Publications by authors named "Revathy Carnagarin"

47 Publications

Role of the sympathetic nervous system in cardiometabolic control: implications for targeted multiorgan neuromodulation approaches.

J Hypertens 2021 Mar 3. Epub 2021 Mar 3.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia, Perth, Western Australia Department of Radiology, Alfred Hospital Department of Surgery, Central Clinical School, Monash University, Melbourne, Victoria Medical School, The University of Western Australia, Perth, Western Australia Baker Heart and Diabetes Institute, Melbourne, Victoria Department of Endocrinology, Medical School, The University of Western Australia Department of Radiology, Royal Perth Hospital, Perth, Western Australia Human Neurotransmitter Lab Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia.

Sympathetic overdrive plays a key role in the perturbation of cardiometabolic homeostasis. Diet-induced and exercise-induced weight loss remains a key strategy to combat metabolic disorders, but is often difficult to achieve. Current pharmacological approaches result in variable responses in different patient cohorts and long-term efficacy may be limited by medication intolerance and nonadherence. A clinical need exists for complementary therapies to curb the burden of cardiometabolic diseases. One such approach may include interventional sympathetic neuromodulation of organs relevant to cardiometabolic control. The experience from catheter-based renal denervation studies clearly demonstrates the feasibility, safety and efficacy of such an approach. In analogy, denervation of the common hepatic artery is now feasible in humans and may prove to be similarly useful in modulating sympathetic overdrive directed towards the liver, pancreas and duodenum. Such a targeted multiorgan neuromodulation strategy may beneficially influence multiple aspects of the cardiometabolic disease continuum offering a holistic approach.
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http://dx.doi.org/10.1097/HJH.0000000000002839DOI Listing
March 2021

Combined renal and common hepatic artery denervation as a novel approach to reduce cardiometabolic risk: technical approach, feasibility and safety in a pre-clinical model.

Clin Res Cardiol 2021 Feb 26. Epub 2021 Feb 26.

Dobney Hypertension Centre, Faculty of Medicine, School of Medicine-Royal Perth Hospital Unit, Dentistry and Health Sciences, The University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

Background: Cardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease.

Objectives: We aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up.

Methods: Five Yorkshire cross pigs underwent combined percutaneous denervation in the renal arteries and the common hepatic artery (CHA) with the iRF Denervation System. Control animals (n = 3) were also studied. Specific energy doses were administered in the renal arteries and CHA. Blood was collected at 30 and 90 days. All animals had a pre-terminal procedure angiography. Tissue samples were collected for norepinephrine (NEPI) bioanalysis. Histopathological evaluation of collateral structures and tissues near the treatment sites was performed to assess treatment safety.

Results: All animals entered and exited the study in good health. No stenosis or vessel abnormalities were present. No significant changes in serum chemistry occurred. NEPI concentrations were significantly reduced in the liver (- 88%, p = 0.005), kidneys (- 78%, p < 0.001), pancreas (- 78%, p = 0.018) and duodenum (- 95%, p = 0.028) following multi-organ denervation treatment compared to control animals. Histologic findings were consistent with favourable tissue responses at 90 days follow-up.

Conclusions: Significant and sustained denervation of the treated organs was achieved at 90 days without major safety events. Our findings demonstrate the feasibility of multi-organ denervation using a novel iRF Denervation System in a single procedure.
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http://dx.doi.org/10.1007/s00392-021-01814-1DOI Listing
February 2021

Increased pulse wave velocity in patients with an orthostatic blood pressure rise independent of other cardiovascular risk factors.

J Hypertens 2021 Jan 19. Epub 2021 Jan 19.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia, Perth, Western Australia, Australia Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Western Australia Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Background: Positional changes in blood pressure (BP) have been shown to have effects on long-term outcomes. Although a BP drop with upright posture is frequently observed, an orthostatic rise in BP can also occur. Here, we aimed to investigate whether the phenotype of orthostatic hypertension is associated with more pronounced vascular hypertension-mediated organ damage (HMOD) and whether this is associated with other cardiovascular risk factors.

