 cm/s) was reduced from baseline (58+/-4 cm/s, P<0.05), with no change in MCA diameter.



Under the conditions of this study, changes in MCA diameter were not detected. Therefore, we conclude that relative changes in CFV were representative of changes in CBF during the physiological stimuli of moderate LBNP or changes in P(ET)CO(2).

title: Cerebral autoregulation dynamics in humans.
abstract: We studied the response of cerebral blood flow to acute step decreases in arterial blood pressure noninvasively and nonpharmacologically in 10 normal volunteers during normocapnia, hypocapnia, and hypercapnia. The step (approximately 20 mm Hg) was induced by rapidly deflating thigh blood pressure cuffs following a 2-minute inflation above systolic blood pressure. Instantaneous arterial blood pressure was measured by a new servo-cuff method, and cerebral blood flow changes were assessed by transcranial Doppler recording of middle cerebral artery blood flow velocity. In hypocapnia, full restoration of blood flow to the pretest level was seen as early as 4.1 seconds after the step decrease in blood pressure, while the response was slower in normocapnia and hypercapnia. The time course of cerebrovascular resistance was calculated from blood pressure and blood flow recordings, and rate of regulation was determined as the normalized change in cerebrovascular resistance per second during 2.5 seconds just after the step decrease in blood pressure. The reference for normalization was the calculated change in cerebrovascular resistance that would have nullified the effects of the step decrease in arterial blood pressure on cerebral blood flow. The rate of regulation was 0.38, 0.20, and 0.11/sec in hypocapnia, normocapnia, and hypercapnia, respectively. There was a highly significant inverse relation between rate of regulation and PaCO2 (p less than 0.001), indicating that the response rate of cerebral autoregulation in awake normal humans is profoundly dependent on vascular tone.

title: On the instantaneous measurement of bloodflow by ultrasonic means
abstract: Part of the problem of determining the flow through a blood vessel is the measurement of the instantaneous average blood velocity over a cross-section of the vessel. In this paper a new method is described to estimate that velocity from the received signal of a Doppler flowmeter using continuous ultrasound. The method is based on the determination of the frequency shift averaged over the power density spectrum of the received signal. Due to a new type of instrumentation this can be done without carrying through a complete frequency analysis of that signal. This provides a rather accurate determination of the instantaneous value of the blood velocity.SommaireUne part du problème de la détermination de l'écoulement à travers un vaisseau sanguin est le mesurage de la vélocité instantanée moyenne du sang sur une section transversale du vaisseau. Dans ce mémoire on décrit une nouvelle méthode pour évaluer cette vélocité du signal reçu d'un enregistreur de l'écoulement Doppler, en utilisant des ultrasons continus. La méthode est basée sur la détermination du changement de la fréquence moyenne réalisée, concernant le spectre de densité de la puissance du signal reçu. Dû à un nouveau type d'instrumentation, ceci peut être fait sans entreprendre une analyse complète de la fréquence de ce signal. Ceci procure une détermination plutôt précise de la valeur instantanée de la vélocité du sang.ZusammenfassungEin Teil des Problems zur Feststellung des Stroms durch ein Blutgefäss ist die Messung der momentanen durchschnittlichen Blutgeschwindigkeit über einem Querschnitt des Gefässes. In diesem Bericht wird eine neue Methode zur Schätzung dieser Geschwindigkeit aus dem erhaltenen Signal eines Doppler Strömungsmessers unter Verwendung von Dauerüberschall beschrieben. Die Methode gründet sich auf die Ermittlung der Frequenzverschiebung, deren Durchschnitt über das Spektrum der Stärkedichte des empfangenen Signals festgestellt wirde. Dank einer neuen Art von Instrumentierung kann dies ohne Durchführung einer vollen Frequenzanalyse dieses Signals festgestellt werden. Dadurch erhält man eine ziemlich genaue Ermittlung des Augenblickwertes der Blutgeschwindigkeit.

title: Evaluation of cerebral arterial flow with transcranial Doppler ultrasound: theoretical development and phantom studies.
abstract: Blood flow information available from transcranial Doppler ultrasound is usually derived from velocity alone because no knowledge of vessel caliber is available. In cases such as vasospasm, where vessel size changes, the inference of flow from velocity becomes questionable. A computational technique was used to calculate a flow index and 2 vessel area indices based on the first and zero moments of the Doppler power spectrum. These indices were tested in a steady and pulsatile flow phantom using 6 different diameter elastic tubes. Changes in the flow index showed good agreement with changes in timed volume flow for different flow rates. The vessel caliber indices correctly predicted changes in area when different diameter tubes were examined. These indices may prove useful in clinical settings where the constancy of flow or vessel diameter between studies are in question.

