Publications by authors named "Emma C Hart"

66 Publications

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

Eur Radiol 2020 Jul 10;30(7):3890-3899. Epub 2020 Mar 10.

BHI CardioNomics Research Group, Clinical Research and Imaging Centre-Bristol, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, BS8 1TD, UK.

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/m, 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/m, 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.
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http://dx.doi.org/10.1007/s00330-020-06752-6DOI Listing
July 2020

Investigation and Treatment of High Blood Pressure in Young People: Too Much Medicine or Appropriate Risk Reduction?

Hypertension 2020 01 18;75(1):16-22. Epub 2019 Nov 18.

From the Bristol Heart Institute CardioNomics Research Group, Bristol Clinical Research and Imaging Centre, School of Physiology, Pharmacology and Neuroscience, University of Bristol, United Kingdom (T.C.H., Z.H.A., R.P.B., K.A.H., J.F.R.P., E.C.H., A.K.N.).

Hypertension among young people is common, affecting 1 in 8 adults aged between 20 and 40 years. This number is likely to increase with lifestyle behaviors and lowering of hypertension diagnostic thresholds. Early-life factors influence blood pressure (BP) although the mechanisms are unclear; BP tracks strongly within individuals from adolescence through to later life. Higher BP at a young age is associated with abnormalities on heart and brain imaging and increases the likelihood of cardiovascular events by middle age. However, diagnosis rates are lower, and treatment is often delayed in young people. This reflects the lack of high-quality evidence that lowering BP in young adults improves cardiovascular outcomes later in life. In this review, we evaluate the current evidence regarding the association between BP in young adult life and adverse cardiovascular outcomes later in life. Following this, we discuss which young people with raised BP should be investigated for secondary causes of hypertension. Third, we assess the current models to assess cardiovascular risk and show a lack of validation in the younger age group. Fourth, we evaluate the evidence for lifestyle interventions in this age group and demonstrate a lack of persistence in BP lowering once the initial intervention has been delivered. Fifth, we address the pros and cons of drug treatment for raised BP in young people. Finally, there are unique life events in young people, such as pregnancy, that require specific advice on management and treatment of BP.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13820DOI Listing
January 2020

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

J Cardiovasc Magn Reson 2019 11 7;21(1):68. Epub 2019 Nov 7.

School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Science, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1186/s12968-019-0578-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839237PMC
November 2019

Cerebral Blood Flow Response to Simulated Hypovolemia in Essential Hypertension: A Magnetic Resonance Imaging Study.

Hypertension 2019 12 28;74(6):1391-1398. Epub 2019 Oct 28.

From the Faculty of Life Sciences, School of Physiology, Pharmacology and Neuroscience (S.N., Z.H.A., J.B., A.K.N., J.P., E.C.H.), University of Bristol, United Kingdom.

Hypertension is associated with raised cerebral vascular resistance and cerebrovascular remodeling. It is currently unclear whether the cerebral circulation can maintain cerebral blood flow (CBF) during reductions in cardiac output (CO) in hypertensive patients thereby avoiding hypoperfusion of the brain. We hypothesized that hypertension would impair the ability to effectively regulate CBF during simulated hypovolemia. In the present study, 39 participants (13 normotensive, 13 controlled, and 13 uncontrolled hypertensives; mean age±SD, 55±10 years) underwent lower body negative pressure (LBNP) at -20, -40, and -50 mmHg to decrease central blood volume. Phase-contrast MR angiography was used to measure flow in the basilar and internal carotid arteries, as well as the ascending aorta. CBF and CO decreased during LBNP (<0.0001). Heart rate increased during LBNP, reaching significance at -50 mmHg (<0.0001). There was no change in mean arterial pressure during LBNP (=0.3). All participants showed similar reductions in CBF (=0.3, between groups) and CO (=0.7, between groups) during LBNP. There was no difference in resting CBF between the groups (=0.36). In summary, during reductions in CO induced by hypovolemic stress, mean arterial pressure is maintained but CBF declines indicating that CBF is dependent on CO in middle-aged normotensive and hypertensive volunteers. Hypertension is not associated with impairments in the CBF response to reduced CO.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069391PMC
December 2019

Left ventricular extracellular volume fraction and atrioventricular interaction in hypertension.