Methods: In a cohort of 200 patients referred to our tertiary hypertension clinic, we prospectively assessed unattended seated automated office BP and the response to 1 min of upright posture. The difference in BP after standing up was calculated and pulse wave velocity (PWV) was assessed as a marker of vascular HMOD. Routine clinical cardiovascular risk markers were also assessed. Regression models were used to assess the association between orthostatic BP changes and pulse wave velocity.

Results: Baseline characteristics and clinic cardiovascular risk factors were similar between orthostatic BP response groups. A U-shaped association was evident between PWV and orthostatic BP changes with elevated PWV in patients with either a fall or a rise in BP in response to upright posture. The regression models remained significant after adjusting for other cardiovascular risk factors, including 24 h ambulatory BP.

Conclusion: Both an orthostatic BP drop and rise were associated with elevated PWV. Although standing BP is commonly measured in elderly hypertensive patients to exclude significant orthostatic hypotension, this simple measurement may provide an additional independent risk factor for vascular HMOD at any age.
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http://dx.doi.org/10.1097/HJH.0000000000002787DOI Listing
January 2021

Retinal capillary rarefaction is associated with arterial and kidney damage in hypertension.

Sci Rep 2021 Jan 13;11(1):1001. Epub 2021 Jan 13.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Perth, Australia.

Microvascular disease and rarefaction are key pathological hallmarks of hypertension. The retina uniquely allows direct, non-invasive investigation of the microvasculature. Recently developed optical coherence tomography angiography now allows investigation of the fine retinal capillaries, which may provide a superior marker of overall vascular damage. This was a prospective cross-sectional study to collect retinal capillary density data on 300 normal eyes from 150 hypertensive adults, and to investigate possible associations with other organ damage markers. The average age of participants was 54 years and there was a greater proportion of males (85; 57%) than females. Multivariate, confounder adjusted linear regression showed that retinal capillary rarefaction in the parafovea was associated with increased pulse wave velocity (β = - 0.4, P = 0.04), log-albumin/creatinine ratio (β = - 0.71, P = 0.003), and with reduced estimated glomerular filtration rate (β = 0.04, P = 0.02). Comparable significant associations were also found for whole-image vascular-density, for foveal vascular-density significant associations were found with pulse wave velocity and estimated glomerular filtration rate only. Our results indicate that retinal capillary rarefaction is associated with arterial stiffness and impaired kidney function. Retinal capillary rarefaction may represent a useful and simple test to assess the integrated burden of hypertension on the microvasculature irrespective of current blood pressure levels.
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http://dx.doi.org/10.1038/s41598-020-79594-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806760PMC
January 2021

Microvascular changes at different stages of chronic kidney disease.

J Clin Hypertens (Greenwich) 2021 Feb 19;23(2):309-316. Epub 2020 Dec 19.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Perth, WA, Australia.

Patients with progressing chronic kidney disease (CKD) are more likely to experience cardio- and cerebrovascular events than progressing to end-stage renal disease. The authors explored whether retinal microvascular calibers differed with the degree of renal impairment and between the standard and extended optic disk and may serve as a simple additional tool for risk stratification in this highly vulnerable patient cohort. The authors analyzed central retinal arteriolar and venular equivalent calibers (CRAE, CRVE) at different retinal zones (zone B&C) using digital retinal imaging in hypertensive patients with stage 2 (n = 66) or stage 3 CKD (n = 30). Results were adjusted for age, sex, HbA1c, and 24-hour diastolic blood pressure. Mean eGFR was 77.7 ± 8.9 and 48.8 ± 7.9 ml/min/1.73 m for stage 2 and 3 CKD, respectively. CRAE and CRVE in zones B and C were significantly lower in patients with stage 3 CKD compared to patients with stage 2 CKD (CRAE-B:141.1 ± 21.4 vs. 130.5 ± 18.9 µm, p = .030; CRAE-C:137.4 ± 19.4 vs 129.2 ± 18.2 µm, p = .049; CRVE-B:220.8 ± 33.0 vs. 206.0 ± 28.4 µm, p = .004; and CRVE-C:215.9 ± 33.0 vs. 201.2 ± 25.1µm, p = .003). In patients with stage 2 CKD, CRAE-B was higher than CRAE-C (141.1 ± 21.4 vs. 137.4 ± 19.4µm, p < .001). In contrast, such a difference was not found in patients with stage 3 CKD. CRAE of both retinal zones correlated with eGFR for the entire cohort. In patients with stage 3 CKD, retinal narrowing is more pronounced compared to patients with stage 2 CKD. Whether the novel observation of difference in arteriolar caliber between zones B and C in stage 2 CKD could serve as an early marker of CKD progression warrants further investigation.
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http://dx.doi.org/10.1111/jch.14138DOI Listing
February 2021