title: Changes of Cerebral Blood Flow during Short-Term Exposure to Normobaric Hypoxia
abstract: Decreased arterial partial oxygen pressure (PaO2) below a certain level presents a strong stimulus for increasing cerebral blood flow. Although several field studies examined the time course of global cerebral blood flow (gCBF) changes during hypoxia at high altitude, little was known about the regional differences in the flow pattern. Positron emission tomography (PET) with [15O]H2O was used on eight healthy volunteers to assess regional cerebral blood flow (rCBF) during short-term exposure to hypoxia corresponding to simulated altitudes of 3,000 and 4,500 m. Scans at the simulated altitudes were preceded and followed by baseline scans at the altitude of Zurich (450 m, baseline-1 and baseline-2). Each altitude stage lasted 20 minutes. From baseline to 4,500 m, gCBF increased from 34.4 ± 5.9 to 41.6 ± 9.0 mL · minute−1 · 100 g−1 (mean ± SD), whereas no significant change was noted at 3,000 m. During baseline-2 the flow values returned to those of baseline-1. Statistical parametric mapping identified the hypothalamus as the only region with excessively increased blood flow at 4,500 m (+32.8% ± 21.9% relative to baseline-1). The corresponding value for the thalamus, the structure with the second largest increase, was 19.2% ± 16.3%. Compared with the rest of the brain, an excessive increase of blood flow during acute exposure to hypoxia is found in the hypothalamus. The functional implications are at present unclear. Further studies of this finding should elucidate its meaning and especially focus on a potential association with the symptoms of acute mountain sickness.

title: Hypertrophic cardiomyopathy: MR measurement of coronary blood flow and vasodilator flow reserve in patients and healthy subjects.
abstract: To evaluate coronary blood flow per gram of myocardial mass and vasodilator flow reserve in patients with hypertrophic cardiomyopathy (HCM) and in healthy subjects by using breath-hold velocity-encoded cine (VEC) magnetic resonance (MR) imaging.



Twenty-nine patients with HCM and nine healthy volunteers were examined. Fast VEC MR images were obtained in an oblique imaging plane perpendicular to the coronary sinus before and after intravenous injection of dipyridamole (0.56 mg/kg). The products of mean velocity and cross-sectional area of the vessel were integrated to measure blood flow. Breath-hold cine MR images encompassing the entire left ventricle were acquired to quantify the left ventricular mass.



In the basal state, the coronary blood flow per gram of myocardial mass was 0.74 mL/min/g +/- 0.23 in healthy subjects and 0.62 mL/min/g +/- 0.27 in patients with HCM. After administration of dipyridamole, coronary blood flow in patients with HCM increased to a level significantly less than that in healthy subjects (1.03 mL/min/g +/- 0.40 vs 2.14 mL/min/g +/- 0.51; P < .01), resulting in a severely depressed flow reserve ratio in patients with HCM compared with that in healthy subjects (1.72 +/- 0.49 vs 3.01 +/- 0.75; P < .01).



Breath-hold VEC MR imaging is a noninvasive technique for evaluating coronary flow per gram of myocardial mass and coronary flow reserve.

title: Magnetic resonance-based assessment of global coronary flow and flow reserve and its relation to left ventricular functional parameters: a comparison with positron emission tomography.
abstract: Measurement of coronary sinus blood flow (CSF) by phase-contrast magnetic resonance (PC-MR) imaging at rest and during hyperemia may allow noninvasive assessment of global coronary hemodynamics.



Sixteen healthy volunteers (age, 22 to 32 years) were examined with MR and PET in random order within 1 to 2 days. At rest and during hyperemia (dipyridamole 0.56 mg/kg), CSF was measured by a cine PC-MR technique (temporal resolution, 40 ms; spatial resolution, 1.25x0.8 mm(2)), and myocardial blood flow (MBF) was measured by [(13)N]NH(3) PET. PET and MR agreed closely for coronary flow reserve (CFR; mean difference, 2.2+/-14.7%; Bland-Altman method). CSF divided by either total left ventricular mass or an estimate of drained myocardium (LVM(drain)) correlated highly with PET flow data (r=0.93 and 0.95, respectively) and with measures of oxygen demand, ie, heart rate, afterload-corrected fiber shortening, and peak systolic stress determined by MR (overall correlation coefficients, 0.81 and 0.87, respectively, multivariate analysis). ) did not differ significantly from PET-derived MBF (difference, 3.6+/-16.6%). In orthotopic heart transplant recipients (n=9), CFR was reduced and blood supply-demand relationships at rest were shifted toward higher flows (P<0.0001).



This integrated MR approach allows comprehensive assessment of autoregulated and hyperemic coronary flow and is suitable for serial measurements in patients. In transplanted hearts, elevated resting flow is the major cause of reduced CFR.

title: Coronary sinus flow measurement by means of velocity-encoded cine MR imaging: validation by using flow probes in dogs.
abstract: To validate coronary sinus flow measurements for quantification of global left ventricular (LV) perfusion by means of velocity-encoded cine (VEC) magnetic resonance (MR) imaging and flow probes.