Eur Radiol 2019 Mar 19;29(3):1574-1585. Epub 2018 Sep 19.

Department of Radiology, Bristol Royal Infirmary, University Bristol NHS Foundation Trust, Bristol, UK.

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/m increase in myocardial interstitial volume (standard β 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.
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http://dx.doi.org/10.1007/s00330-018-5700-zDOI Listing
March 2019

Antihypertensive Treatment Fails to Control Blood Pressure During Exercise.

Hypertension 2018 07;72(1):102-109

From the Bristol Heart Institute (BHI) CardioNomics Research Group, Clinical Research and Imaging Centre, School of Physiology, Pharmacology, Neuroscience (B.C., M.B., T.H., J.F.R.P., E.C.H.)

An exaggerated blood pressure (BP) response to maximal exercise is an independent risk factor for cardiovascular events and mortality. It is unclear whether treating BP to guideline recommended levels could normalize the rise in BP during exercise, which is mediated by the metaboreflex. We aimed to assess the BP response to incremental exercise testing and metaboreflex activation in treated-controlled hypertension (n=16), treated-uncontrolled hypertension (n=16), and untreated hypertension (n=11) and 16 control participants with normal BP (n=16). All groups were matched for age and body mass index. BP was measured during an incremental Vo peak test on a cycle ergometer and during metaboreflex isolation using postexercise ischemia. Data were analyzed using 2-way ANOVA with Tukey test for multiple comparisons. Aerobic fitness was similar among groups (=0.97). The rise in absolute systolic BP from baseline at peak exercise was similar in controlled, uncontrolled, and untreated hypertension but greater compared with normotensive controls (Δ71±3, 81±7, 79±8.5 versus 47±5 mm Hg; =0.0001). Metaboreflex sensitivity was also similar in controlled, uncontrolled, and untreated hypertension but augmented compared with normotensive controls (Δsystolic BP: 21±2, 28±2, 25±3 versus 12±2 mm Hg; <0.0001). An amplified pressor response to exercise occurred in patients taking antihypertensive medication, despite having controlled BP at rest and was potentially caused (in part) by enhanced metaboreflex sensitivity. Poor BP control during exercise, partially mediated by the metaboreflex, may contribute to the heightened risk of an adverse cardiovascular event even in treated-controlled patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11076DOI Listing
July 2018

Noctural dipping status and left ventricular hypertrophy: A cardiac magnetic resonance imaging study.

J Clin Hypertens (Greenwich) 2018 04 8;20(4):784-793. Epub 2018 Mar 8.

NIHR Bristol Cardiovascular Biomedical Research Unit, Cardiac Magnetic Resonance Department, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

We investigate the impact of dipper status on cardiac structure with cardiovascular magnetic resonance (CMR). Ambulatory blood pressure monitoring and 1.5T CMR were performed in 99 tertiary hypertension clinic patients. Subgroup analysis by extreme dipper (n = 9), dipper (n = 39), non-dipper (n = 35) and reverse dipper (n = 16) status was performed, matched in age, gender and BMI. Left ventricular (LV) mass was significantly higher for extreme dippers than dippers after correction for covariates (100 ± 6 g/m vs 79 ± 3 g/m , P = .004). Amongst extreme dippers and dippers (n = 48), indexed LV mass correlated positively with the extent of nocturnal blood pressure dipping (R = .403, P = .005). On post-hoc ANCOVA, the percentage of nocturnal dip had significant effect on indexed LV mass (P = .008), but overall SBP did not (P = .348). In the tertiary setting, we found a larger nocturnal BP drop was associated with more LV hypertrophy. If confirmed in larger studies, this may have implications on nocturnal dosing of anti-hypertensive medications.
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http://dx.doi.org/10.1111/jch.13235DOI Listing
April 2018

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

Clin Auton Res 2017 Jun 9;27(3):149-155. Epub 2017 May 9.

Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1007/s10286-017-0420-zDOI Listing
June 2017

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

Am J Physiol Heart Circ Physiol 2017 May 31;312(5):H1031-H1051. Epub 2017 Mar 31.

Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota.

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/.
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http://dx.doi.org/10.1152/ajpheart.00703.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146303PMC
May 2017

Chronic Deep Brain Stimulation Decreases Blood Pressure and Sympathetic Nerve Activity in a Drug- and Device-Resistant Hypertensive Patient.