Supine blood pressure-A clinically relevant determinant of vascular target organ damage in hypertensive patients.

J Clin Hypertens (Greenwich) 2021 Jan 3;23(1):44-52. Epub 2020 Dec 3.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia, Perth, WA, Australia.

Night-time blood pressure (BP) is an important predictor of cardiovascular outcomes. Its assessment, however, remains challenging due to limited accessibility to ambulatory BP devices in many settings, costs, and other factors. We hypothesized that BP measured in a supine position during daytime may perform similarly to night-time BP when modeling their association with vascular hypertension-mediated organ damage (HMOD). Data from 165 hypertensive patients were used who as part of their routine clinic workup had a series of standardized BP measurements including seated attended office, seated and supine unattended office, and ambulatory BP monitoring. HMOD was determined by assessment of kidney function and pulse wave velocity. Correlation analysis was carried out, and univariate and multivariate models were fitted to assess the extent of shared variance between the BP modalities and their individual and shared contribution to HMOD variables. Of all standard non-24-hour systolic BP assessments, supine systolic BP shared the highest degree of variance with systolic night-time BP. In univariate analysis, both systolic supine and night-time BP were strong determinants of HMOD variables. In multivariate models, supine BP outperformed night-time BP as the most significant determinant of HMOD. These findings indicate that supine BP may not only be a clinically useful surrogate for night-time BP when ambulatory BP monitoring is not available, but also highlights the possibility that unattended supine BP may be more closely related to HMOD than other BP measurement modalities, a proposition that requires further investigations in prospective studies.
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http://dx.doi.org/10.1111/jch.14114DOI Listing
January 2021

Vascular compression of the rostral ventrolateral medulla: a relevant indicator of sympathetically driven blood pressure variability?

J Hypertens 2020 12;38(12):2380-2381

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Western Australia.

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http://dx.doi.org/10.1097/HJH.0000000000002646DOI Listing
December 2020

Interventional Approaches for Loin Pain Hematuria Syndrome and Kidney-Related Pain Syndromes.

Curr Hypertens Rep 2020 10 31;22(12):103. Epub 2020 Oct 31.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

Purpose Of Review: Loin pain hematuria syndrome (LPHS) frequently presents with severe chronic pain that poses a clinical challenge. Current treatment approaches are mostly empirical and include a wide range of therapeutic strategies such as physical therapy, local and systemic analgesia, interventional and surgical approaches usually flanked by psycho-behavioral therapy, and other strategies. LPHS often impacts negatively on quality of life particularly in patients who are refractory to treatment.

Recent Findings: With recent advances in catheter-based treatment approaches and better understanding of the pathophysiology of LPHS, intraluminal renal denervation (RDN) has been proposed as a valuable treatment option for kidney-related pain syndromes. The present review provides a brief overview of the clinical challenges associated with LPHS, highlights recent insights into its underlying mechanisms, and summarizes currently available data on the use of RDN in the context of LPHS and kidney-related pain syndromes. Renal denervation via various approaches including surgical and catheter-based techniques has shown promise in alleviating kidney-related pain syndromes. Randomized controlled trials are now required to better define its role in the management of these conditions.
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http://dx.doi.org/10.1007/s11906-020-01110-9DOI Listing
October 2020

Nocturnal hypertension: a common phenotype in a tertiary clinical setting associated with increased arterial stiffness and central blood pressure.

