Amy E Burchell

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 …

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.

Unilateral Carotid Body Resection in Resistant Hypertension A Safety and Feasibility Trial

Summary Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Arteriovenous Anastomosis: Is This the Way to Control Hypertension?

One in 4 people will develop hypertension, and there are estimated to be ≈1 billion patients with hypertension worldwide.1 Hypertension confers an incremental cardiovascular risk; with each 20 mm Hg rise in systolic blood pressure (BP) or 10 mm Hg rise in diastolic BP >115/75 mm Hg giving a doubling in the risk of death from cardiovascular disease in adults aged 40 to 69 years.2 Financial estimates indicate that if BP could be reduced to <140/90 mm Hg, the National Health Service in the UK could save ≈£97.2 million from reduced complications such as stroke, heart failure (HF), and renal failure.3 With increasing longevity, the number of people with hypertension is predicted to reach 1.5 billion by 2025.1 Despite the availability of a plethora of medications designed to treat hypertension, nearly half remain above target BP, leaving them at risk of cardiovascular, renal, and neurological morbidity and mortality. Recently, it has been suggested that as many as 14% of patients with hypertension on medication will develop resistance to current drug therapy.4,5 Moreover, patients fail to sustain concordance to lifelong polypharmacy for numerous reasons, including real or perceived drug-related side effects or intolerance, cost, inconvenience, or lifestyle decision. Thus, there remains a substantial unmet clinical need to find new treatment strategies that efficiently enable patients to obtain target BP without side effects that exceed the estimated clinical benefits associated with attaining optimal BP control. Here, we look at the ROX Coupler, a device currently undergoing trials for the control of arterial hypertension, which proposes to fill this treatment gap by providing an immediate and sustained reduction in BP with a device using a mechanism substantially different from the current raft of devices that target the neurohumoral and sympathetic regulatory systems. The ROX Coupler creates …

Comprehensive characterisation of hypertensive heart disease left ventricular phenotypes

Objective Myocardial intracellular/extracellular structure and aortic function were assessed among hypertensive left ventricular (LV) phenotypes using cardiovascular magnetic resonance (CMR). Methods An 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. Results 88 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. Conclusions Myocardial 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.

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.

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.

ECG strain pattern in hypertension is associated with myocardial cellular expansion and diffuse interstitial fibrosis: a multi-parametric cardiac magnetic resonance study

Aims In hypertension, the presence of left ventricular (LV) strain pattern on 12-lead electrocardiogram (ECG) carries adverse cardiovascular prognosis. The underlying mechanisms are poorly understood. We investigated whether hypertensive ECG strain is associated with myocardial interstitial fibrosis and impaired myocardial strain, assessed by multi-parametric cardiac magnetic resonance (CMR). Methods and results A total of 100 hypertensive patients [50 ± 14 years, male: 58%, office systolic blood pressure (SBP): 170 ± 30 mmHg, office diastolic blood pressure (DBP): 97 ± 14 mmHg) underwent ECG and 1.5T CMR and were compared with 25 normotensive controls (46 ± 14 years, 60% male, SBP: 124 ± 8 mmHg, DBP: 76 ± 7 mmHg). Native T1 and extracellular volume fraction (ECV) were calculated with the modified look-locker inversion-recovery sequence. Myocardial strain values were estimated with voxel-tracking software. ECG strain (n = 20) was associated with significantly higher indexed LV mass (LVM) (119 ± 32 vs. 80 ± 17 g/m2, P < 0.05) and ECV (30 ± 4 vs. 27 ± 3%, P < 0.05) compared with hypertensive subjects without ECG strain (n = 80). ECG strain subjects had significantly impaired circumferential strain compared with hypertensive subjects without ECG strain and controls (−15.2 ± 4.7 vs. −17.0 ± 3.3 vs. −17.3 ± 2.4%, P < 0.05, respectively). In subgroup analysis, comparing ECG strain subjects to hypertensive subjects with elevated LVM but no ECG strain, a significantly higher ECV (30 ± 4 vs. 28 ± 3%, P < 0.05) was still observed. Indexed LVM was the only variable independently associated with ECG strain in multivariate logistic regression analysis [odds ratio (95th confidence interval): 1.07 (1.02–1.12), P < 0.05). Conclusion In hypertension, ECG strain is a marker of advanced LVH associated with increased interstitial fibrosis and associated with significant myocardial circumferential strain impairment.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control

We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test–re‐test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age‐related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti‐hypertensive medication.

The Relationship Between Left Ventricular Wall Thickness, Myocardial Shortening, and Ejection Fraction in Hypertensive Heart Disease: Insights From Cardiac Magnetic Resonance Imaging

Hypertensive heart disease is often associated with a preserved left ventricular ejection fraction despite impaired myocardial shortening. The authors investigated this paradox in 55 hypertensive patients (52±13 years, 58% male) and 32 age‐ and sex‐matched normotensive control patients (49±11 years, 56% male) who underwent cardiac magnetic resonance imaging at 1.5T. Long‐axis shortening (R=0.62), midwall fractional shortening (R=0.68), and radial strain (R=0.48) all decreased (P<.001) as end‐diastolic wall thickness increased. However, absolute wall thickening (defined as end‐systolic minus end‐diastolic wall thickness) was maintained, despite the reduced myocardial shortening. Absolute wall thickening correlated with ejection fraction (R=0.70, P<.0001). In multiple linear regression analysis, increasing wall thickness by 1 mm independently increased ejection fraction by 3.43 percentage points (adjusted β‐coefficient: 3.43 [2.60–4.26], P<.0001). Increasing end‐diastolic wall thickness augments ejection fraction through preservation of absolute wall thickening. Left ventricular ejection fraction should not be used in patients with hypertensive heart disease without correction for degree of hypertrophy.