Effects of 3 months of multi-nutrient supplementation on the immune system and muscle and respiratory function of older adults in aged care (The Pomerium Study): protocol for a randomised controlled trial.

INTRODUCTION: Immunosenescence leads to increased morbidity and mortality associated with viral infections and weaker vaccine responses. This has been well documented for seasonal influenza and the current pandemic with SARS-CoV-2 (COVID-19), which disproportionately impact older adults, particularly those in residential aged care facilities. Inadequate nutrient intakes associated with impaired immunity, respiratory and muscle function are likely to augment the effects of immunosenescence. In this study, we test whether the impact of inadequate nutrition can be reversed using multi-nutrient supplementation, consequently enhancing vaccine responses, reducing the risk of viral infections and improving respiratory and muscle function. METHODS AND ANALYSIS: The Pomerium Study is a 3-month, single-blind, randomised, controlled trial testing the effects of two daily servings of an oral multi-nutrient supplement (330 kcal, 20 g protein, 1.5 g calcium 3-hydroxy-3-methylbutyrate monohydrate (CaHMB), 449 mg calcium, 500 IU vitamin D3 and 25 vitamins and minerals) on the immune system and muscle and respiratory function of older adults in aged care in Melbourne, Australia. 160 older adults (≥75 years old) will be recruited from aged care facilities and randomised to treatment (multi-nutrient supplement) or control (usual care). The primary outcome is a change in T-cell subsets CD8 + and CD28null counts at months 1 and 3. Secondary outcomes measured at baseline and month 3 are multiple markers of immunosenescence (also at 1 month), body composition (bioimpedance), handgrip strength (dynamometer), physical function (short physical performance battery), respiratory function (spirometry) and quality of life (EQ-5D-5L). Incidence and complications of COVID-19 and/or viral infections (ie, hospitalisation, complications or death) will be recorded throughout the trial, including 3 months after supplementation is ceased. ETHICS AND DISSEMINATION: This study was approved by Melbourne Health Human Research Ethics Committee (Ref No. HREC/73985/MH-2021, ERM Ref No. RMH73985, Melbourne Health Site Ref No. 2021.115). Written informed consent will be obtained from participants. Results will be published in peer-reviewed journals and made available to key aged care stakeholders, including providers, residents, and government bodies. TRIAL REGISTRATION NUMBER: ACTRN12621000420842.

Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study.

BACKGROUND: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. METHODS: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. FINDINGS: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23-31) greater accuracy than that of conventional imaging (92% [88-95] vs 65% [60-69]; p<0·0001). We found a lower sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28-35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18-26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10-22] vs 41 [28%] men [21-36]; p=0·008) and had more equivocal findings (23% [17-31] vs 7% [4-13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT. INTERPRETATION: PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning. FUNDING: Movember and Prostate Cancer Foundation of Australia. VIDEO ABSTRACT.

Successful renal denervation decreases the platelet activation status in hypertensive patients.

AIMS: To determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status. METHODS AND RESULTS: We investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN. CONCLUSION: Our results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.

A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension.