J Hypertens 2021 Feb;39(2):250-258

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, University of Western Australia.

Objective: Although the detrimental effect of increased mean blood pressure (BP) is well established, the role of the dynamic and circadian features of BP is less well defined but may be similarly important. In this prospective analysis of hypertensive patients from a tertiary hospital hypertension clinic, we investigated whether the presence of night-time systolic hypertension is associated with more pronounced end-organ damage as assessed by measures of pulse wave analysis (PWA) and pulse wave velocity (PWV).

Methods: A cohort of 222 consecutive hypertensive patients underwent ambulatory blood pressure measurements, PWA, PWV testing and collection of routine clinical data. Group differences and group-effects of daytime and night-time hypertension on target organ damage and cardiovascular risk parameters were analysed.

Results: Nocturnal hypertension was evident in more than half of the study population. PWV, central systolic, mean arterial and pulse pressure were higher in patients with nocturnal hypertension. Stratification into four groups according to daytime and night-time hypertension status revealed group differences in all outcome parameters. Posthoc testing for individual group differences demonstrated significant differences between fully controlled individuals and the group with high daytime and night-time BP. In a regression analysis for independent effects of categorical night-time and daytime hypertension, nocturnal hypertension was a significant predictor for all PWA and PWV outcomes.

Conclusion: Nocturnal hypertension was a highly prevalent phenotype in this population and associated with increased central BP and more pronounced target organ damage as indicated by elevated PWV. Regression analysis confirmed the role of night-time hypertension as an independent explanatory variable for elevated PWV.
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http://dx.doi.org/10.1097/HJH.0000000000002620DOI Listing
February 2021

Sympathetic hyperactivity after coronary artery bypass graft surgery: an important player in the development of postoperative atrial fibrillation?

Europace 2021 Jan;23(1):158

Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA 6000, Australia.

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http://dx.doi.org/10.1093/europace/euaa285DOI Listing
January 2021

May Measurement Month 2018: an analysis of blood pressure screening results from Australia.

Eur Heart J Suppl 2020 Aug 28;22(Suppl H):H17-H19. Epub 2020 Aug 28.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

May Measurement Month (MMM), originally initiated as a temporary solution to address the lack of blood pressure (BP) screening programs worldwide, emerged as an effective annual campaign to increase the awareness of hypertension. MMM18, a cross-sectional survey of volunteers aged ≥18 years was carried out during May 2018 predominantly in capital cities across Australia following the standard MMM protocol. Blood pressure screening along with additional information including anthropometric data and responses to questionnaires on demographic, lifestyle, and environmental factors were collected from 3 352 individuals across Australia. After multiple imputation, 1 026 (30.6%) adult Australians had hypertension. Of the 2 936 individuals not on antihypertensive treatment, 610 (20.8%) were hypertensive, and 237 (57.1%) of the 416 individuals receiving antihypertensive treatment had uncontrolled BP. In line with MMM17 results and other previous surveys, MMM18 revealed that close to one-third of the screened population (30.6%) had hypertension, 57.1% of individuals treated with BP-lowering medication remained uncontrolled indicating suboptimal management of the condition in the majority of patients. Most importantly, only 49.0% of those with hypertension were aware of their elevated BP, highlighting lack of awareness of elevated BP in nearly half of the affected population. Elevated BP was directly associated with alcohol consumption, overweight, and obesity. Our findings demonstrate the need for (i) continued efforts to increase BP awareness in the population, (ii) optimization of BP management strategies, and (iii) tackling some of the major contributors to BP elevation, including alcohol consumption and obesity.
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http://dx.doi.org/10.1093/eurheartj/suaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455264PMC
August 2020

Renal denervation as a synergistic tool for the treatment of polymorphic ventricular ectopic beats: A case report.

Medicine (Baltimore) 2020 Jul;99(29):e21098

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Crawley, Australia.