Hypertension 2017 04 27;69(4):522-528. Epub 2017 Feb 27.

From the School of Physiology and Pharmacology (E.L.O'C., E.C.H., J.F.R.P.), CardioNomics, Clinical Research and Imaging Centre (E.C.H., A.E.B., A.K.N., J.F.R.P.), University of Bristol, United Kingdom; Department of Neurosurgery (H.S.-W., S.J., N.K.P.), Department of Cardiology (M.P.), North Bristol NHS Trust, Southmead Hospital, United Kingdom; Department of Cardiology, Bristol Heart Institute, United Kingdom (A.E.B., A.K.N.); Institute for Clinical Pharmacology (J.T., K.H., J.J.) and Department of Nephrology (J.M., H.H.), Hannover Medical School, Germany; and Institute for Aerospace Medicine, German Center for Aerospace Medicine, Cologne, Germany (J.T., J.J.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.08972DOI Listing
April 2017

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

Clin Auton Res 2017 Jun 16;27(3):157-165. Epub 2017 Feb 16.

Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1007/s10286-017-0403-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604236PMC
June 2017

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

Am J Physiol Heart Circ Physiol 2017 Feb 6;312(2):H340-H346. Epub 2016 Dec 6.

Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, Iowa

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 ( > 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 ( < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women ( < 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 ( < 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 ( > 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. 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.
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http://dx.doi.org/10.1152/ajpheart.00447.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336574PMC
February 2017

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

J Clin Hypertens (Greenwich) 2016 11 17;18(11):1119-1127. Epub 2016 Jun 17.

Medical School, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1111/jch.12849DOI Listing
November 2016

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

JACC Basic Transl Sci 2016 Aug 29;1(5):313-324. Epub 2016 Aug 29.

School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences, University of Bristol, Bristol, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.jacbts.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063532PMC
August 2016

Comprehensive First-Line Magnetic Resonance Imaging in Hypertension: Experience From a Single-Center Tertiary Referral Clinic.

J Clin Hypertens (Greenwich) 2017 01 19;19(1):13-22. Epub 2016 Oct 19.

CardioNomics Research Group, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK.

European guidelines recommend that patients with hypertension be assessed for asymptomatic organ damage and secondary causes. The authors propose that a single magnetic resonance imaging (MRI) scan can provide comprehensive first-line imaging of patients assessed via a specialist hypertension clinic. A total of 200 patients (56% male, aged 51±15 years, office BP 168±30/96±16 mm Hg) underwent MRI of the heart, kidneys, renal arteries, adrenals and aorta. Comparisons were made with other imaging modalities where available. A total of 61% had left ventricular hypertrophy (LVH), 14% had reduced ejection fraction, and 15 patients had myocardial infarcts. Echocardiography overdiagnosed LVH in 15% of patients and missed LVH in 14%. Secondary causes were identified in 14.5% of patients: 12 adrenal masses, 10 renal artery stenoses, seven thyroid abnormalities, one aortic coarctation, one enlarged pituitary gland, one polycystic kidney disease, and one renal coloboma syndrome. This comprehensive MRI protocol is an effective method of screening for asymptomatic organ damage and secondary causes of hypertension.
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http://dx.doi.org/10.1111/jch.12920DOI Listing
January 2017

Is High Blood Pressure Self-Protection for the Brain?

Circ Res 2016 Dec 26;119(12):e140-e151. Epub 2016 Sep 26.

From the Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, United Kingdom (E.A.H.W., R.G.W.); CardioNomics Research Group, Clinical Research and Imaging Centre (J.C.L.R., A.E.B., S.N., L.E.K.R., N.E.M., A.K.N., J.F.R.P., E.C.H.) and School of Physiology, Pharmacology, and Neuroscience, Biomedical Sciences (J.C.L.R., S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.), University of Bristol, United Kingdom; University Hospitals Bristol NHS Foundation Trust, United Kingdom (S.N., L.E.K.R., Z.A., J.F.R.P., E.C.H.); Department of Radiology, University of Calgary, Canada (A.D.H.); and CAIR Program, Alberta Children's Hospital Research Institute, University of Calgary, Hotchkiss Brain Institute, Canada (A.D.H.).