Measurements of coronary sinus flow were performed in seven dogs by using VEC MR imaging at baseline, single coronary arterial stenosis, dipyridamole stress, and reactive hyperemia. These measurements were compared with flow probe measurements of coronary blood flow (CBF) in the left anterior descending coronary (LAD) and circumflex (CFX) arteries (CBF(LAD+CFX)) and coronary sinus. LV blood perfusion was calculated in milliliters per minute per gram from coronary sinus flow, and LV mass was obtained by using VEC and cine MR imaging. LV mass was validated at autopsy.



CBF(LAD+CFX) and coronary sinus flow at VEC MR imaging showed close correlation (r = 0.98, P: <.001). The difference between CBF(LAD+CFX) and MR coronary sinus flow was 3.1 mL/min +/- 8.5 (SD). LV mass at cine MR imaging was not significantly different from that at autopsy (73.2 g +/- 12.8 vs 69. 4 g +/- 12.8). At baseline, myocardial perfusion was 0.40 mL/min/g +/- 0.09 at VEC MR imaging, and CBF(LAD+CFX) was 0.44 mL/min/g +/- 0. 08 (not significant). Reactive hyperemia resulted in 2.7- and 2. 3-fold increases in coronary sinus flow at VEC MR imaging and flow probe CBF(LAD+CFX), respectively.



VEC MR imaging has the potential to measure coronary sinus flow during different physiologic conditions and can serve as a noninvasive modality to quantify global LV perfusion in patients.

title: Reactivity of cerebral blood flow to carbon dioxide in hypertensive patients: evaluation by the transcranial Doppler method.
abstract: To evaluate hypertensive cerebral involvement before cerebrovascular accidents.



Cerebral microvascular responses to changes in the arterial partial pressure of CO2 (pCO2; the CO2 reactivity) were compared among patients with different stages and severity of hypertensive disease.



Fifty-eight patients with hypertension, 11 with borderline hypertension, 15 hypertensives with cerebral infarction and 58 normotensive controls were studied.



The cerebrovascular CO2 reactivity was determined by measuring simultaneously the end-tidal pCO2 and the blood flow velocity in the middle cerebral artery using transcranial Doppler sonography under hypocapnic, normocapnic and hypercapnic conditions.



CO2 reactivity was impaired in the hypertensive patients compared with in the normotensive controls, but less so than in the symptomatic hemisphere of the hypertensive patients with cerebral infarction. The CO2 reactivity in the borderline hypertensive patients was greater than that in both the symptomatic and asymptomatic hemispheres of the hypertensive patients with cerebral infarction. In the subjects without cerebral infarction, two risk factors for cerebral atherosclerosis (age and hypertension) were negatively correlated with cerebrovascular CO2 reactivity. In the hypertensive patients age and the estimated duration of hypertension were negatively correlated with cerebrovascular CO2 reactivity. CO2 reactivity in the patients with hypertensive or arteriosclerotic retinopathy or ST-T changes on their electrocardiogram was impaired compared with that in the patients without such changes.



Hypertension affected the microvascular reactivity of the brain before the development of cerebrovascular accidents, and its effect varied dependently on the extent of involvement of other target organs.

title: Impaired cerebrovascular reactivity as a risk marker for first-ever lacunar infarction: A case-control study.
abstract: Functional assessment of small arteries and arterioles could provide valuable information regarding the extent of diffuse arteriolosclerosis in patients with small-vessel disease. Therefore we attempted to clarify the role of cerebrovascular reactivity (CVR) as a risk marker for first-ever symptomatic lacunar infarction.



Forty-six patients with lacunar infarction and 46 sex- and age-matched control subjects were prospectively evaluated. Cerebral hemodynamics were studied with transcranial Doppler ultrasonography. CVR was examined by calculating the percent increase in mean flow velocity occurring after 15 mg/kg acetazolamide administration (Diamox test).



CVR was significantly (P<0.0001, Student's t test) lower in cases (50.0+/-12. 7%) as compared with control subjects (65.2+/-12.4%). A multiple logistic regression analysis identified male sex (odds ratio [OR] 2. 3, P=0.02), age (OR 3.6, P<0.005), and the presence of lacunar infarction on magnetic resonance imaging (OR 5.3, P<0.001) as significant and independent factors associated with a reduction of CVR. Moreover, a cut-point of 55.6% (sensitivity 67%, specificity 82%) was established as the threshold value for distinguishing between pathological and normal CVR. CVR was significantly (P=0.02) lower in patients with multiple (46.38+/-12.6%) than with single (54. 83+/-11.58%) lacunar infarction. In addition, a trend of negative correlation was found between CVR and the number of lacunar infarctions (r=-0.26, P=0.08). In the multiple logistic model, history of hypertension (OR 7.24; 95% confidence interval 2.95 to 17. 79) and CVR (OR 0.8; 95% confidence interval 0.81 to 0.93) emerge as significant and independent predictors of first-ever lacunar infarction.



These data suggest that impaired CVR is a risk marker for first-ever lacunar infarction.