Introduction: Ventricular ectopic beats (VEBs) are very common and often occur in hypertensive or obese individuals, as well as in patients presenting with either sleep apnea or structural cardiac disease. Sympathetic overactivity plays a crucial role in the development, continuation, and exacerbation of ventricular arrhythmias. Recent studies have reported the relevance of sympathetic activation in patients with ventricular arrhythmias and suggested a potential role for catheter-based renal denervation (RDN) in reducing the arrhythmic burden.

Patient Concerns: We describe a 38-year-old female symptomatic patient that at the time of presentation was complaining of fatigue in response to minor and medium efforts and not tolerating any physical activity, and episodes of tachycardia associated with dyspnoea, pre-syncope, and syncope.

Diagnosis: She had a high incidence of polymorphic VEBs on 24-hour-Holter monitoring who also presented with left ventricular (LV) hypertrophy for which she was treated with bisoprolol 10 mg/d. The 24-hour-Holter on bisoprolol at baseline showed sinus rhythm with an average heart rate of 92 bpm. There were 44,743 isolated VEBs. A total of 2538 nonsustained ventricular tachycardia events were registered. Her cardiac magnetic resonance imaging showed an increase in LV diastolic diameter and impairment of the right ventricle.

Interventions: The patient underwent endocardial ablation of the right ventricular outflow tract and the LV free lateral wall, and concomitantly underwent bilateral RDN.

Outcomes: Three months post-procedure, her 24-hour-Holter off medication demonstrated an average heart rate 72 bpm and a substantially reduced number of 2823 isolated monomorphic VEBs. Thus far, 18-months follow-up, she has been asymptomatic and doing physical exercises.

Conclusion: In our current patient, we used RDN as a synergistic method to attenuate the sympathetic overactivity, which is narrowly linked to VEBs appearance. Our case report highlighted that RDN may become a potential adjuvant treatment for VEBs in the future.
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http://dx.doi.org/10.1097/MD.0000000000021098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373520PMC
July 2020

An evaluation of empagliflozin and it's applicability to hypertension as a therapeutic option.

Expert Opin Pharmacother 2020 Jul 17;21(10):1157-1166. Epub 2020 Apr 17.

Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, University of Western Australia , Perth, Australia.

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits.

Areas Covered: This review outlines the pharmacokinetics, pharmacodynamics, safety, and tolerability of Empagliflozin and discusses its role in diabetes-associated hypertension.

Expert Opinion: Empagliflozin was the first in class to not only demonstrate safety of SGLT2 inhibition but also cardio- and reno-protective effects in an adequately powered cardiovascular outcome trial. The EMPA-REG study showed significant reductions in mortality from cardiovascular causes, hospitalization for heart failure, and progression of diabetic kidney disease. These benefits cannot be attributed to glycemic control alone, suggesting the involvement of other SGLT2 inhibition-mediated mechanisms. Recent data suggests the potential utility of SGLT2 inhibition in other conditions including type 1 diabetes (T1D) and non-diabetic heart failure patients with clinical trials currently being conducted. In concert with ongoing pre-clinical investigations to unravel the mechanisms contributing to cardiorenal protection, the full therapeutic potential of SGLT2 inhibition will become apparent over the next few years and promises to be one of the major success stories in clinical medicine.

Abbreviations: T1D: type 1 diabetes; T2D: type 2 diabetes; SGLT2: sodium-glucose cotransporter 2; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; SNS: sympathetic nervous system; BP: blood pressure; CV: cardiovascular; ZDF: Zucker diabetic fatty; CKD: chronic kidney disease; FDA: Food and Drug Administration.
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http://dx.doi.org/10.1080/14656566.2020.1751815DOI Listing
July 2020

SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection.

JACC Basic Transl Sci 2020 Feb 29;5(2):169-179. Epub 2020 Jan 29.

Dobney Hypertension Centre, School of Biomedical Science, Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.

Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.
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http://dx.doi.org/10.1016/j.jacbts.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046513PMC
February 2020

Does sympathetic hyperactivity adversely impact on the effect of implantable cardioverter-defibrillator in patients with diabetes and non-ischaemic systolic heart failure?

Europace 2020 02;22(2):331

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western, Level 3, MRF Building, Rear 50 Murray St., Perth WA 6000, Australia.

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http://dx.doi.org/10.1093/europace/euz298DOI Listing
February 2020

The role of afferent renal denervation in renovascular hypertension-another brick in the wall.

Pflugers Arch 2020 03 5;472(3):323-324. Epub 2020 Feb 5.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

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http://dx.doi.org/10.1007/s00424-020-02354-9DOI Listing
March 2020

Sympathetic Activation in Hypertensive Chronic Kidney Disease - A Stimulus for Cardiac Arrhythmias and Sudden Cardiac Death?

Front Physiol 2019 14;10:1546. Epub 2020 Jan 14.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia.

Studies have revealed a robust and independent correlation between chronic kidney disease (CKD) and cardiovascular (CV) events, including death, heart failure, and myocardial infarction. Recent clinical trials extend this range of adverse CV events, including malignant ventricular arrhythmias and sudden cardiac death (SCD). Moreover, other studies point out that cardiac structural and electrophysiological changes are a common occurrence in this population. These processes are likely contributors to the heightened hazard of arrhythmias in CKD population and may be useful indicators to detect patients who are at a higher SCD risk. Sympathetic overactivity is associated with increased CV risk, specifically in the population with CKD, and it is a central feature of the hypertensive state, occurring early in its clinical course. Sympathetic hyperactivity is already evident at the earliest clinical stage of CKD and is directly related to the progression of renal failure, being most pronounced in those with end-stage renal disease. Sympathetic efferent and afferent neural activity in kidney failure is a crucial facilitator for the perpetuation and evolvement of the disease. Here, we will revisit the role of the feedback loop of the sympathetic neural cycle in the context of CKD and how it may aggravate several of the risk factors responsible for causing SCD. Targeting the overactive sympathetic nervous system therapeutically, either pharmacologically or with newly available device-based approaches, may prove to be a pivotal intervention to curb the substantial burden of cardiac arrhythmias and SCD in the high-risk population of patients with CKD.
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http://dx.doi.org/10.3389/fphys.2019.01546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974800PMC
January 2020

The molecular basis for the neutral effect of renal denervation in patients with chronic heart failure not responding to cardiac resynchronisation therapy - a perspective.

Postepy Kardiol Interwencyjnej 2019 8;15(4):503-504. Epub 2019 Dec 8.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Perth, Australia.

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http://dx.doi.org/10.5114/aic.2019.90231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956452PMC
December 2019

Shades of grey: a matter relevant to sympathetic activity and blood pressure control?

J Hypertens 2020 02;38(2):206-207

Department of Medicine and Surgery, Milano-Bicocca University, Milan, Milan, Italy.

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http://dx.doi.org/10.1097/HJH.0000000000002325DOI Listing
February 2020

Does sympathetic hyperactivity adversely impact on the effect of pre-ablation bariatric surgery and atrial fibrillation recurrence in morbidly obese patients undergoing atrial fibrillation ablation?

Europace 2020 03;22(3):506

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth WA 6000, Australia.

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http://dx.doi.org/10.1093/europace/euz316DOI Listing
March 2020

Renal denervation for treating congenital long QT syndrome: shortening the QT interval or modulating sympathetic tone?

Europace 2019 11;21(11):1755-1756

Dobney Hypertension Centre, School of Medicine-Royal, Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, Australia.

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http://dx.doi.org/10.1093/europace/euz251DOI Listing
November 2019

The Schlager mouse as a model of altered retinal phenotype.

Neural Regen Res 2020 Mar;15(3):512-518

Dobney Hypertension Centre, School of Biomedical Science - Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.