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.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.309493DOI Listing
December 2016

Carotid body resection for sympathetic modulation in systolic heart failure: results from first-in-man study.

Eur J Heart Fail 2017 03 20;19(3):391-400. Epub 2016 Sep 20.

Department of Cardiology, Centre for Heart Disease, 4th Military Hospital, Wroclaw, Poland.

Aims: Augmented reflex responses from peripheral chemoreceptors, which are mainly localized in the carotid bodies (CBs), characterize patients with systolic heart failure and contribute to adrenergic hyperactivation. We investigated whether surgical resection of CBs in these patients can be performed safely to decrease sympathetic tone.

Methods And Results: We studied 10 male patients with systolic heart failure (age, 59 ± 3 years; LVEF, 27 ± 7%) who underwent unilateral right-sided CB resection (four patients) or bilateral CB resection (six patients). Primary endpoints of the study were changes in muscle sympathetic nerve activity (MSNA) and peripheral chemosensitivity measured as ventilatory response to hypoxia from baseline to 1 month post-CB resection. Safety analysis included analysis of arterial blood gas and oxygenation at night through 2 months post-procedure and adverse events assessed up to 12 months. At the 1-month visit, CB resection was associated with a significant decrease both in MSNA (86.6 ± 3.1 vs. 79.7 ± 4.2 bursts/100 beats, P = 0.03) and in peripheral chemosensitivity (1.35 ± 0.19 vs. 0.41 ± 0.17 L/min/SpO , P = 0.005). It also resulted in improved exercise tolerance. Amongst some patients with bilateral CB resection, there was a trend towards worsening of oxygen saturation at night, which in one case required therapy with non-invasive ventilation.

Conclusion: We present first-in-man evidence that CB resection in patients with systolic heart failure is associated with a decrease in sympathetic activity. A bilateral procedure may carry a risk of worsening oxygenation at night. CB modulation constitutes an interesting research avenue, but careful consideration of the balance between safety and efficacy is necessary before further clinical trials.
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http://dx.doi.org/10.1002/ejhf.641DOI Listing
March 2017

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

Nat Med 2016 10 5;22(10):1151-1159. Epub 2016 Sep 5.

School of Physiology, Pharmacology &Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1038/nm.4173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750397PMC
October 2016

Human hypertension, sympathetic activity and the selfish brain.

Authors:
Emma C Hart

Exp Physiol 2016 12;101(12):1451-1462

School of Physiology, Pharmacology and Neuroscience, Clinical Research and Imaging Centre, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1113/EP085775DOI Listing
December 2016

Evaluating the carotid bodies and renal nerves as therapeutic targets for hypertension.

Auton Neurosci 2017 05 3;204:126-130. Epub 2016 Aug 3.

Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand; School of Physiology, Pharmacology & Neuroscience, Biomedical Sciences, University of Bristol, Bristol, UK.

Despite the plethora of current treatment options, hypertension remains a difficult condition to adequately control, and there is a pressing need for novel therapeutic strategies. The carotid body has recently become the focus of considerable interest as a potential novel treatment target in essential hypertension. Herein, we appraise the current literature suggesting that the carotid body plays an important causative role to generate sympathetic overactivity and drive increases in arterial pressure, in animal models of hypertension. We also review evidence from human studies showing cardiovascular benefits to the transient inactivation, or surgical removal of carotid bodies, and evaluate the potential benefits of pre-screening to identify patients likely to respond to carotid body-targeted therapy. Finally, given that a high proportion of patients who have undergone renal nerve ablation procedures remain hypertensive, we examine whether the renal nerves are necessary for the drop in blood pressure seen with carotid body removal.
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http://dx.doi.org/10.1016/j.autneu.2016.08.002DOI Listing
May 2017

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

Eur Radiol 2017 Mar 1;27(3):1125-1135. Epub 2016 Jul 1.

NIHR Bristol Cardiovascular Biomedical Research Unit, Cardiac Magnetic Resonance Department, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol, BS2 8HW, UK.

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 vs. 91±31g/m, 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.
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http://dx.doi.org/10.1007/s00330-016-4468-2DOI Listing
March 2017

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

Eur Heart J Cardiovasc Imaging 2017 Apr;18(4):441-450

NIHR Bristol Cardiovascular Biomedical Research Unit, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol BS2 8HW, UK.

