Aging in females is associated with changes in respiratory modulation of sympathetic nerve activity and blood pressure.

Sympathetic nerve activity (SNA) is tightly coupled with the respiratory cycle. In healthy human males, respiratory modulation of SNA does not change with age. However, it is unclear how this modulation is affected by age in females. We investigated whether respiratory sympathetic modulation is altered in healthy postmenopausal (PMF) versus premenopausal female (YF), and younger male (YM) adults, and determined its relationship to resting blood pressure. Muscle SNA (MSNA; microneurography), respiration (transducer belt), ECG, and continuous blood pressure were measured in 12 YF, 13 PMF, and 12 YM healthy volunteers. Respiratory modulation of MSNA was quantified during two phases of the respiratory cycle: mid-late expiration and inspiration/postinspiration. All groups showed respiratory modulation of MSNA (P < 0.0005). There was an interaction between the respiratory phase and group for MSNA [bursts/100 heartbeats (HB) (P = 0.004) and bursts/min (P = 0.029)], with smaller reductions in MSNA during inspiration observed in PMF versus the other groups. Respiratory modulation of blood pressure was also reduced in PMF versus YF (6 [2] vs. 12 [9] mmHg, P = 0.008) and YM (13 [13] mmHg, P = 0.001, median [interquartile range]). The magnitude of respiratory sympathetic modulation was related to resting blood pressure in PMF only, such that individuals with less modulation had greater resting blood pressure. The data indicate that aging in postmenopausal females is associated with less inspiratory inhibition of MSNA. This correlated with a higher resting blood pressure in PMF only. Thus, the reduced modulation of MSNA could contribute to the age-related rise in blood pressure that occurs in females.NEW & NOTEWORTHY The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

Retrograde blood flow in the internal jugular veins of humans with hypertension may have implications for cerebral arterial blood flow.

OBJECTIVES: To use multi-parametric magnetic resonance imaging (MRI) to test the hypothesis that hypertensives would have higher retrograde venous blood flow (RVBF) in the internal jugular veins (IJV) vs. normotensives, and that this would inversely correlate with arterial inflow and gray matter, white matter, and cerebrospinal fluid volumes. METHODS: Following local institutional review board approval and written consent, a prospective observational 3-T MRI study of 42 hypertensive patients (53 ± 2 years, BMI 28.2 ± 0.6 kg/m2, ambulatory daytime systolic BP 148 ± 2 mmHg, ambulatory daytime diastolic BP 101 ± 2 mmHg) and 35 normotensive patients (48 ± 2 years, BMI 25.2 ± 0.8 kg/m2, ambulatory daytime systolic BP 119 ± 3 mmHg, ambulatory daytime diastolic BP 90 ± 2 mmHg) was performed. Phase contrast imaging calculated percentage retrograde venous blood flow (%RVBF), brain segmentation estimated regional brain volumes from 3D T1-weighted images, and pseudo-continuous arterial spin labeling measured regional cerebral blood perfusion. Statistical analysis included two-sample equal variance Student's T tests, two-way analysis of variance with Tukey's post hoc correction, and permutation-based two-group general linear modeling (p < 0.05). RESULTS: In the left IJV, %RVBF was higher in hypertensives (6.1 ± 1.5%) vs. normotensives (1.1 ± 0.3%, p = 0.003). In hypertensives, there was an inverse relationship of %RVBF (permutation-based general linear modeling) to cerebral blood flow in several brain regions, including the left occipital pole and the cerebellar vermis (p < 0.01). Percentage retrograde flow in the left IJV correlated inversely with the total matter volume (gray plus white matter volume) in hypertensives (r = - 0.49, p = 0.004). CONCLUSION: RVBF in the left IJV is greater in hypertensives vs. normotensives and is linked to regional hypoperfusion and brain total matter volume. KEY POINTS: • Hypertensive humans have higher retrograde cerebral venous blood flow, associated with regional brain hypoperfusion and lower tissue volume, compared with controls. • Cerebral retrograde venous blood flow may add further stress to already hypoperfused tissue in hypertensive patients. • The amount of retrograde venous blood flow in hypertensive patients may predict which patients might be at higher risk of developing cerebral pathologies.