Hypertension is a risk factor for a large number of vision-threatening eye disorders. In this study, we investigated for the first time the retinal neural structure of the hypertensive BPH/2J mouse (Schlager mouse) and compared it to its control counterpart, the normotensive BPN/3J strain. The BPH/2J mouse is a selectively inbred mouse strain that develops chronic hypertension due to elevated sympathetic nervous system activity. When compared to the BPN/3J strain, the hypertensive BPH/2J mice showed a complete loss of outer layers of the neural retina at 21 weeks of age, which was indicative of a severe vision-threatening disease potentially caused by hypertension. To elucidate whether the retinal neural phenotype in the BPH/2J strain was attributed to increased BP, we investigated the neural retina of both BPN/3J and BPH/2J mice at 4 weeks of age. Our preliminary results showed for the first time that the BPH/2J strain develops severe retinal neural damage at a young age. Our findings suggest that the retinal phenotype in the BPH/2J mouse is possibly due to elevated blood pressure and may be contributed by an early onset spontaneous mutation which is yet to be identified or a congenital defect occurring in this strain. Further characterization of the BPH/2J mouse strain is likely to i) elucidate gene defects underlying retinal disease; ii) understand mechanisms leading to neural retinal disease and iii) permit testing of molecules for translational research to interfere with the progression of retinal disease. The animal experiments were performed with the approval of the Royal Perth Hospital Animal Ethics Committee (R535/17-18) on June 1, 2017.
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http://dx.doi.org/10.4103/1673-5374.266069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921339PMC
March 2020

New Molecules for Treating Resistant Hypertension: a Clinical Perspective.

Curr Hypertens Rep 2019 09 10;21(10):80. Epub 2019 Sep 10.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit / Medical Research Foundation, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia.

Purpose Of Review: To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions.

Recent Findings: RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.
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http://dx.doi.org/10.1007/s11906-019-0978-zDOI Listing
September 2019

Diuretics and skin cancer: should a common prescription come with advice to avoid sun exposure?

J Hypertens 2019 10;37(10):1961-1962

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Crawley.

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http://dx.doi.org/10.1097/HJH.0000000000002174DOI Listing
October 2019

Effects of sympathetic modulation in metabolic disease.

Ann N Y Acad Sci 2019 10 19;1454(1):80-89. Epub 2019 Aug 19.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Perth, Western Australia, Australia.

Sympathetic overdrive contributes to the derangement of glucose metabolism evident in clinical conditions, such as obesity, metabolic syndrome, type 2 diabetes, obstructive sleep apnea, and others. Targeting the sympathetic nervous system directly therefore appears as an attractive therapeutic approach to restore impaired glucose metabolism. Indeed, lifestyle interventions, including healthier diets and exercise, have been shown to exert their beneficial effects at least in part by reducing sympathetic nervous system activity. Pharmacologic inhibition of exaggerated central sympathetic outflow has also been demonstrated to beneficially impact on body weight and glucose and lipid metabolism. More recently, catheter-based renal denervation, an intervention applied predominantly to lower elevated blood pressure in patients with resistant hypertension, revealed salutary effects on glucose metabolism. Here, we review the mechanisms that contribute to the beneficial effects of targeting the sympathetic nervous system directly and discuss how these approaches may best be embedded in routine clinical practice.
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http://dx.doi.org/10.1111/nyas.14217DOI Listing
October 2019

New insights about post-exercise albuminuria in hypertensive patients.

J Clin Hypertens (Greenwich) 2019 08 8;21(8):1180-1182. Epub 2019 Jul 8.

Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1111/jch.13632DOI Listing
August 2019

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure-Targeting the Sympathetic Nervous System.

Int J Mol Sci 2019 May 16;20(10). Epub 2019 May 16.

Dobney Hypertension Cenre, School of Medicine-Royal Perth Hospital Unit, Faculty of Medicine, Dentistry & Health Sciences, The University of Western Australia Level 3, MRF Building, Rear 50 Murray St, Perth 6000, MDBP: M570, Australia.

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the I-metaiodobenzylguanidine (I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.
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http://dx.doi.org/10.3390/ijms20102430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567277PMC
May 2019

May Measurement Month 2017: an analysis of blood pressure screening results from Australia-South-East Asia and Australasia.