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.
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http://dx.doi.org/10.1093/ehjci/jew117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837603PMC
April 2017

Comprehensive characterisation of hypertensive heart disease left ventricular phenotypes.

Heart 2016 10 3;102(20):1671-9. Epub 2016 Jun 3.

NIHR Bristol Cardiovascular Biomedical Research Unit, Cardiac Magnetic Resonance Department, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Bristol, UK Department of Cardiology, Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

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/m(2) vs concentric LVH: 73±15 mL/m(2) vs concentric remodelling: 55±9 mL/m(2), p<0.05, respectively) and interstitial fibrosis (eccentric LVH: 33±10 mL/m(2) vs concentric LVH: 30±10 mL/m(2) vs concentricremodelling: 19±2 mL/m(2), 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.
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http://dx.doi.org/10.1136/heartjnl-2016-309576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099214PMC
October 2016

Controversies Surrounding Renal Denervation: Lessons Learned From Real-World Experience in Two United Kingdom Centers.

J Clin Hypertens (Greenwich) 2016 06 9;18(6):585-92. Epub 2016 Feb 9.

CardioNomics Research Group, Clinical Research & Imaging Centre-Bristol, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Bristol, UK.

Renal denervation (RDN) is a therapy that targets treatment-resistant hypertension (TRH). The Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity) HTN-1 and Symplicity HTN-2 trials reported response rates of >80%; however, sham-controlled Symplicity HTN-3 failed to reach its primary blood pressure (BP) outcome. The authors address the current controversies surrounding RDN, illustrated with real-world data from two centers in the United Kingdom. In this cohort, 52% of patients responded to RDN, with a 13±32 mm Hg reduction in office systolic BP (SBP) at 6 months (n=29, P=.03). Baseline office SBP and number of ablations correlated with office SBP reduction (R=-0.47, P=.01; R=-0.56, P=.002). RDN appears to be an effective treatment for some patients with TRH; however, individual responses are highly variable. Selecting patients for RDN is challenging, with only 10% (33 of 321) of the screened patients eligible for the study. Medication alterations and nonadherence confound outcomes. Adequate ablation is critical and should impact future catheter design/training. Markers of procedural success and improved patient selection parameters remain key research aims.
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http://dx.doi.org/10.1111/jch.12789DOI Listing
June 2016

Prevalence and predictors of asymmetric hypertensive heart disease: insights from cardiac and aortic function with cardiovascular magnetic resonance.

Eur Heart J Cardiovasc Imaging 2016 Dec 24;17(12):1405-1413. Epub 2015 Dec 24.

NIHR Bristol Cardiovascular Biomedical Research Unit, Cardiac Magnetic Resonance Department, Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol BS2 8HW, UK.

Aims: We sought to determine the prevalence of asymmetric hypertensive heart disease (HHD) overlapping morphologically with hypertrophic cardiomyopathy (HCM) and to determine predictors of this pattern of hypertensive remodelling.

Methods And Results: One hundred and fifty hypertensive patients underwent 1.5 T cardiovascular magnetic resonance imaging. Twenty-one patients were excluded due to concomitant cardiac pathology that may confound the hypertrophic response, e.g. myocardial infarction, moderate-severe valvular disease, or other cardiomyopathy. Asymmetric HHD was defined as a segmental wall thickness of ≥15 mm and >1.5-fold the opposing wall in ≥1 myocardial segments, measured from short-axis cine stack at end-diastole. Ambulatory blood pressure, myocardial replacement fibrosis, aortic distensibility and aortoseptal angle were investigated as predictors of asymmetric HHD by multivariate logistic regression. Out of 129 hypertensive subjects (age: 51 ± 15 years, 50% male, systolic blood pressure: 170 ± 30 mmHg, diastolic blood pressure: 97 ± 16 mmHg), asymmetric HHD occurred in 21%. Where present, maximal end-diastolic wall thickness (EDWT) was 17.8 ± 1.9 mm and located exclusively in the basal or mid septum. In asymmetric HHD, aortoseptal angle (114 ± 10° vs. 125 ± 9° vs. 123 ± 12°, P < 0.05, respectively) was significantly reduced compared to concentric left ventricular hypertrophy (LVH) and compared to no LVH, respectively. Aortic distensibility in asymmetric HHD (1.01 ± 0.60 vs. 1.83 ± 1.65 mm/mmHg × 10, P < 0.05, respectively) was significantly reduced compared to subjects with no LVH. Age (odds ratio [95th confidence interval]: 1.10 [1.02-1.18], P < 0.05) and indexed LV mass (1.09 [0.98-1.28], P < 0.0001) were significant, independent predictors of asymmetric HDD.

