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Female reproductive hormones exert important non-reproductive influences on autonomic regulation of body temperature and blood pressure. Estradiol and progesterone influence thermoregulation both centrally and peripherally, where estradiol tends to promote heat dissipation, and progesterone tends to promote heat conservation and higher body temperatures. Changes in thermoregulation over the course of the menstrual cycle and with hot flashes at menopause are mediated by hormonal influences on neural control of skin blood flow and sweating. The influence of estradiol is to promote vasodilation, which, in the skin, results in greater heat dissipation. In the context of blood pressure regulation, both central and peripheral hormonal influences are important as well. Peripherally, the vasodilator influence of estradiol contributes to the lower blood pressures and smaller risk of hypertension seen in young women compared to young men. This is in part due to a mechanism by which estradiol augments beta-adrenergic receptor mediated vasodilation, offsetting alpha-adrenergic vasoconstriction, and resulting in a weak relationship between muscle sympathetic nerve activity and total peripheral resistance, and between muscle sympathetic nerve activity and blood pressure. After menopause, with the loss of reproductive hormones, sympathetic nerve activity, peripheral resistance and blood pressure become more strongly related, and sympathetic nerve activity (which increases with age) becomes a more important contributor to the prevailing level of blood pressure. Continuing to increase our understanding of sex hormone influences on body temperature and blood pressure regulation will provide important insight for optimization of individualized health care for future generations of women.

A small-molecule antagonist of the P2X3 receptor reduces blood pressure in hypertensive rats via its action on the carotid body, pointing to a new drug target for treating hypertension. In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 ( P2rx3 , also known as P2x3 ) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.

Background Expanded extracellular volume (ECV) is an early marker of myocardial interstitial fibrosis in patients with hypertension. Animal studies suggest that surges in sympathetic nerve activity (SNA) might contribute more to the development of interstitial fibrosis than the resting level of SNA. The aim of this study was to investigate whether resting SNA or greater SNA reactivity to a stressor may be associated with expanded ECV in humans across a range of blood pressures. Methods This was a cross-sectional study in 19 individuals with varying levels of ambulatory systolic blood pressure (111–153 mmHg, 48 ± 13 years, 26.5 ± 2.6 kg/m 2 , n  = 10 diagnosed with hypertension and n  = 9 normotensive controls). Beat-to-beat non-invasive blood pressure (Finometer), heart rate (3-lead ECG) and muscle SNA (MSNA; peroneal microneurography) were recorded simultaneously during baseline, and throughout a cold pressor test (physiological stress), with hand immersion in 3–4 °C water. LV chamber size, wall thickness and ECV were assessed using cardiac magnetic resonance imaging. Results Resting MSNA was not associated with cardiac ECV ( B coefficient = − 0.07, 95% CI (− 0.24–0.10), P  = 0.549), but SNA reactivity to the cold pressor test was a predictor of ECV independent of daytime systolic blood pressure ( B coefficient = 0.12, 95% CI (0.05–0.20), P  = 0.007). We determined associations between ECV and MSNA variables using liner regressions, with ECV as the dependent variable. Conclusions Our findings show that SNA responses to physiological stress were predictive of ECV, whereas resting SNA was not, independent of the level of blood pressure. Thus, surges in SNA during stress might be more important in cardiac remodelling than overall resting levels of SNA. Further studies should test this hypothesis in larger cohorts.

