Cerebrovascular CO2 Reactivity Research Articles

Cerebrovascular Conductance Responses to Carbon Dioxide are Attenuated by the Presence of Hypertension in Patients with Atrial Fibrillation

The cerebral vasculature is highly sensitive to carbon dioxide (CO2) and cerebrovascular CO2 reactivity (CVRCO2) is widely used to index cerebral vascular health. Some studies have shown that both atrial fibrillation (AF) and hypertension (HTN) are independently associated with reduced CVRCO2. However, it is unknown if these effects on CVRCO2 are synergistic when AF and HTN are present together. In this study we tested the hypothesis that CVRCO2 was lower in patients with both AF and HTN (AF+HTN) compared to normotensive patients with AF. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCA Vm) in AF (n=31) and AF+HTN (n=57) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). The ratio of MCA Vm and mean arterial pressure (MAP) was defined as cerebrovascular conductance index (CVCi). CVRCO2 was taken as the linear slope for MCA Vm and MCA CVCi versus PETCO2. As expected, baseline MAP was higher in AF+HTN than AF (107±9 vs. 98±9 mmHg, respectively; p<0.001). Baseline MCA Vm was numerically lower in AF+HTN than AF, but this did not reach statistical significance (50 [44-60] vs. 52 [45-63] cm.s−1, respectively; p=0.075), while baseline CVCi was lower in AF+HTN compared to AF (0.46 [0.42-0.57] vs. 0.54 [0.44-0.63] cm.s−1.mmHg−1; p<0.001). MCA Vm CVRCO2 was not different between groups (1.70 [1.47-2.19] and 1.74 [1.54-2.52] cm/s/mmHg−2 for AF+HTN and AF, respectively; p=0.221), whereas MCA CVCi CVRCO2 was 13% lower in AF+HTN compared to AF (0.013 ± 0.004 vs. 0.015 ± 0.005 cm.s.mmHg−2; p=0.047). Stepwise linear regression analysis identified that cardiac rhythm during data acquisition (AF or normal sinus rhythm) was a predictor of baseline MCA CVCi and MCA CVCi CVRCO2. In summary, our results demonstrate impaired MCA CVCi CVRCO2 in AF+HTN and suggest that the presence of HTN worsens cerebrovascular function in AF. Such cerebrovascular alterations may be important for the development of cognitive decline and diminished brain health in AF. Funding provided by Bristol-Myers Squibb/Pfizer Alliance Project Grant (CV185-481), British Heart Foundation Project Grant (PG/15/45/31579) and the National Institute of Health Research Clinical Research Network (NIHR CRN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multi-modal Magnetic Resonance Imaging to Assess Cerebrovascular Function in Atrial Fibrillation Patients

Atrial fibrillation (AF) is associated with an increased risk of cognitive decline, dementia, and stroke. Low cerebral blood flow (CBF) and low cerebrovascular carbon dioxide reactivity (CVRCO2) are associated with poor brain health outcomes. In the current study we employed magnetic resonance imaging (MRI) to quantify resting CBF and CVRCO2 in patients with AF and age-matched normal sinus rhythm (NSR) controls. We hypothesised that both resting CBF and CVRCO2 would be lower in patients with AF. Patients with AF (n=11, 65±14 years, 2 women) and NSR (n=12, 63±9 years, 7 women) underwent arterial spin labelling (ASL) at rest, and blood oxygen level-dependent (BOLD) MRI during a single-step increase in partial pressure of carbon dioxide (measured by end-tidal carbon dioxide (PETCO2)) induced by changing the fraction of inspired CO2 to 5% (21% O2, balance N2). Region of interest time courses were extracted with grey matter, middle cerebral artery, and posterior cerebral artery territory masks. CVRCO2 was defined as the percentage change (%Δ) in BOLD signal vs %Δ in PETCO2. Baseline CBF was not different between NSR and AF in grey matter (62±17 vs. 58±10 ml/min/100g, respectively; p=0.226), middle cerebral artery (59±16 vs. 56±14 ml/min/100g; p=0.361) and posterior cerebral artery (61±17 vs 53±15 ml/min/100g; p=0.138) territories. BOLD-derived CVRC02 was not different between NSR and AF groups in grey matter (0.11±0.04 vs. 0.12±0.03 %ΔBOLD/%ΔmmHg, respectively; p=0.372), middle cerebral artery (0.09±0.04 vs. 0.10±0.03 %ΔBOLD/%ΔmmHg; p=0.405) and posterior cerebral artery (0.13±0.04 vs. 0.14±0.05 %ΔBOLD/%ΔmmHg; p=0.367) territories. Collectively, these pilot data suggest that MRI-derived cerebrovascular CO2 responsiveness is not different in patients with AF and age-matched NSR controls that have similar resting CBF. Further investigations are required to extend these preliminary findings to a larger cohort to fully elucidate the effects of AF on cerebrovascular function. Support provided by the Royal Society of New Zealand Te Apārangi Marsden Fund (19-UOA-170). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of hypertension on cerebrovascular carbon dioxide reactivity in atrial fibrillation patients.

