Reinforcing rigor and reproducibility expectations for use of sex and gender in cardiovascular research

Lindsey, Merry L.; LeBlanc, Amanda J.; Ripplinger, Crystal M.; Carter, Jason R.; Kirk, Jonathan A.; Keehan, Kara Hansell; Brunt, Keith R.; Kleinbongard, Petra; Kassiri, Zamaneh

doi:10.1152/ajpheart.00418.2021

Cited by 63 publications

(21 citation statements)

References 71 publications

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“…Inclusion of both sexes is vital to a full understanding of the roles of NO, Hb, Hct, and viscosity in CBF regulation and for physiological research generally. 81 Thus the results of the current study cannot be extrapolated to females and future research is needed to address this limitation. 81 Abundant opportunities are available for future research regarding this matter to assess possible sex-related differences, the influence of androgens and estrogens, across the female menstrual cycle, pre versus post menopause, and pre versus post puberty.…”

Section: Discussionmentioning

confidence: 88%

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

Carr

Ainslie

MacLeod

et al. 2022

J Cereb Blood Flow Metab

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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.

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Section: Discussionmentioning

confidence: 88%

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

Carr

Ainslie

MacLeod

et al. 2022

J Cereb Blood Flow Metab

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“…However, oestrogen may increase NO-related signalling (Hisamoto et al 2001;Florian et al 2004) and this could impact the contribution of NO to CVR at different stages of the menstrual cycle in females. Thus, the results of the current study cannot be extrapolated to females and future research is needed to address this limitation (Lindsey et al 2021).…”

Section: Discussionmentioning

confidence: 91%

“…Thus, the results of the current study cannot be extrapolated to females and future research is needed to address this limitation (Lindsey et al . 2021).…”

Section: Discussionmentioning

confidence: 99%

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

Hoiland

Caldwell

Carr

et al. 2021

The Journal of Physiology

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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 PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$. 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 ± 34.2 nM; P = 0.03). The steady‐state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCnormalO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. −1.8 ± 8.2 nM/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 ± 12.1 ml/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.

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“…Consequently, women were not studied because it was not possible to adequately control for menstrual phase or attain the sample size requirements needed to account for sex‐based differences during this window of experimentation. However, we strongly advocate full representation in future experimental designs (Lindsey et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia‐induced sympathetic long‐term facilitation

Shafer

Incognito

Vermeulen

et al. 2022

The Journal of Physiology

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Columbia Okanagan in Canada and is mentored by Dr Glen Foster. She is currently investigating neurovascular reflex regulation of arterial blood pressure in response to homeostatic disturbances in oxygen tension. In the future, she aims to continue her research on sympathetic discharge properties and blood pressure governing mechanisms, particularly as it pertains to hypertension development in patients with obstructive sleep apnoea.

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Reinforcing rigor and reproducibility expectations for use of sex and gender in cardiovascular research

Cited by 63 publications

References 71 publications

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

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

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

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia‐induced sympathetic long‐term facilitation

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Reinforcing rigor and reproducibility expectations for use of sex and gender in cardiovascular research

Cited by 63 publications

References 71 publications

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

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

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

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia‐induced sympathetic long‐term facilitation

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

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