Objectives European guidelines state left ventricular (LV) end-diastolic wall thickness (EDWT) ≥15mm suggests hypertrophic cardiomyopathy (HCM), but distinguishing from hypertensive heart disease (HHD) is challenging. We identify cardiovascular magnetic resonance (CMR) predictors of HHD over HCM when EDWT ≥15mm. Methods 2481 consecutive clinical CMRs between 2014 and 2015 were reviewed. 464 segments from 29 HCM subjects with EDWT ≥15mm but without other cardiac abnormality, hypertension or renal impairment were analyzed. 432 segments from 27 HHD subjects with EDWT ≥15mm but without concomitant cardiac pathology were analyzed. Magnitude and location of maximal EDWT, presence of late gadolinium enhancement (LGE), LV asymmetry (>1.5-fold opposing segment) and systolic anterior motion of the mitral valve (SAM) were measured. Multivariate logistic regression was performed. Significance was defined as p <0.05. Results HHD and HCM cohorts were age-/gender-matched. HHD had significantly increased indexed LV mass (110±27g/m 2 vs. 91±31g/m 2 , p =0.016) but no difference in site or magnitude of maximal EDWT. Mid-wall LGE was significantly more prevalent in HCM. Elevated indexed LVM, mid-wall LGE and absence of SAM were significant multivariate predictors of HHD, but LV asymmetry was not. Conclusions Increased indexed LV mass, absence of mid-wall LGE and absence of SAM are better CMR discriminators of HHD from HCM than EDWT ≥15mm. Key Points • Hypertrophic cardiomyopathy (HCM) is often diagnosed with end-diastolic wall thickness ≥15mm. • Hypertensive heart disease (HHD) can be difficult to distinguish from HCM. • Retrospective case-control study showed that location and magnitude of EDWT are poor discriminators. • Increased left ventricular mass and midwall fibrosis are independent predictors of HHD. • Cardiovascular magnetic resonance parameters facilitate a better discrimination between HHD and HCM.

Background It has been estimated that 20–30% of repaired aortic coarctation (CoA) patients develop hypertension, with significant cardiovascular morbidity and mortality. Vertebral artery hypoplasia (VAH) with an incomplete posterior circle of Willis (ipCoW; VAH + ipCoW) is associated with increased cerebrovascular resistance before the onset of increased sympathetic nerve activity in borderline hypertensive humans, suggesting brainstem hypoperfusion may evoke hypertension to maintain cerebral blood flow: the “selfish brain” hypothesis. We now assess the “selfish brain” in hypertension post-CoA repair. Methods Time-of-flight cardiovascular magnetic resonance angiography from 127 repaired CoA patients (34 ± 14 years, 61% male, systolic blood pressure (SBP) 138 ± 19 mmHg, diastolic blood pressure (DBP) 76 ± 11 mmHg) was compared with 33 normotensive controls (42 ± 14 years, 48% male, SBP 124 ± 10 mmHg, DBP 76 ± 8 mmHg). VAH was defined as < 2 mm and ipCoW as hypoplasia of one or both posterior communicating arteries. Results VAH + ipCoW was more prevalent in repaired CoA than controls (odds ratio: 5.8 [1.6–20.8], p  = 0.007), after controlling for age, sex and body mass index (BMI). VAH + ipCoW was an independent predictor of hypertension (odds ratio: 2.5 [1.2–5.2], p  = 0.017), after controlling for age, gender and BMI. Repaired CoA subjects with VAH + ipCoW were more likely to have difficult to treat hypertension (odds ratio: 3.3 [1.01–10.7], p  = 0.049). Neither age at time of CoA repair nor any specific repair type were significant predictors of VAH + ipCoW in univariate regression analysis. Conclusions VAH + ipCoW predicts arterial hypertension and difficult to treat hypertension in repaired CoA. It is unrelated to age at time of repair or repair type. CoA appears to be a marker of wider congenital cerebrovascular problems. Understanding the “selfish brain” in post-CoA repair may help guide management. Journal subject codes High Blood Pressure; Hypertension; Magnetic Resonance Imaging (MRI); Cardiovascular Surgery; Cerebrovascular Malformations.