OBJECTIVES: Noradrenaline released from sympathetic nerves is rapidly inactivated via the action of the noradrenaline transporter (NET). We aimed to determine whether a single nucleotide polymorphism (SNP) in the NET gene, rs7194256, was associated with blood pressure and plasma noradrenaline concentration in patients with resistant hypertension. METHODS: Ninety-two consecutive patients with resistant hypertension participated in this study (age 62 ±â€Š1.3 years, BMI 32 ±â€Š0.6 kg/m, mean ±â€ŠSEM). Blood pressure was assessed using 24-h ambulatory blood pressure monitoring. Genotyping of rs7194256 (C/T) was performed using a predeveloped TaqMan SNP Genotyping Assay. Plasma catecholamines were analyzed using high-performance liquid chromatography. RESULTS: There were no differences in anthropometric measures between those carrying a T allele or the CC genotype. Patients carrying a T allele had significantly higher SBP: 24-h mean 148 ±â€Š2.6 vs. 140 ±â€Š2.4; 24-h max 189 ±â€Š3.2 vs. 179 ±â€Š2.6; 24-h min 114 ±â€Š3.0 vs. 105 ±â€Š2.3; night mean 141 ±â€Š3.0 vs. 131 ±â€Š2.5; night max 170 ±â€Š3.6 vs. 159 ±â€Š3.1; night min 118 ±â€Š3.4 vs. 109 ±â€Š2.4 (all P < 0.05). T-allele carriers had a significantly higher arterial noradrenaline concentration: 573 ±â€Š53 vs. 377 ±â€Š35 pg/ml (P = 0.002) and lower ratio of the intraneuronal noradrenaline metabolite, 3,4-dihydroxyphenylglycol, to noradrenaline (3.01 ±â€Š0.4 vs. 4.08 ±â€Š0.3 pg/ml; P = 0.024). CONCLUSION: A SNP in the NET gene in patients with resistant hypertension is associated with higher plasma noradrenaline concentration and elevated SBP. Impaired NET function may be a contributor to the pronounced activation of the sympathetic nervous system characteristic of patients with resistant hypertension.

Ambulatory arterial stiffness index as a predictor of blood pressure response to renal denervation.

BACKGROUND: Renal denervation (RDN) can reduce blood pressure (BP) in patients with resistant hypertension, but less so in patients with isolated systolic hypertension. A possible explanation is that patients with stiffer arteries may have lesser neural contribution to their hypertension. METHOD: We hypothesized that arterial stiffness predicts the response to RDN. From ambulatory BP monitoring (ABPM), ambulatory arterial stiffness index (AASI) was calculated as 1 - the regression slope of DBP versus SBP. RESULTS: In 111 patients with resistant hypertension, RDN reduced office and 24-h SBP after 3, 6, and 12 months (by -11 ±â€Š22, -11 ±â€Š25, -14 ±â€Š21 mmHg for office, and -4 ±â€Š11, -5 ±â€Š12, -5 ±â€Š15 mmHg for 24-h SBP, respectively, P < 0.01). Patients with baseline AASI above the median (>0.51) showed no change in 24-h SBP at 6 months after RDN (-0.4 ±â€Š12.3 mmHg, P > 0.05), whereas an AASI below 0.51was associated with a marked reduction (-9.3 ±â€Š11.0 mmHg, P < 0.01). Across AASI quartiles, patients in the highest quartile (AASI ≥ 0.60) had lower muscle sympathetic nerve activity than the other three quartiles (39 ±â€Š13 versus 49 ±â€Š13 bursts/min, P = 0.035). The responder rate, defined as a 24-h SBP reduction of at least 5% was 58% in the lowest AASI quartile (<0.45) and 16% in the highest quartile (≥0.60). After adjustment for age, sex, BMI, office and 24-h SBP, an AASI less than 0.51predicted those who respond to RDN (odds ratio 3.46, P = 0.04). CONCLUSION: We conclude that in patients with resistant hypertension, a lower AASI is an independent predictor of the BP response to RDN, possibly explained by a more pronounced neurogenic rather than biomechanical contribution to their BP elevation.

The Effect of Renal Denervation on Plasma Adipokine Profile in Patients with Treatment Resistant Hypertension.

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. Clinical Trial Registration Number: NCT00483808, NCT00888433.

Effect of renal denervation on kidney function in patients with chronic kidney disease.