Eur Heart J Suppl 2019 Apr 24;21(Suppl D):D14-D16. Epub 2019 Apr 24.

Dobney Hypertension Centre, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, Australia.

Increased blood pressure (BP) is the single biggest contributing risk factor to the global disease burden. May Measurement Month (MMM) is a global initiative of the International Society of Hypertension aimed at raising awareness of high BP. In Australia, hypertension affects around six million adults and continues to remain the greatest attributable cause of cardiovascular mortality and morbidity (48.3%), stroke deaths (28%), and kidney disease (14%). An opportunistic cross-sectional survey was carried out during May 2017 predominantly in capital cities across Australia which included adult volunteers. Blood pressure measurement, the definition of hypertension and statistical analysis followed the standard MMM protocol. Additional information obtained included anthropometric data and responses to questionnaires on demographic, lifestyle, and environmental factors. Data were collected from 3817 individuals. After multiple imputation, of the 3758 individuals for whom a mean of the second and third BP reading was available, 1188 (31.2%) had hypertension. Of 3213 individuals not receiving antihypertensive treatment, 591 (18.4%) were hypertensive, and 239 (40.1%) of the 596 individuals receiving treatment had uncontrolled BP. Adjusted BP was higher in association with antihypertensive medication, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm and on Tuesdays. MMM17 was one of the largest BP screening campaigns undertaken in Australia using standardized BP measurements. In line with previous surveys, around one-third of screened adults had hypertension and approximately 40% of treated individuals remained uncontrolled. These results suggest that opportunistic screening can identify significant numbers with raised BP.
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http://dx.doi.org/10.1093/eurheartj/suz052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479418PMC
April 2019

Relevance of Targeting the Distal Renal Artery and Branches with Radiofrequency Renal Denervation Approaches-A Secondary Analysis from a Hypertensive CKD Patient Cohort.

J Clin Med 2019 Apr 27;8(5). Epub 2019 Apr 27.

Nephrology Division, Department of Medicine, Universidade Federal Fluminense, Niterói, RJ 24033-900, Brazil.

We searched for an association between changes in blood pressure (BP) at 12 and 24 months after renal denervation (RDN) and the different patterns of ablation spots placement along the renal artery vasculature. We performed a post-hoc analysis of a 24-month follow-up evaluation of 30 patients who underwent RDN between 2011 and 2012 using our previous database. Patients who had (i) resistant hypertension, as meticulously described previously, and (ii) Chronic kidney disease (CKD) stages 2, 3 and 4. Correlations were assessed using the Pearson or Spearman correlation tests as appropriate. The mean change in systolic ambulatory BP monitoring (ABPM) compared to baseline was -19.4 ± 12.7 mmHg at the 12th (p < 0.0001) and -21.3 ± 14.1 mmHg at the 24th month (p < 0.0001). There was no correlation between the ABPM Systolic Blood Pressure (SBP)-lowering effect and the total number of ablated spots in renal arteries (17.7 ± 6.0) either at 12 (r = -0.3, p = 0.1542) or at 24 months (r = -0.2, p = 0.4009). However, correlations between systolic BP-lowering effect and the number of ablation spots performed in the distal segment and branches were significant at the 12 (r = -0.7, p < 0.0001) and 24 months (r = -0.8, p < 0.0001) follow-up. Our findings indicate a substantial correlation between the numbers of ablated sites in the distal segment and branches of renal arteries and the systolic BP-lowering effect in the long-term.
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http://dx.doi.org/10.3390/jcm8050581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572309PMC
April 2019

Self-monitoring of blood pressure to guide titration of antihypertensive medication-a new era in hypertension management?

Cardiovasc Diagn Ther 2019 Feb;9(1):94-99

Dobney Hypertension Centre, School of Medicine - Royal, Perth Hospital Unit/Medical Research Foundation, University of Western Australia, Crawley WA, Australia.

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http://dx.doi.org/10.21037/cdt.2018.08.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382658PMC
February 2019