Left ventricular extracellular volume fraction and atrioventricular interaction in hypertension.

OBJECTIVES: Left atrial enlargement (LAE) predicts cardiovascular morbidity and mortality. Impaired LA function also confers poor prognosis. This study aimed to determine whether left ventricular (LV) interstitial fibrosis is associated with LAE and LA impairment in systemic hypertension. METHODS: Following informed written consent, a prospective observational study of 86 hypertensive patients (49 ± 15 years, 53% male, office SBP 168 ± 30 mmHg, office DBP 97 ± 4 mmHg) and 20 normotensive controls (48 ± 13 years, 55% male, office SBP 130 ± 13 mmHg, office DBP 80 ± 11 mmHg) at 1.5-T cardiovascular magnetic resonance was conducted. Extracellular volume fraction (ECV) was calculated by T1-mapping. LA volume (LAV) was measured with biplane area-length method. LA reservoir, conduit and pump function were calculated with the phasic volumetric method. RESULTS: Indexed LAV correlated with indexed LV mass (R = 0.376, p < 0.0001) and ECV (R = 0.359, p = 0.001). However, ECV was the strongest significant predictor of LAE in multivariate regression analysis (odds ratio [95th confidence interval] 1.24 [1.04-1.48], p = 0.017). Indexed myocardial interstitial volume was associated with significant reductions in LA reservoir (R = -0.437, p < 0.0001) and conduit (R = -0.316, p = 0.003) but not pump (R = -0.167, p = 0.125) function. Multiple linear regression, correcting for age, gender, BMI, BP and diabetes, showed an independent decrease of 3.5% LA total emptying fraction for each 10 ml/m2 increase in myocardial interstitial volume (standard ß coefficient -3.54, p = 0.002). CONCLUSIONS: LV extracellular expansion is associated with LAE and impaired LA reservoir and conduit function. Future studies should identify if targeting diffuse LV fibrosis is beneficial in reverse remodelling of LA structural and functional pathological abnormalities in hypertension. KEY POINTS: • Left atrial enlargement (LAE) and impairment are markers of adverse prognosis in systemic hypertension but their pathophysiology is poorly understood. • Left ventricular extracellular volume fraction was the strongest independent multivariate predictor of LAE and was associated with impaired left atrial reservoir and conduit function. • LV interstitial expansion may play a central role in the pathophysiology of adverse atrioventricular interaction in systemic hypertension.

Repaired coarctation of the aorta, persistent arterial hypertension and the selfish brain.

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.

Is High Blood Pressure Self-Protection for the Brain?

RATIONALE: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients. OBJECTIVE: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. METHODS AND RESULTS: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). CONCLUSIONS: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.

Influence of sympathetic nerve activity on aortic hemodynamics and pulse wave velocity in women.

Central (aortic) blood pressure, arterial stiffness, and sympathetic nerve activity increase with age in women. However, it is unknown if the age-related increase in sympathetic activity influences aortic hemodynamics and carotid-femoral pulse wave velocity (cfPWV), an index of central aortic stiffness. The goal of this study was to determine if aortic hemodynamics and cfPWV are directly influenced by sympathetic nerve activity by measuring aortic hemodynamics, cfPWV, and muscle sympathetic nerve activity (MSNA) in women before and during autonomic ganglionic blockade with trimethaphan camsylate. We studied 12 young premenopausal (23 ± 4 yr) and 12 older postmenopausal (57 ± 3 yr) women. These women did not differ in body mass index or mean arterial pressure (P > 0.05 for both). At baseline, postmenopausal women had higher aortic pulse pressure, augmented pressure, augmentation index adjusted for a heart rate of 75 beats/min, wasted left ventricular pressure energy, and cfPWV than young women (P < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women (P < 0.05). Additionally, baseline MSNA was negatively correlated with the reductions in aortic pulse pressure, augmented pressure, and wasted left ventricular pressure energy during ganglionic blockade in postmenopausal women (P < 0.05) but not young women. Baseline MSNA was not correlated with the changes in augmentation index adjusted for a heart rate of 75 beats/min or cfPWV in either group (P > 0.05 for all). Our results suggest that some aortic hemodynamic parameters are influenced by sympathetic activity to a greater extent in older postmenopausal women than in young premenopausal women.NEW & NOTEWORTHY Autonomic ganglionic blockade results in significant decreases in multiple aortic pulse wave characteristics (e.g., augmented pressure) and central pulse wave velocity in older postmenopausal women but not in young premenopausal women. Certain aortic pulse wave parameters are negatively influenced by sympathetic activity to a greater extent in older postmenopausal women.