Atrial fibrillation (AF) and hypertension (HTN) are both associated with impaired cerebrovascular carbon dioxide reactivity (CVRCO2), an indicator of cerebral vasodilatory reserve. We hypothesised that CVRCO2 would be lower in patients with both AF and HTN (AF + HTN) compared to normotensive AF patients, due to an additive effect of AF and HTN on CVRCO2. Forty AF (68 ± 9 years) and fifty-seven AF + HTN (68 ± 8 years) patients underwent transcranial Doppler ultrasound measurement of middle cerebral artery blood velocity (MCA Vm) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). A cerebrovascular conductance index (CVCi) was calculated as the ratio of MCA Vm and mean arterial pressure (MAP). CVRCO2 was determined from the linear slope for MCA Vm and MCA CVCi vs PETCO2. Baseline MAP was higher in AF + HTN than AF (107 ± 9 vs. 98 ± 9 mmHg, respectively; p < 0.001), while MCA Vm was not different (AF + HTN:49.6 [44.1-69.0]; AF:51.7 [45.2-63.3] cm.s-1; p = 0.075), and CVCi was lower in AF + HTN (0.46 [0.42-0.57] vs. 0.54 [0.44-0.63] cm.s-1.mmHg-1; p < 0.001). MCA Vm CVRCO2 was not different (AF + HTN: 1.70 [1.47-2.19]; AF 1.74 [1.54-2.52] cm/s/mmHg-2; p = 0.221), while CVCi CVRCO2 was 13% lower in AF + HTN (0.013 ± 0.004 vs 0.015 ± 0.005 cm.s-1.mmHg-1; p = 0.047). Our results demonstrate blunted cerebral vasodilatory reserve (determined as MCA CVCi CVRCO2) in AF + HTN compared to AF alone. This may implicate HTN as a driver of further cerebrovascular dysfunction in AF that may be important for the development of AF-related cerebrovascular events and downstream cognitive decline. We demonstrated reduced cerebrovascular CO2 responsiveness in atrial fibrillation with hypertension (AF+HTN) vs. atrial fibrillation (AF). Furthermore, AF per se (as opposed to normal sinus rhythm) predicts reduced cerebrovascular CO2 responsiveness. Our findings suggest additional cerebrovascular dysfunction in AF+HTN vs. AF.

CO2 cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid, and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

Impaired cerebrovascular CO2 reactivity at high altitude in prematurely born adults.

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2days at high altitude (3375m), 16 young preterm-born (gestational age, 29 ± 1weeks) and 15 age-matched term-born (40 ± 0weeks) adults were exposed to two consecutive 4min bouts of hyperoxic hypercapnic conditions (3% CO2 -97% O2 ; 6% CO2 -94% O2 ), followed by two periods of voluntary hyperventilation-induced hypocapnia. We measured middle cerebral artery blood velocity, end-tidal CO2 , pulmonary ventilation, beat-by-beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term-born (+24 ± 39%, P=0.036), but not in preterm-born (-4 ± 27%, P=0.278) adults. The end-tidal CO2 , pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term-born adults (+173 ± 326%, P=0.026) but not in preterm-born adults (-21 ± 107%, P=0.572). Hypercapnic reactivity was altered at altitude only in preterm-born adults (+125 ± 144%, P<0.001). Collectively, at high altitude, term-born participants showed higher hypocapnic (P=0.012) and lower hypercapnic (P=0.020) CO2 reactivity compared with their preterm-born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm- compared with term-born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm-born adults, which might predispose these individuals to an increased risk of high-altitude illnesses. KEY POINTS: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term-born and prematurely born adults. In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction. Cardiovascular and ventilatory responses to both hypo- and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm-born adults at high altitude.

