Emma C J Hart

Sex Differences in Sympathetic Neural-Hemodynamic Balance Implications for Human Blood Pressure Regulation

Among young normotensive men, a reciprocal balance between cardiac output and sympathetic nerve activity is important in the regulation of arterial pressure. In young women, the balance among cardiac output, peripheral resistance, and sympathetic nerve activity is unknown. Consequently, the aim of this study was to examine the relationship of cardiac output and total peripheral resistance to muscle sympathetic nerve activity in young women. Multiunit peroneal recordings of muscle sympathetic nerve activity were obtained in 17 women (mean±SEM: age 24±3 years) and 21 men (mean±SEM: age 25±5 years). Mean resting muscle sympathetic nerve activity was lower in women compared with men (19±3 versus 25±1 bursts minute−1; P<0.05), as was mean arterial pressure (89±1 versus 94±2 mm Hg; P<0.05). Mean arterial pressure was not related to muscle sympathetic nerve activity in men (P=0.80) or women (P=0.62). There was a positive relationship between total peripheral resistance and muscle sympathetic nerve activity (r=0.62; P<0.05) and an inverse relationship between cardiac output and muscle sympathetic nerve activity (r=−0.69; P<0.05) in men. Unexpectedly, muscle sympathetic nerve activity had no relationship to either total peripheral resistance (r=−0.27; P>0.05) or cardiac output (r=0.23; P>0.05) in women. Our results demonstrate that men and women rely on different integrated physiological mechanisms to maintain a normal arterial pressure despite widely varying sympathetic nerve activity among individuals. These findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women.

The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases

Hypertension, heart failure (HF), type II diabetes mellitus, and chronic kidney disease represent significant and growing global health issues.1 The rates of control of blood pressure and the therapeutic efforts to prevent progression of HF, chronic kidney disease, diabetes mellitus, and their sequelae remain unsatisfactory.2–5 Although patient nonadherence and nonpersistence with medications participate in this failure, especially in asymptomatic disorders, the inherent complexity of drug titration, drug interactions, and both the real and perceived adverse events collectively contribute to the failure of lifelong polypharmacy. Furthermore, therapy targeting the potentially unique contribution of autonomic imbalance is limited by the poorly tolerated systemic adverse effects of adrenergic blocking agents. Recent introduction of medical procedures, such as renal denervation,6,7 and devices such as deep brain stimulation,8 baroreceptor stimulation,9 and direct vagus nerve stimulation10 begin to address these gaps in selective patients. The contribution of excessive sympathetic nerve activity to the development and progression of hypertension, insulin resistance, and HF has been demonstrated in both preclinical and human experiments. Preclinical experiments in models of these diseases have successfully used sympathetic or parasympathetic modifications to alter the time course of their progression.11,12 Reduction of blood pressure after dorsal rhizotomy in rats with renal hypertension and reduced total body noradrenaline and muscle sympathetic nerve activity in humans after renal denervation confirm that the afferent signals from the kidney underlie some of the excessive sympathetic drive seen in these states.13,14 However, additional afferent signals may arise from sites elsewhere in the body and in particular the carotid body (CB). We propose targeting the CB in patients with increased chemosensitivity to address the underlying autonomic imbalance seen in hypertension, HF, insulin resistance, and chronic kidney disorders. ### The CB: A Peripheral Chemosensor The CB (Figure 1), the dominant …

Sex and ageing differences in resting arterial pressure regulation: the role of the β-adrenergic receptors

Non‐Technical Summary  In young men, sympathetic nerve activity is directly related to the level of vasoconstrictor tone in the peripheral vasculature. However, in young women this relationship does not exist, suggesting that certain factors (potentially related to the female sex hormones) offset the transfer of sympathetic nerve activity into vasoconstrictor tone in this population. In the present study we show that, in young women, the β‐adrenergic receptors (which cause vasodilatation in response to noradrenaline) blunt the vasoconstrictor effect of resting sympathetic nerve activity in young women. This mechanism does not occur in young men or postmenopausal women. It is possible that the β‐adrenergic receptors may partially protect young women against the sometimes harmful effects of high sympathetic nerve activity. This may explain why the risk of developing hypertension is greater in young men and postmenopausal women (who have very high sympathetic nerve activity) compared to young women.

Carotid body removal for treatment of chronic systolic heart failure

BACKGROUND Augmented reflex response from peripheral chemoreceptors characterises chronic heart failure (CHF), contributes to autonomic imbalance and exercise intolerance and predicts poor outcome. METHODS AND RESULTS We present a case of a 56-year-old male patient with ischaemic CHF, who underwent surgical, unilateral carotid body resection to reduce peripheral chemosensitivity. At 2-month and 6-month follow-ups, we document a persistent decrease in peripheral chemosensitivity accompanied by an improvement in exercise capacity, sleep disordered breathing and quality of life. Autonomic balance was favourably affected as evidenced by improved heart rate variability and augmented cardiac baroreflex sensitivity. There were no procedure-related adverse events. CONCLUSIONS Denervation of a carotid body may offer a clinical strategy to restore autonomic balance and improve morbidity in heart failure (NCT01653821).

Sex, ageing and resting blood pressure

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 β–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 β–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.