AIMS: Renal denervation (RDN) can reduce blood pressure (BP) and slow the decline of renal function in chronic kidney disease (CKD) up to one year. Whether this effect is maintained beyond 12months and whether the magnitude of BP reduction affects estimated glomerular filtration rate (eGFR) is unknown. METHODS AND RESULTS: We examined eGFR in 46 CKD patients (baseline eGFR ≤60mL/min/1.73m2) on a yearly basis from 60months before to 3, 6, 12 and 24months after RDN. Ambulatory BP was measured before and after RDN. Linear mixed models analysis demonstrated a significant progressive decline in eGFR from months 60 to 12months (-15.47±1.98mL/min/1.73m2, P<0.0001) and from 12months to baseline prior to RDN (-3.41±1.64mL/min/1.73m2, P=0.038). Compared to baseline, RDN was associated with improved eGFR at 3months (+3.73±1.64mL/min/1.73m2, P=0.02) and no significant changes at 6 (+2.54±1.66mL/min/1.73m2, P=0.13), 12 (+1.78±1.64mL/min/1.73m2, P=0.28), and 24 (-0.24±2.24mL/min/1.73m2, P=0.91) months post procedure were observed. RDN significantly reduced daytime SBP from baseline to 24months post procedure (148±19 vs 136±17mmHg, P=0.03) for the entire cohort. Changes in SBP were unrelated to the eGFR changes at 6 (r=0.033, P=0.84), 12 (r=0.01, P=0.93) and 24months (r=-0.42, P=0.17) follow-up. CONCLUSION: RDN can slow further deterioration of renal function irrespective of BP lowering effects in CKD. RDN-induced inhibition of sympathetic outflow to the renal vascular bed may account for improved eGFR via alterations of intrarenal and glomerular hemodynamics.

Renal Denervation Reduces Monocyte Activation and Monocyte-Platelet Aggregate Formation: An Anti-Inflammatory Effect Relevant for Cardiovascular Risk.

Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5±11.2/81.0±11.2 mm Hg to 144.7±11.8/77.9±11.0 mm Hg), which was sustained at 6 months (144.7±13.8/78.6±11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months (P<0.01) and 6 months (P<0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months (P<0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte-platelet aggregates (3 months, P<0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P<0.0001; 6 months, P<0.05), interleukin-1ß (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-α (3 months, P<0.01; 6 months, P<0.05), and interleukin-12 (3 months, P<0.01; 6 months, P<0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.

Renal artery anatomy affects the blood pressure response to renal denervation in patients with resistant hypertension.

BACKGROUND: Renal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear. METHODS: We measured office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up. RESULTS: RDN significantly reduced office and daytime SBP in group 1 at both 3 and 6 months follow-up (P<0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P<0.05). There was no deterioration in kidney function in any group. CONCLUSION: While RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences.

Health-related quality of life and blood pressure 12 months after renal denervation.

AIM: To examine the effect of renal denervation (RDN) on blood pressure (BP) and health-related quality of life (QoL) in patients with resistant hypertension, pseudoresistant hypertension due to a white-coat effect and in patients with uncontrolled masked hypertension. METHODS: Using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and Spielberger's state and trait anxiety questionnaires, we examined QoL, symptoms of depression and anxiety prior to and 12 months following RDN. BP was assessed from clinic and ambulatory blood pressure monitoring (ABPM) recordings. RESULTS: Patients with uncontrolled masked hypertension had the highest BDI and anxiety scores among all groups at baseline. Twelve months following RDN clinic and ambulatory BP were reduced only in those patients with resistant hypertension (delta SBP: clinic -16 ±â€Š3 mmHg, ABPMday -8 ±â€Š2 mmHg, ABPMnight -8 ±â€Š2 mmHg, all P < 0.01). Clinic BP was reduced in the pseudoresistant group (-17 ±â€Š6 mmHg, P < 0.01) but was elevated in the uncontrolled masked group (+13 ±â€Š6 mmHg, P = 0.02). In all patients, trait anxiety (P < 0.05), BDI scores (P < 0.05) and the SF-36 mental component summary (MCS) score (P < 0.001) were improved. The improvement in the SF-36 MCS was confined to those patients with resistant hypertension (+4.0 ±â€Š1.1, P < 0.01). The change in clinic BP after RDN was related to the baseline clinic BP (systolic: r = 0.54, P < 0.001; diastolic r = 0.43, P < 0.001), the number of ablations delivered (both clinic and mean day ABPM systolic r = 0.24, P < 0.05) and to the change in SF-36 MCS score (systolic: r = 0.25, P = 0.01; diastolic r = 0.24, P = 0.02). CONCLUSION: These results indicate that in patients with confirmed resistant hypertension, RDN is associated with a reduction in BP and a sustained improvement in mental health-related aspects of QoL.