Cerebrovascular CO2 reactivity and dynamic cerebral autoregulation through the eighth decade of life and their implications for cognitive decline

Aging is accompanied by a decrease in cerebral blood flow (CBF), especially in the presence of preclinical cognitive decline. The role of cerebrovascular physiology including regulatory mechanisms of CBF in processes underlying aging and subclinical cognitive decline is, however, not fully understood. We explored changes in cerebrovascular CO2 reactivity and dynamic cerebral autoregulation (dCA) through the eighth decade of life, and their relation with early cognitive decline. After 10.9 years, twenty-eight (age, 80.0 ± 3.5 years; 46% female) out of forty-eight healthy older adults who had participated in a previous study (age at baseline, 70 ± 4 years; 42% female), underwent repeated transcranial Doppler assessments. Linear mixed-model analyses revealed small reductions in cerebrovascular CO2 reactivity with aging (−0.37%/mmHg, P = 0.041), whereas dCA was modestly enhanced (gain: −0.009 cm/s/mmHg, P = 0.038; phase: +8.9 degrees, P = 0.004). These changes were more pronounced in participants who had developed subjective memory complaints at follow-up. Our observations confirm that dCA is not impaired in aging, despite lower cerebral perfusion and cerebrovascular reactivity. Altogether, this unique longitudinal study highlights the involvement of cerebrovascular health in preclinical cognitive decline, which is of clinical relevance in the development of dementia management strategies.

Exposure to passive heat and cold stress differentially modulates cerebrovascular-CO2 responsiveness.

Heat and cold stress influence cerebral blood flow (CBF) regulatory factors (e.g., arterial CO2 partial pressure). However, it is unclear whether the CBF response to a CO2 stimulus (i.e., cerebrovascular-CO2 responsiveness) is maintained under different thermal conditions. This study aimed to compare cerebrovascular-CO2 responsiveness between normothermia, passive heat, and cold stress conditions. Sixteen participants (8 females; 25 ± 7 yr) completed two experimental sessions (randomized) comprising normothermic and either passive heat or cold stress conditions. Middle and posterior cerebral artery velocity (MCAv, PCAv) were measured during rest, hypercapnia (5% CO2 inhalation), and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 mmHg). The linear slope of the cerebral blood velocity (CBv) response to changing end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness, and cerebrovascular conductance (CVC) was used to examine responsiveness independent of blood pressure. CBv-CVC-CO2 responsiveness to hypocapnia was greater during heat stress compared with cold stress (MCA: +0.05 ± 0.08 cm/s/mmHg/mmHg, P = 0.04; PCA: +0.02 ± 0.02 cm/s/mmHg/mmHg, P = 0.002). CBv-CO2 responsiveness to hypercapnia decreased during heat stress (MCA: -0.67 ± 0.89 cm/s/mmHg, P = 0.02; PCA: -0.64 ± 0.62 cm/s/mmHg; P = 0.01) and increased during cold stress (MCA: +0.98 ± 1.33 cm/s/mmHg, P = 0.03; PCA: +1.00 ± 0.82 cm/s/mmHg; P = 0.01) compared with normothermia. However, CBv-CVC-CO2 responsiveness to hypercapnia was not different between thermal conditions (P > 0.08). Overall, passive heat, but not cold, stress challenges the maintenance of cerebral perfusion. A greater cerebrovascular responsiveness to hypocapnia during heat stress likely reduces an already impaired cerebrovascular reserve capacity and may contribute to adverse events (e.g., syncope).NEW & NOTEWORTHY This study demonstrates that thermoregulatory-driven perfusion pressure changes, from either cold or heat stress, impact cerebrovascular responsiveness to hypercapnia. Compared with cold stress, heat stress poses a greater challenge to the maintenance of cerebral perfusion during hypocapnia, challenging cerebrovascular reserve capacity while increasing cerebrovascular-CO2 responsiveness. This likely exacerbates cerebral hypoperfusion during heat stress since hyperthermia-induced hyperventilation results in hypocapnia. No regional differences in middle and posterior cerebral artery responsiveness were found with thermal stress.

The jugular venous-to-arterial difference during rebreathing and end-tidal forcing: Relationship with cerebral perfusion.

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous and arterial difference (Pjv-a CO2 )] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv-a CO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end-tidal forcing (ETF) protocols (termed: ETF-1 and ETF-2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n=9), ETF-1 (n=11) and ETF-2 (n=10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv-a CO2 difference was not abolished during rebreathing (6.2± 2.6mmHg; P<0.001), ETF-1 (9.3± 1.5mmHg; P<0.001) or ETF-2 (8.6±1.4mmHg; P<0.001). The Pjv-a CO2 difference did not change during the rebreathing protocol (-0.1±1.2mmHg; P=0.83), but was reduced during the ETF-1 (-3.9±1.1mmHg; P<0.001) and ETF-2 (-3.4±1.2mmHg; P=0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv-a CO2 difference during ETF (-0.095±0.089mmHgcm-1 s-1 ; P=0.001) but not during rebreathing (-0.028±0.045mmHg·cm-1 ·s-1 ; P=0.067). These findings suggest that, although the Pjv-a CO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2 . KEY POINTS: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue . Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow. We assessed these assumptions by measuring arterial and jugular venous bulb and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end-tidal forcing. The difference between arterial and jugular venous bulb remained present during both rebreathing and end-tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the difference during end-tidal forcing but not rebreathing. These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings.