Conclusions: Asymmetric HHD morphologically overlapping with HCM, according to the current ESC guidelines, is common. Postulating a diagnosis of HCM on the basis of EDWT of ≥15 mm should be made with caution in the presence of arterial hypertension particular in male subjects with elevated LV mass.
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http://dx.doi.org/10.1093/ehjci/jev329DOI Listing
December 2016

The major cerebral arteries proximal to the Circle of Willis contribute to cerebrovascular resistance in humans.

J Cereb Blood Flow Metab 2016 08 20;36(8):1384-95. Epub 2015 Nov 20.

Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK

Cerebral autoregulation ensures constant cerebral blood flow during periods of increased blood pressure by increasing cerebrovascular resistance. However, whether this increase in resistance occurs at the level of major cerebral arteries as well as at the level of smaller pial arterioles is still unknown in humans. Here, we measure cerebral arterial compliance, a measure that is inversely related to cerebrovascular resistance, with our novel non-invasive magnetic resonance imaging-based measurement, which employs short inversion time pulsed arterial spin labelling to map arterial blood volume at different phases of the cardiac cycle. We investigate the differential response of the cerebrovasculature during post exercise ischemia (a stimulus which leads to increased cerebrovascular resistance because of increases in blood pressure and sympathetic outflow). During post exercise ischemia in eight normotensive men (30.4 ± 6.4 years), cerebral arterial compliance decreased in the major cerebral arteries at the level of and below the Circle of Willis, while no changes were measured in arteries above the Circle of Willis. The reduction in arterial compliance manifested as a reduction in the arterial blood volume during systole. This study provides the first evidence that in humans the major cerebral arteries may play an important role in increasing cerebrovascular resistance.
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http://dx.doi.org/10.1177/0271678X15617952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976750PMC
August 2016

Oral Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women.

Hypertension 2015 Sep 22;66(3):590-7. Epub 2015 Jun 22.

From the Department of Anesthesiology, Mayo Clinic, Rochester, MN (R.E.H., T.B.C., M.J.J., J.N.B.); School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom (E.C.H.); Thermal and Mountain Medicine Division, U.S. Army Research Institute of Environmental Medicine, Natick, MA (N.C.); Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton (J.R.C.); Institute for Exercise and Environmental Medicine at Texas Health Presbyterian Hospital Dallas, University of Texas Southwestern Medical Center (Q.F.); and Department of Human Physiology, University of Oregon, Eugene (C.T.M.).

Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ≈80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18-35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25±4 years) and women with natural menstrual cycles (n=74; 25±4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89±1 versus 85±1 mm Hg, respectively; P=0.01), although MSNA was similar in both groups (MSNA burst incidence, 16±1 versus 18±1 bursts/100 heartbeats, respectively; P=0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9±0.2 versus 4.7±0.2 L/min, respectively; P=0.47) and total peripheral resistance (19.2±0.8 versus 20.0±0.9 U, respectively; P=0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.05179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537364PMC
September 2015

Neural control of the circulation: how sex and age differences interact in humans.

Compr Physiol 2015 Jan;5(1):193-215

Thermal and Mountain Medicine Division, US Army Research Institute of Environmental Medicine, Natick, Massachusetts.

The autonomic nervous system is a key regulator of the cardiovascular system. In this review, we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked interindividual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β2-mediated vasodilation that offsets α-adrenergic vasoconstriction. These differences reflect both central sympatho-inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast postmenopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These major findings in humans are discussed in the context of differences in population-based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex-specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted.
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http://dx.doi.org/10.1002/cphy.c140005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459710PMC
January 2015

Deep brain stimulation for the treatment of resistant hypertension.

Curr Hypertens Rep 2014 Nov;16(11):493

School of Physiology & Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.

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.
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http://dx.doi.org/10.1007/s11906-014-0493-1DOI Listing
November 2014