Recording sympathetic nerve activity in conscious humans and other mammals: guidelines and the road to standardization.

Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.

Hypertensive heart disease versus hypertrophic cardiomyopathy: multi-parametric cardiovascular magnetic resonance discriminators when end-diastolic wall thickness ≥ 15 mm.

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/m2 vs. 91±31g/m2, 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.

Autonomic control of body temperature and blood pressure: influences of female sex hormones.

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.

Neural control of blood pressure in women: differences according to age.

PURPOSE: The blood pressure "error signal" represents the difference between an individual's mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the "T50"). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause. METHODS: We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25 ± 1 years) and 12 postmenopausal women (61 ± 2 years) before and during complete autonomic blockade with trimethaphan camsylate. RESULTS: At baseline, young women had a negative error signal (-8 ± 1 versus 2 ± 1 mmHg, p < 0.001; respectively) and lower muscle sympathetic nerve activity (15 ± 1 versus 33 ± 3 bursts/min, p < 0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r = -0.725, p = 0.008) but not in young women (r = -0.337, p = 0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r = 0.886, p < 0.001; older: r = 0.870, p < 0.001). CONCLUSIONS: Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Human hypertension, sympathetic activity and the selfish brain.

NEW FINDINGS: What is the topic of this review? This review article revisits an historical hypothesis that cerebral hypoperfusion, caused by elevated cerebral vascular resistances, causes the onset of high sympathetic nerve activity and hypertension in humans. What advances does it highlight? The review article highlights new evidence indicating that congenital cerebrovascular abnormalities, namely vertebral artery hypoplasia and an incomplete posterior circle of Willis, may play a role in the onset of hypertension. Despite the harmful consequences of high blood pressure (hypertension; e.g. stroke, renal failure, dementia and even death), the underlying physiological mechanisms that cause the onset of hypertension are poorly understood. The most established finding is that hypertension occurs alongside activation of the sympathetic nervous system, yet exactly what triggers this in humans is ambiguous. This review discusses evidence for elevated sympathetic nerve activity, particularly in human hypertension, and revisits an historical theory regarding the aetiology underlying human hypertension that was proposed by Seymour Kety and John Dickinson in the 1940s-1950s. My research group hypothesizes that elevated sympathetic nerve activity and hypertension develop as a fundamental mechanism to maintain adequate cerebral blood flow, which is now termed Cushing's mechanism or the selfish brain hypothesis. Moreover, it goes against the traditional belief that high cerebrovascular resistance is a consequence of hypertension; we propose that this elevated resistance drives hypertension. This review discusses historical and new evidence in animals and humans supporting this hypothesis. In particular, unique human data indicating a higher prevalence of congenital cerebral vascular abnormalities in hypertension are considered.

Sympathetic nerve activity and peripheral vasodilator capacity in young and older men.

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 µg·100 ml(-1)·min(-1); Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men (P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP (r = -0.83 and r = -0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.

Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure.