Menstrual phase influences cerebrovascular responsiveness in females but may not affect sex differences.

Background and aims: Sex differences in the rate and occurrence of cerebrovascular diseases (e.g., stroke) indicate a role for female sex hormones (i.e., oestrogen and progesterone) in cerebrovascular function and regulation. However, it remains unclear how cerebrovascular function differs between the sexes, and between distinct phases of the menstrual cycle. This study aimed to compare cerebrovascular-CO2 responsiveness in 1) females during the early follicular (EF), ovulatory (O) and mid-luteal (ML) phases of their menstrual cycle; and 2) males compared to females during phases of lower oestrogen (EF) and higher oestrogen (O). Methods: Eleven females (25 ± 5years) complete experimental sessions in the EF (n = 11), O (n = 9) and ML (n = 11) phases of the menstrual cycle. Nine males (22 ± 3years) completed two experimental sessions, approximately 2weeks apart for comparison to females. Middle and posterior cerebral artery velocity (MCAv, PCAv) was measured at rest, during two stages of hypercapnia (2% and 5% CO2 inhalation) and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 and 24mmHg). The linear slope of the cerebral blood velocity response to changes in end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness.. Results: In females, MCAv-CO2 responsiveness to hypocapnia was lower during EF (-.78 ± .45cm/s/mmHg) when compared to the O phase (-1.17 ± .52cm/s/mmHg; p < .05) and the ML phase (-1.30 ± .82; p < .05). MCAv-CO2 responsiveness to hypercapnia and hypo-to-hypercapnia, and PCAv-CO2 responsiveness across the CO2 range were similar between menstrual phases (p ≥ .20). MCAv-CO2 responsiveness to hypo-to hypercapnia was greater in females compared to males (3.12 ± .91cm/s/mmHg vs. 2.31 ± .46cm/s/mmHg; p = .03), irrespective of menstrual phase (EF or O). Conclusion: Females during O and ML phases have an enhanced vasoconstrictive capacity of the MCA compared to the EF phase. Additionally, biological sex differences can influence cerebrovascular-CO2 responsiveness, dependent on the insonated vessel.

Cerebral O2 and CO2 transport in isovolumic haemodilution: Compensation of cerebral delivery of O2 and maintenance of cerebrovascular reactivity to CO2

This study investigated the influence of acute reductions in arterial O2 content (CaO2) via isovolumic haemodilution on global cerebral blood flow (gCBF) and cerebrovascular CO2 reactivity (CVR) in 11 healthy males (age; 28 ± 7 years: body mass index; 23 ± 2 kg/m2). Radial artery and internal jugular vein catheters provided measurement of blood pressure and gases, quantification of cerebral metabolism, cerebral CO2 washout, and trans-cerebral nitrite exchange (ozone based chemiluminescence). Prior to and following haemodilution, the partial pressure of arterial CO2 (PaCO2) was elevated with dynamic end-tidal forcing while gCBF was measured with duplex ultrasound. CVR was determined as the slope of the gCBF response and PaCO2. Replacement of ∼20% of blood volume with an equal volume of 5% human serum albumin (Alburex® 5%) reduced haemoglobin (13.8 ± 0.8 vs. 11.3 ± 0.6 g/dL; P < 0.001) and CaO2 (18.9 ± 1.0 vs 15.0 ± 0.8 mL/dL P < 0.001), elevated gCBF (+18 ± 11%; P = 0.002), preserved cerebral oxygen delivery (P = 0.49), and elevated CO2 washout (+11%; P = 0.01). The net cerebral uptake of nitrite (11.6 ± 14.0 nmol/min; P = 0.027) at baseline was abolished following haemodilution (−3.6 ± 17.9 nmol/min; P = 0.54), perhaps underpinning the conservation of CVR (61.7 ± 19.0 vs. 69.0 ± 19.2 mL/min/mmHg; P = 0.23). These findings demonstrate that the cerebrovascular responses to acute anaemia in healthy humans are sufficient to support the maintenance of CVR.