Background The symptoms of long COVID, which include fatigue, breathlessness, dysregulated breathing, and exercise intolerance, have unknown mechanisms. These symptoms are also observed in heart failure and are partially driven by increased sensitivity of the carotid chemoreflex. As the carotid body has an abundance of ACE2 (the cell entry mechanism for SARS-CoV-2), we investigated whether carotid chemoreflex sensitivity was elevated in participants with long COVID. Methods Non-hositalised participants with long-COVID ( n  = 14) and controls ( n  = 14) completed hypoxic ventilatory response (HVR; the measure of carotid chemoreflex sensitivity) and cardiopulmonary exercise tests. Parametric and normally distributed data were compared using Student’s unpaired t-tests or ANOVA. Nonparametric equivalents were used where relevant. Peason’s correlation coefficient was used to examine relationships between variables. Results During cardiopulmonary exercise testing the V E /VCO 2 slope (a measure of breathing efficiency) was higher in the long COVID group (37.8 ± 4.4) compared to controls (27.7 ± 4.8, P  = 0.0003), indicating excessive hyperventilation. The HVR was increased in long COVID participants (−0.44 ± 0.23 l/min/ SpO 2 %, R 2  = 0.77 ± 0.20) compared to controls (−0.17 ± 0.13 l/min/SpO 2 %, R 2  = 0.54 ± 0.38, P  = 0.0007). The HVR correlated with the V E /VCO 2 slope ( r  = −0.53, P  = 0.0036), suggesting that excessive hyperventilation may be related to carotid body hypersensitivity. Conclusions The carotid chemoreflex is sensitised in long COVID and may explain dysregulated breathing and exercise intolerance in these participants. Tempering carotid body excitability may be a viable treatment option for long COVID patients. Plain language summary Patients with long COVID suffer from breathlessness during exercise, leading to exercise intolerance. We know that SARS-CoV-2, the virus that causes COVID-19, can infect carotid bodies which is a small sensory organ that sends signals to the brain for regulating breathing and blood pressure. This is called the carotid chemoreflex. However, it is not clear if SARS-CoV-2 infection affects carotid chemoreflex. Here, we examine whether the normal functioning of carotid chemoreflex is disrupted in non-hospitalised patients with long COVID and if this is linked to excessive breathing during exercise. Our study shows that carotid chemoreflex is more sensitive in long COVID patients, who are otherwise healthy. The carotid bodies could be a good therapeutic target for treating breathlessness in patients with long COVID. El-Medany, Adams, Blythe et al. Investigate whether the carotid chemoreflex could be a mechanism underlying unexplained breathlessness in non-hospitalised patients with long COVID. Results show that carotid chemoreflex is sensitised in patients with long COVID and may explain dysregulated breathing and exercise intolerance in these participants.

Background In 2020, 1.4 and 2.3 million new cases of prostate cancer and breast cancer respectively were diagnosed globally. In the UK, prostate cancer is the most common male cancer, while breast cancer is the most common female cancer. Engaging in physical activity (PA) is a key component of treatment. However, rates of PA are low in these clinical populations. This paper describes the protocol of CRANK-P and CRANK-B , two pilot randomised controlled trials, involving an e-cycling intervention aimed at increasing PA in individuals with prostate cancer or breast cancer respectively. Methods These two trials are single-centre, stratified, parallel-group, two-arm randomised waitlist-controlled pilot trials in which forty individuals with prostate cancer ( CRANK-P ) and forty individuals with breast cancer ( CRANK-B ) will be randomly assigned, in a 1:1 allocation ratio, to an e-cycling intervention or waitlist control. The intervention consists of e-bike training with a certified cycle instructor, followed by the provision of an e-bike for 12 weeks. Following the intervention period, participants in the e-bike condition will be directed to community-based initiatives through which they can access an e-bike. Data will be collected at baseline (T0), immediately post intervention (T1) and at 3-month follow-up (T2). In addition, in the intervention group, data will be collected during the intervention and follow-up periods. Quantitative and qualitative methods will be used. The primary objectives are to determine effective recruitment strategies, establish recruitment and consent rates, adherence and retention in the study, and determine the feasibility and acceptability of the study procedures and intervention. The potential impact of the intervention on clinical, physiological and behavioural outcomes will be assessed to examine intervention promise. Data analyses will be descriptive. Discussion The findings from these trials will provide information on trial feasibility and highlight the potential of e-cycling as a strategy to positively impact the health and behaviour of individuals with prostate cancer and breast cancer. If appropriate, this information can be used to design and deliver a fully powered definitive trial. Trial registration CRANK-B: [ISRCTN39112034]. CRANK-P [ISRCTN42852156]. Registered [08/04/2022] https://www.isrctn.com .