While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1 month after CBR [median (interquartile range): age, 58.5 (56-61) years old; and ejection fraction, 32 (25-34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (91%, P < 0.05), SBP (71%, P < 0.05) and DBP slopes (59%, P = 0.07). In contrast, the HR slope remained unchanged. The dissociation between the blood pressure and HR responses after CBR shows involvement of a different chemoreceptive site(s) maintaining the response to acute hypoxia. We conclude that carotid bodies are responsible for ventilatory and blood pressure responses, while the HR response might be mediated by the aortic bodies. The significant reduction of the blood pressure response to hypoxia after CBR suggests a decrease in sympathetic tone, which is of particular clinical relevance in congestive heart failure.

Deep brain stimulation for the treatment of resistant hypertension.

Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.

Carotid body dysregulation contributes to Long COVID symptoms.

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 VE/VCO2 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/ SpO2%, R2 = 0.77 ± 0.20) compared to controls (-0.17 ± 0.13 l/min/SpO2%, R2 = 0.54 ± 0.38, P = 0.0007). The HVR correlated with the VE/VCO2 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.

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.

Chemohypersensitivity and autonomic modulation of venous capacitance in the pathophysiology of acute decompensated heart failure.

Heart failure is increasing in prevalence around the world, with hospitalization and re-hospitalization as a result of acute decompensated heart failure (ADHF) presenting a huge social and economic burden. The mechanism for this decompensation is not clear. Whilst in some cases it is due to volume expansion, over half of patients with an acute admission for ADHF did not experience an increase in total body weight. This calls into question the current treatment strategy of targeting salt and water retention in ADHF. An alternative hypothesis proposed by Fallick et al. is that an endogenous fluid shift from the splanchnic bed is implicated in ADHF, rather than an exogenous fluid gain. The hypothesis states further that this shift is triggered by an increase in sympathetic tone causing vasoconstriction in the splanchnic bed, a mechanism that can translocate blood rapidly into the effective circulating volume, generating the raised venous pressure and congestion seen in ADHF. This hypothesis encourages a new clinical paradigm which focuses on the underlying mechanisms of congestion, and highlights the importance of fluid redistribution and neurohormonal activation in its pathophysiology. In this article, we consider the concept that ADHF is attributable to episodic sympathetic hyperactivity, resulting in fluid shifts from the splanchnic bed. Chemosensitivity is a pathologic autonomic mechanism associated with mortality in patients with systolic heart failure. Tonic and episodic activity of the peripheral chemoreceptors may underlie the syndrome of acute decompensation without total body salt and water expansion. We suggest in this manuscript that chemosensitivity in response to intermittent hypoxia, such as experienced in sleep disordered breathing, may explain the intermittent sympathetic hyperactivity underlying renal sodium retention and acute volume redistribution from venous storage sites. This hypothesis provides an alternative structure to guide novel diagnostic and treatment strategies for ADHF.

Ventilatory Efficiency Is Reduced in People With Hypertension During Exercise.

Background An elevated ventilatory efficiency slope during exercise (minute ventilation/volume of expired CO2; VE/VCO2 slope) is a strong prognostic indicator in heart failure. It is elevated in people with heart failure with preserved ejection, many of whom have hypertension. However, whether the VE/VCO2 slope is also elevated in people with primary hypertension versus normotensive individuals is unknown. We hypothesize that there is a spectrum of ventilatory inefficiency in cardiovascular disease, reflecting an increasingly abnormal physiological response to exercise. The aim of this study was to evaluate the VE/VCO2 slope in patients with hypertension compared with age-, peak oxygen consumption-, and sex-matched healthy subjects. Methods and Results Ramped cardiovascular pulmonary exercise tests to peak oxygen consumption were completed on a bike ergometer in 55 patients with primary hypertension and 24 normotensive controls. The VE/VCO2 slope was assessed from the onset of exercise to peak oxygen consumption. Data were compared using unpaired Student t test. Age (mean±SD, 66±6 versus 64±6 years; P=0.18), body mass index (25.4±3.5 versus 24±2.4 kg/m2; P=0.13), and peak oxygen consumption (23.2±6.6 versus 24±7.3 mL/min per kg; P=0.64) were similar between groups. The VE/VCO2 slope was elevated in the hypertensive group versus controls (31.8±4.5 versus 28.4±3.4; P=0.002). Only 27% of the hypertensive group were classified as having a normal VE/VCO2 slope (20-30) versus 71% in the control group. Conclusions Ventilatory efficiency is impaired people with hypertension without a diagnosis of heart failure versus normotensive individuals. Future research needs to establish whether those patients with hypertension with elevated VE/VCO2 slopes are at risk of developing future heart failure.