Cerebrovascular reactivity depending on rheumatoid factor and anticitrullinated protein antibody positivity in hypertensive patients with rheumatoid arthritis

Objective – to investigate cerebrovascular reactivity (CVR) depending on rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in hypertensive patients with rheumatoid arthritis (RA).Subjects and methods. A single cross-sectional study included 61 patients (mean age 59.8±7.7 years; 6 men and 55 women) with combined RA and grade 1–2 hypertension (HTN). The duration of RA was 11.2±7.4 years. The duration of HTN was 12.1±8.6 years. All patients were treated with methotrexate. RA patients were categorized into RF/ACPA seronegative and RF/ACPA seropositive subgroups. CVR was evaluated by bilateral transcranial Doppler sonography of the middle cerebral arteries (MCA) in a hyperoxic test (O2 CVR) and in a hypercapnic test (CO2 CVR). We measured MCA mean blood flow velocity (Vmn), time average maximal blood flow velocity (TAMX), peak systolic velocity (Vps) at baseline, within 2 minutes of 100% oxygen inhalation and within 3 minutes of recovery phase (hyperoxic test). We calculated the following indicators for assessing CVR: index changes of flow velocity mean (IFVm), speed modification of velocity (SMFVm) and normalized answer of reserve (NAR). Then, according to the same scheme, we performed a hypercapnic test with the inhalation of a 4% mixture of carbon dioxide with air. Values are presented as Me [Q1 ; Q3 ].Results and discussion. Hypertensive patients with RA had a decrease in response power of MCA blood flow to hyperoxia. RF-seropositive RA patients had a more pronounced decrease in the power of the response to hyperoxia compared with RF-seronegative RA patients. The values of IFVm in the hyperoxic test were –13.4 [–19.9; –0.9] versus –16.2 [–22.7; –13.4]% (р=0.0453), respectively. ACPA-seropositive RA patients had not only a more pronounced decrease in the power of the response of MCA blood flow to hyperoxia, but also a more pronounced slowdown in the response velocity of MCA blood flow to hyperoxia compared with ACPA-seronegative RA patients. The values of IFVm in the hyperoxic test were –9.74 [–15.9; 2.84] versus –20.9 [–25.0; –14.7]% (р=0.0062), the values of SMFVm were –0.05 [–0.09; 0.02] versus –0.09 [–0.20; –0.05] sm/s2 (р=0.0488) respectively. Combined RA and HTN patients had a decrease in response power of MCA blood flow to hypercapnia. However, no statistical differences were found in the state of CO2 CVR between patients with seropositive RA and seronegative RA.Conclusion. Hypertensive patients with seropositive RA have a more pronounced O2 CVR disorder in compared to seronegative RA patients.

Dynamic Cerebral Autoregulation is Intact in Chronic Kidney Disease

IntroductionChronic Kidney Disease (CKD) patients experience an elevated risk for cerebrovascular disease and neurocognitive dysfunction. One mechanism that may contribute to this heightened risk is an impairment in dynamic cerebral autoregulation; the ability of cerebral vessels to stabilize changes in cerebral blood flow during fluctuations in arterial pressure. We compared dynamic cerebral autoregulation between patients with CKD stages III‐IV, and controls (CON) without CKD matched for age, race, sex, and anti‐hypertensive medication use. We hypothesized that dynamic cerebral autoregulation would be impaired in CKD compared to CON.Methods12 CKD participants (age=63±3y, eGFR=40±3 mL/min/1.73m2), and 16 CON participants (age=58±2y), performed 2, 5‐minute bouts of repeated sit‐to‐stand maneuvers at 0.05Hz (10‐s sit, 10‐s stand) and 0.10Hz (5‐s sit, 5‐s stand) which correspond to the frequency ranges in which cerebral autoregulation is operant. The order of protocols was randomized and separated by a 5‐minute rest period. Heart rate (via ECG), arterial pressure (via finger photoplethysmography), middle cerebral artery velocity (MCAv; via transcranial Doppler ultrasonography), and end‐tidal carbon dioxide (etCO2) were measured continuously throughout both protocols. Dynamic cerebral autoregulation was characterized by performing a transfer function analysis on the mean arterial pressure‐middle cerebral artery velocity (MAP‐MCAv) relationship to derive coherence, phase, and gain. MAP‐MCAv coherence, phase, and gain were compared between groups during each of the 2 maneuvers via unpaired, 2‐tailed T‐tests.ResultsAs expected, MAP‐MCAv coherence approached 1.0 during both maneuvers (≥0.8 during 0.05Hz and ≥0.6 during 0.10Hz) with no differences between groups (P≥0.60) supporting reliability of phase and gain measures. We observed no group differences in MAP‐MCAv phase or gain during the 0.05Hz maneuver (Phase: CKD=1.4±0.09, CON=1.2±0.07, P=0.14; Gain: CKD=0.70±0.07, CON=0.75±0.05, P=0.59) suggesting no impairment in the myogenic component of cerebral autoregulation in CKD. Not all participants were able to perform the 0.10Hz maneuver due to musculoskeletal limitations, thus N=6 CKD and N=12 CON during 0.10Hz repeated sit‐to‐stand. Similarly, we observed no group differences in phase or gain measurements during the 0.10Hz maneuver (Phase: CKD=1.4±0.12, CON=1.3±0.09, P=0.35; Gain: CKD=0.69±0.08, CON=0.88±0.06, P=0.11) suggesting no impairment in the neurogenic component of cerebral autoregulation in CKD.DiscussionContrary to our hypothesis, we observed no impairment in cerebral autoregulation in CKD stages III‐IV. These findings suggest that other mechanisms likely contribute to the increased cerebrovascular disease risk observed in CKD. Future work should explore the role of other cerebrovascular regulatory mechanisms such as cerebrovascular CO2 reactivity and neurovascular coupling as potential mediators of the increased cerebrovascular disease risk exhibited in CKD.