Sympathetic neural function is essential to human blood pressure regulation, and overactivity of sympathetic nerves may have an important role in the development of hypertension and related cardiovascular disorders. Importantly, there is extensive interindividual variability in sympathetic vasoconstrictor nerve activity, even among healthy, young, normotensive people. Therefore, the relevance of each person’s level of sympathetic nerve activity for his or her blood pressure must be evaluated in the context of other factors contributing to the overall level of blood pressure, including cardiac output and vascular adrenergic responsiveness. We include evidence showing that the balance of factors contributing to normal blood pressure in young people is influenced by sex. Hypertension itself can be multifactorial, but it is often associated with elevated sympathetic nerve activity, which can be reversed by some pharmacologic antihypertensive treatments. Although much work remains to be done in this area, an appropriate recognition of the complexity of integrated physiological regulation and of the importance of interindividual variability will be key factors in moving forward to even better understanding and treatment.

There is evidence of sympathetic overdrive in a significant proportion of patients with essential hypertension and an animal model of the condition, the spontaneously hypertensive rat (SHR). The reasons for this remain elusive. However, there is also evidence of narrowing of the arteries supplying the brainstem in the SHR and hypertensive humans. In this review, we discuss the possible role of brainstem hypoperfusion in driving increased sympathetic activity and hypertension.

ObjectiveMyocardial intracellular/extracellular structure and aortic function were assessed among hypertensive left ventricular (LV) phenotypes using cardiovascular magnetic resonance (CMR).MethodsAn observational study from consecutive tertiary hypertension clinic patients referred for CMR (1.5 T) was performed. Four LV phenotypes were defined: (1) normal with normal indexed LV mass (LVM) and LVM to volume ratio (M/V), (2) concentric remodelling with normal LVM but elevated M/V, (3) concentric LV hypertrophy (LVH) with elevated LVM but normal indexed end-diastolic volume (EDV) or (4) eccentric LVH with elevated LVM and EDV. Extracellular volume fraction was measured using T1-mapping. Circumferential strain was calculated by voxel-tracking. Aortic distensibility was derived from high-resolution aortic cines and contemporaneous blood pressure measurements.Results88 hypertensive patients (49±14 years, 57% men, systolic blood pressure (SBP): 167±30 mm Hg, diastolic blood pressure (DBP): 96±14 mm Hg) were compared with 29 age-matched/sex-matched controls (47±14 years, 59% men, SBP: 128±12 mm Hg, DBP: 79±10 mm Hg). LVH resulted from increased myocardial cell volume (eccentric LVH: 78±19 mL/m2 vs concentric LVH: 73±15 mL/m2 vs concentric remodelling: 55±9 mL/m2, p<0.05, respectively) and interstitial fibrosis (eccentric LVH: 33±10 mL/m2 vs concentric LVH: 30±10 mL/m2 vs concentricremodelling: 19±2 mL/m2, p<0.05, respectively). LVH had worst circumferential impairment (eccentric LVH: −12.8±4.6% vs concentric LVH: −15.5±3.1% vs concentric remodelling: –17.1±3.2%, p<0.05, respectively). Concentric remodelling was associated with reduced aortic distensibility, but not with large intracellular/interstitial expansion or myocardial dysfunction versus controls.ConclusionsMyocardial interstitial fibrosis varies across hypertensive LV phenotypes with functional consequences. Eccentric LVH has the most fibrosis and systolic impairment. Concentric remodelling is only associated with abnormal aortic function. Understanding these differences may help tailor future antihypertensive treatments.