Study protocol for two pilot randomised controlled trials aimed at increasing physical activity using electrically assisted bicycles to enhance prostate or breast cancer survival.

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 .

Sex, ageing and resting blood pressure: gaining insights from the integrated balance of neural and haemodynamic factors.

Young women tend to have lower blood pressure, and less risk of hypertension, compared to young men. As people age, both blood pressure and the risk of hypertension increase in both sexes; this occurs most strikingly in women after menopause. However, the mechanisms for these influences of sex and age remain incompletely understood. In this review we are specifically interested in the interaction between neural (sympathetic nerve activity; SNA) and haemodynamic factors (cardiac output, blood pressure and vascular resistance) and how these change with sex and age. While peripheral vascular SNA can vary 7- to 10-fold among normotensive young men and women, it is reproducible in a given individual. Surprisingly, higher levels of SNA are not associated with higher blood pressures in these groups. In young men, high SNA is associated with higher total peripheral vascular resistance (TPR), and appears to be balanced by lower cardiac output and less peripheral vascular responsiveness to adrenergic stimulation. Young women do not exhibit the SNA-TPR relationship. Recent evidence suggests that ß-adrenergic vasodilatation offsets the vasoconstrictor effects of α-adrenergic vasoconstriction in young women, which may contribute to the generally lower blood pressures in this group. Sympathetic nerve activity increases with age, and in groups over 40, levels of SNA are more tightly linked to levels of blood pressure. The potentially protective ß-adrenergic effect seen in young women appears to be lost after menopause and probably contributes to the increased blood pressure and increased risk of hypertension seen in older women.

Influence of age and sex on the pressor response following a spontaneous burst of muscle sympathetic nerve activity.

The sympathetic nervous system is critical for the beat-to-beat regulation of arterial blood pressure (BP). Although studies have examined age- and sex-related effects on BP control, findings are inconsistent and limited data are available in postmenopausal women. In addition, the majority of studies have focused on time-averaged responses without consideration for potential beat-to-beat alterations. Thus we examined whether the ability of muscle sympathetic nerve activity (MSNA) to modulate BP on a beat-to-beat basis is affected by age or sex. BP and MSNA were measured during supine rest in 40 young (20 men) and 40 older (20 men) healthy subjects. Beat-to-beat fluctuations in mean arterial pressure (MAP) were characterized for 15 cardiac cycles after each MSNA burst using signal averaging. The rise in MAP following an MSNA burst was similar between young men and women (+2.64 ± 0.3 vs. +2.57 ± 0.3 mmHg, respectively). However, the magnitude of the increase in MAP after an MSNA burst was reduced in older compared with young subjects (P < 0.05). Moreover, the attenuation of the pressor response was greater in older women (+1.20 ± 0.1 mmHg) compared with older men (+1.72 ± 0.2 mmHg; P < 0.05). Interestingly, in all groups, MAP consistently decreased after cardiac cycles without MSNA bursts (nonbursts) with the magnitude of fall greatest in older men. In summary, healthy aging is associated with an attenuated beat-to-beat increase in BP after a spontaneous MSNA burst, and this attenuation is more pronounced in postmenopausal women. Furthermore, our nonburst findings highlight the importance of sympathetic vasoconstrictor activity to maintain beat-to-beat BP, particularly in older men.