Cerebrovascular Carbon Dioxide Reactivity with Hyperoxia and Hypoxia in Humans with Treated Hypertension

Hypertension increases the risk of cerebrovascular diseases such as stroke and dementia, but the underlying mechanisms are currently unclear. While chronic hypertension can lead to anatomical and functional adaptations within the cerebral circulation, its effect on cerebral blood flow (CBF) control remains poorly understood. We tested the hypothesis that the CBF responses to CO2 with either high or low oxygen levels are impaired in treated hypertensive patients compared to normotensive aged‐matched controls.In 14 treated hypertensive patients (age: 68±5 years, mean±SD) and 8 normotensive age‐matched controls (age: 66±6 years), we assessed cardiorespiratory and cerebrovascular variables at rest, during voluntary hyperventilation (partial pressure of end‐tidal CO2 [PETCO2] ~25 mmHg), and hyperoxic and hypoxic rebreathing. Using transcranial Doppler ultrasound and finger photoplethysmography, we measured beat‐to‐beat middle cerebral artery blood velocity (MCAv: index of CBF) and BP, respectively, while PETCO2 was assessed using a gas analyzer. Linear regression was used to determine the MCAv‐CO2 slope (i.e., cerebrovascular CO2 reactivity).At rest, mean BP was higher in the hypertensive patients (108±9 mmHg) compared to normotensive controls (93±10 mmHg, p=0.001), while MCAv (46.8±11.4 vs. 53.3±10.4 cm/s) and PETCO2 (41±4 vs. 42±3 mmHg) were not different between groups (p&lt;0.05). Hyperventilation‐induced hypocapnia elicited similar reductions in MCAv in the hypertensive and normotensive groups (Δ14.8±4.7 vs. Δ16.5±5.7 cm/s, p=0.484). Similarly, the MCAv‐CO2slope was not different between the hypertensive and normotensive groups during either hyperoxic rebreathing (1.53±1.05 vs. 1.98±0.56 cm/s/mmHg, p=0.320) or hypoxic rebreathing (1.94±1.04 vs. 2.21±1.13 cm/s/mmHg, p=0.815).These preliminary findings indicate that in treated hypertensive patients, the MCAv responses to hypocapnia, and hypercapnia administrated with either high or low oxygen levels, do not differ from that observed in age‐matched normotensive controls.

Site-specific different dynamic cerebral autoregulation and cerebrovascular response to carbon dioxide in posterior cerebral circulation during isometric exercise in healthy young men.

Different cerebral blood flow (CBF) responses to exercise between the posterior cerebral artery (PCA) and vertebral artery (VA) have been previously observed, though the physiological mechanisms remain unknown. There is regional heterogeneity in sympathetic innervation between the PCA and VA, which may affect CBF regulation, especially during sympathoexcitation. Thus, in the present study, we hypothesized that different CBF regulatory mechanisms between PCA and VA contribute to heterogeneous CBF responses to isometric exercise. To test this hypothesis, in thirteen healthy young men, dynamic cerebral autoregulation (CA) and cerebrovascular CO2 reactivity (CVR), were identified in each artery during a 2-min isometric handgrip (IHG) exercise at 30% of maximum voluntary contraction. Similar to previous data, PCA cerebrovascular conductance (CVC) index was decreased from rest (P<0.004), but not VA CVC during IHG exercise (P>0.084). Dynamic CA in both PCA and VA were unaltered during the IHG exercise (P=0.129). On the other hand, PCA CVR was increased during the IHG exercise (P<0.001) while VA CVR was unchanged (P=0.294). In addition, individual exercise-induced changes in end-tidal partial pressure of CO2 was related to the individual change in PCA blood velocity (P<0.046), but was not observed for VA blood flow (P>0.420). Therefore, these exercise-induced differences in CVR between PCA and VA may contribute to exercise-induced heterogeneous CBF response in the posterior cerebral circulation. These findings indicate that the site-specific posterior CBF should be considered in further research for assessing posterior cerebral circulation.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3±39.9 vs. 98.1±34.2nM; P=0.03). The steady-state CVR (20.1±11.6nM/min at baseline vs. 3.2±16.7nM/min at +9 mmHg ; P=0.017) and transient cSMD tests (3.4±5.9nM/min at baseline vs. -1.8±8.2nM/min at 120 s post-CO2 ; P=0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2±14.6 vs. 54.1±12.1ml/min/mmHg; P=0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2±4.5 vs. 6.2±5.0% dilatation; P=0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91±1.38 vs. 4.65±2.50%; P=0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.