Translational Examination of Changes in Baroreflex Function After Renal Denervation in Hypertensive Rats and Humans

Renal denervation has shown promise in the treatment of resistant hypertension, although the mechanisms underlying the blood pressure (BP) reduction remain unclear. In a translational study of spontaneously hypertensive rats (n=7, surgical denervation) and resistant hypertensive human patients (n=8; 5 men, 33–71 years), we examined the relationship among changes in BP, sympathetic nerve activity, and cardiac and sympathetic baroreflex function after renal denervation. In humans, mean systolic BP (SBP; sphygmomanometry) and muscle sympathetic nerve activity (microneurography) were unchanged at 1 and 6 months after renal denervation (P<0.05). Interestingly, 4 of 8 patients showed a 10% decrease in SBP at 6 months, but sympathetic activity did not necessarily change in parallel with SBP. In contrast, all rats showed significant and immediate decreases in telemetric SBP and lumbar sympathetic activity (P<0.05), 7 days after denervation. Despite no change in SBP, human cardiac and sympathetic baroreflex function (sequence and threshold techniques) showed improvements at 1 and 6 months after denervation, particularly through increased sympathetic baroreflex sensitivity to falling BP. This was mirrored in spontaneously hypertensive rats; cardiac and sympathetic baroreflex sensitivity (spontaneous sequence and the Oxford technique) improved 7 days after denervation. The more consistent results in rats may be because of a more complete (>90% reduction in renal norepinephrine content) denervation. We conclude that (1) renal denervation improves BP in some patients, but sympathetic activity does not always change in parallel, and (2) baroreflex sensitivity is consistently improved in animals and humans, even when SBP has not decreased. Determining procedural success will be crucial in advancing this treatment modality.

Relationship Between Muscle Sympathetic Nerve Activity and Aortic Wave Reflection Characteristics in Young Men and Women

Increased arterial stiffness is associated with higher levels of aortic wave reflection and aortic blood pressure. Recent evidence suggests a link between muscle sympathetic nerve activity and indices of arterial stiffness. Therefore, the aims of this study were to examine the relationship between resting muscle sympathetic nerve activity and characteristics of aortic pressure wave reflection and the influence of sex on these relationships. In 44 subjects (23 females and 21 males; 25±1 years of age), we measured muscle sympathetic nerve activity via peroneal microneurography. In addition, noninvasive aortic pressure waveforms were synthesized from radial pressure waveforms obtained from applanation tonometry. Aortic blood pressure, augmentation index, wave reflection amplitude, and wasted left ventricular energy were calculated. Resting sympathetic activity (bursts/100 heart beats) was not associated with any of the aortic pressure wave reflection characteristics for all patients. However, there was a positive relationship between sympathetic activity and augmentation index (r=0.46; P=0.05) in men. Further, sympathetic activity in men was related to wave reflection amplitude (r=0.53; P<0.05) and wasted left ventricular energy (r=0.57; P<0.01). In contrast to men, women demonstrated strong inverse relationships between sympathetic activity and augmentation index (r=−0.63), wave reflection amplitude (r=−0.59), and wasted left ventricular energy (r=−0.58; P<0.01 for all). Our results suggest another possible mechanism by which young women are protected against the development of cardiovascular disease.

Beta-adrenergic receptor desensitization in man

Desensitization of the β‐adrenoreceptors (β‐AR) may contribute to a post‐exercise reduction in left ventricular (LV) function. However, attenuation of the chronotropic and inotropic responses to a β‐AR agonist may depend upon alterations in parasympathetic tone. Furthermore, changes in cardiac output and LV diastolic function in response to a β‐AR agonist, pre‐ to post‐prolonged exercise, remain unclear. Seven trained males (mean ±s.d., age 27 ± 6 years) performed 4 h of ergometer rowing. Peak heart rate (HR) and LV systolic and diastolic functional responses to incremental isoproterenol (isoprenaline) infusion (2, 4 and 6 μg kg min−1) were assessed after vagal blockade (glycopyrrolate, 1.2 mg). LV systolic function was assessed by the pressure/volume ratio (systolic blood pressure/end systolic volume) and , whilst diastolic function was evaluated as peak early and late transmitral filling velocities. Following exercise, the pressure/volume ratio decreased by 25% (P < 0.05), whereas was unchanged (P > 0.05). The early/late filling ratio was reduced by 36% after exercise, due to an elevation in late LV filling (P < 0.01). The increase in HR response to isoproterenol infusion was blunted post‐exercise at both 4 and 6 μg kg min−1 (127 ± 7 and 132 ± 6 beats min−1) compared with pre‐exercise (138 ± 8 and 141 ± 12 beats min−1, P < 0.05). Additionally, the pressure/volume ratio and were blunted post‐exercise in response to isoproterenol (P < 0.05). In contrast, diastolic function was similar before and after exercise during isoproterenol infusion (P > 0.05). Desensitization of the β‐AR contributes to an attenuated left ventricular systolic but not diastolic function following prolonged exercise.

Purinergic receptors in the carotid body as a new drug target for controlling 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.

Postexercise Changes in Left Ventricular Function: The Evidence So Far

Whether prolonged exercise results in a transient depression in left ventricular (LV) function has been the focus of numerous studies since the 1960s. This review attempts to summarize the findings of this growing body of research. Understanding in this area has followed the advances in imaging techniques and specifically in echocardiographic technology. As such, the review focuses on evidence from the traditional echocardiographic technology (two-dimensional and Doppler measures), the more advanced technique of tissue Doppler imaging (TDI), and finally the assessment of myocardial strain and strain rate. Although many of the studies have adopted a similar cross-sectional pre- to postexercise design, there are often significant differences in terms of subject characteristics, exercise duration, and exercise modality. Accordingly, we draw together the common findings from this growing body of research in an attempt to reach a consensus regarding the influence of prolonged exercise on LV function.