Multi-vendor and multisite evaluation of cerebrovascular reactivity mapping using hypercapnia challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain's vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials.

The stability of cerebrovascular CO2 reactivity following attainment of physiological steady-state.

What is the central question of this study? During a steady-state cerebrovascular CO2 reactivity test, do different data extraction time points change the outcome for cerebrovascular CO2 reactivity? What is the main finding and its importance? Once steady-state end-tidal pressure of CO2 and haemodynamics were achieved, cerebral blood flow was stable, and so cerebrovascular CO2 reactivity values remained unchanged regardless of data extraction length (30 vs. 60s) and time point (at 2-5min). This study assessed cerebrovascular CO2 reactivity (CVR) and examined data extraction time points and durations with the hypotheses that: (1) there would be no difference in CVR values when calculated with cerebral blood flow (CBF) measures at different time points following the attainment of physiological steady-state, (2) once steady-state was achieved there would be no difference in CVR values derived from 60 to 30s extracted means, and (3) that changes in would not be associated with any changes in CVR. We conducted a single step iso-oxic hypercapnic CVR test using dynamic end-tidal forcing (end-tidal , +9.4 ± 0.7mmHg), and transcranial Doppler and Duplex ultrasound of middle cerebral artery (MCA) and internal carotid artery (ICA), respectively. From the second minute of hypercapnia onwards, physiological steady-state was apparent, with no subsequent changes in end-tidal , or mean arterial pressure. Therefore, CVR measured in the ICA and MCA was stable following the second minute of hypercapnia onwards. Data extraction durations of 30 or 60s did not give statistically different CVR values. No differences in CVR were detected following the second minute of hypercapnia after accounting for mean arterial pressure via calculated conductance or covariation of mean arterial pressure. These findings demonstrate that, provided the stimulus remains in a steady-state, data extracted from any minute of a CVR test during physiological steady-state conditions produce equivalent CVR values; any change in the CVR value would represent a failure of CVR mechanisms, a change in the magnitude of the stimulus, or measurement error.

Regulation of cerebral blood flow by arterial PCO2 independent of metabolic acidosis at 5050 m

We investigated the influence of arterial PCO2 (PaCO2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5,050 m. At sea level and high-altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via two days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3 - ). Total resting CBF was unchanged between trials within each altitude even though arterial pH and [HCO3 - ] (i.e., buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H+ ]/pH were consistent with the altered relationship between PaCO2 and [H+ ]/pH following ACZ at high-altitude (i.e., leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high-altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. Alterations in acid-base balance with progressive acclimatization to high-altitude have been well-established; however, how respiratory alkalosis and resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5,050 m; involving: 1) resting acid-base balance (control); 2) following metabolic acidosis via two days of oral acetazolamide at 250 mg every 8 hours (ACZ; pH: Δ -0.07±0.04 and base excess: Δ -5.7±1.9 mEq⋅l-1 , trial effects: P<0.001 and P<0.001, respectively); and 3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ+HCO3 - ; pH: Δ -0.01±0.04 and base excess: Δ -1.5±2.1 mEq⋅l-1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO2 (PaCO2 ); i.e., cerebrovascular CO2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e., Δ -3.4±2.3 mmHg PaCO2 , trial effect: P<0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high-altitude, we observed consistent leftward shifts in both the PaCO2 -pH and CBV-pH responses across the CO2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO2 was unchanged between trials at high-altitude. Taken together, following acclimatization, CO2 -mediated changes in cerebrovascular tone rather than arterial [H+ ]/pH is integral to CBF regulation at high-altitude. This article is protected by copyright. All rights reserved.

The effect of propofol-sufentanil intravenous anesthesia on systemic and cerebral circulation, cerebral autoregulation and CO2 reactivity: a case series

Background and objectivesThe aim of our study was to assess systemic and cerebral hemodynamic changes as well as cerebral CO2-reactivity during propofol anesthesia. Methods27 patients undergoing general anesthesia were enrolled. Anesthesia was maintained using the Target-Controlled Infusion (TCI) method according to the Schnider model, effect site propofol concentration of 4 μg.mL-1. Ventilatory settings (respiratory rate and tidal volume) were adjusted to reach and maintain 40, 35, and 30 mmHg EtCO2 for 5 minutes, respectively. At the end of each period, transcranial Doppler and hemodynamic parameters using applanation tonometry were recorded. ResultsSystemic mean arterial pressure significantly decreased during anesthetic induction and remained unchanged during the entire study period. Central aortic and peripherial pulse pressure did not change significantly during anesthetic induction and maintenance, whereas augmentation index as marker of arterial stiffness significantly decreased during the anesthetic induction and remained stable at the time points when target CO2 levels were reached. Both cerebral autoregulation and cerebral CO2-reactivity was maintained during propofol anesthesia. ConclusionsPropofol at clinically administered doses using the Total Intravenous Anesthesia (TIVA/TCI) technique decreases systemic blood pressure, but does not affect static cerebral autoregulation, flow-metabolism coupling and cerebrovascular CO2 reactivity. According to our measurements, propofol may exert its systemic hemodynamic effect through venodilation. Trial registrationThe study was registered at http://www.clinicaltrials.gov, identifier: NCT02203097, registration date: July 29, 2014.

Arterial carbon dioxide and bicarbonate rather than pH regulate cerebral blood flow in the setting of acute experimental metabolic alkalosis.

We investigated the influence of arterial ( ) with and without acutely elevated arterial pH and bicarbonate ([HCO3- ]) on cerebral blood flow (CBF) regulation in the internal carotid artery and vertebral artery. We assessed stepwise iso-oxic alterations in (i.e. cerebrovascular CO2 reactivity) prior to and following i.v. sodium bicarbonate infusion (NaHCO3- ) to acutely elevate arterial pH and [HCO3- ]. Total CBF was unchanged irrespective of a higher arterial pH at each matched stage of , indicating that CBF is acutely regulated by rather than arterial pH. The cerebrovascular responses to changes in arterial H+ /pH were altered in keeping with the altered relationship between and H+ /pH following NaHCO3- infusion (i.e. changes in buffering capacity). Total CBF was ∼7% higher following NaHCO3- infusion during isocapnic breathing providing initial evidence for a direct vasodilatory influence of HCO3- independent of levels. Cerebral blood flow (CBF) regulation is dependent on the integrative relationship between arterial ( ), pH and cerebrovascular tone; however, pre-clinical studies indicate that intrinsic sensitivity to pH, independent of changes in or intravascular bicarbonate ([HCO3- ]), principally influences cerebrovascular tone. Eleven healthy males completed a standardized cerebrovascular CO2 reactivity (CVR) test utilizing radial artery catheterization and Duplex ultrasound (CBF); consisting of matched stepwise iso-oxic alterations in (hypocapnia: -5, -10mmHg; hypercapnia: +5, +10 mmHg) prior to and following i.v. sodium bicarbonate (NaHCO3- ; 8.4%, 50 mEq50mL-1 ) to elevate pH (7.408±0.020 vs. 7.461±0.030; P<0.001) and [HCO3- ] (26.1±1.4 vs. 29.3±0.9 mEqL-1 ; P<0.001). Absolute CBF was not different at each stage of CO2 reactivity (P=0.629) following NaHCO3- , irrespective of a higher pH (P<0.001) at each matched stage of (P=0.927). Neither hypocapnic (3.44±0.92 vs. 3.44±1.05% permmHg ; P=0.499), nor hypercapnic (7.45±1.85 vs. 6.37±2.23% permmHg ; P=0.151) reactivity to were altered pre- to post-NaHCO3- . When indexed against arterial [H+ ], the relative hypocapnic CVR was higher (P=0.019) and hypercapnic CVR was lower (P=0.025) following NaHCO3- , respectively. These changes in reactivity to [H+ ] were, however, explained by alterations in buffering between and arterial H+ /pH consequent to NaHCO3- . Lastly, CBF was higher (688±105 vs. 732±89 mLmin-1 , 7%±12%; P=0.047) following NaHCO3- during isocapnic breathing providing support for a direct influence of HCO3- on cerebrovascular tone independent of . These data indicate that in the setting of acute metabolic alkalosis, CBF is regulated by rather than arterial pH.