Opposing effects of shear-mediated dilation and myogenic constriction on artery diameter in response to handgrip exercise in humans.

While the impact of changes in blood flow and shear stress on artery function are well documented, the acute effects of increases in arterial pressure are less well described in humans. The aim of this study was to assess the effect of 30 min of elevated blood pressure, in the absence of changes in shear stress or sympathetic nervous system (SNS) activation, on conduit artery diameter. Ten healthy male subjects undertook three sessions of 30 min unilateral handgrip exercise at 5, 10, and 15% of maximal voluntary contractile (MVC) strength. Brachial artery shear rate and blood flow profiles were measured simultaneously during exercise in the active and contralateral resting arms. Bilateral brachial artery diameter was simultaneously assessed before and immediately postexercise. In a second experiment, six subjects repeated the 15% MVC condition while continuous vascular measurements were collected during muscle sympathetic nerve activity (MSNA) assessment using peroneal microneurography. We found that unilateral handgrip exercise at 5, 10, and 15% MVC strength induced stepwise elevations in blood pressure (P < 0.01, Δmean arterial pressure: 7.06 ± 2.44, 8.50 ± 2.80, and 18.35 ± 3.52 mmHg, P < 0.01). Whereas stepwise increases were evident in shear rate in the exercising arm (P < 0.001), no changes were apparent in the nonexercising limb (P = 0.42). Brachial artery diameter increased in the exercising arm (P = 0.02), but significantly decreased in the nonexercising arm (P = 0.03). At 15% MVC, changes in diameter were significantly different between arms (interaction effect: P = 0.01), whereas this level of exertion produced no significant changes in MSNA. We conclude that acute increases in transmural pressure, independent of shear rate and changes in SNS activation, reduce arterial caliber in normotensive humans in vivo. These changes in diameter were mitigated by exercise-induced elevations in shear rate in the active limb.

Reverse cardiac remodeling after renal denervation: Atrial electrophysiologic and structural changes associated with blood pressure lowering.

BACKGROUND: Hypertension is the most common modifiable risk factor associated with atrial fibrillation. OBJECTIVE: The purpose of this study was to determine the effects of blood pressure (BP) lowering after renal denervation on atrial electrophysiologic and structural remodeling in humans. METHODS: Fourteen patients (mean age 64 ± 9 years, duration of hypertension 16 ± 11 years, on 5 ± 2 antihypertensive medications) with treatment-resistant hypertension underwent baseline 24-hour ambulatory BP monitoring, echocardiography, cardiac magnetic resonance imaging, and electrophysiologic study. Electrophysiologic study included measurements of P-wave duration, effective refractory periods, and conduction times. Electroanatomic mapping of the right atrium was completed using CARTO3 to determine local and regional conduction velocity and tissue voltage. Bilateral renal denervation was performed, and all measurements repeated after 6 months. RESULTS: After renal denervation, mean 24-hour BP reduced from 152/84 mm Hg to 141/80 mm Hg at 6-month follow-up (P < .01). Global conduction velocity increased significantly (0.98 ± 0.13 m/s to 1.2 ± 0.16 m/s at 6 months, P < .01), conduction time shortened (32 ± 5 ms to 27 ± 6 ms, P < .01), and complex fractionated activity was reduced (37% ± 14% to 19% ± 12%, P = .02). Changes in conduction velocity correlated positively with changes in 24-hour mean systolic BP (R(2) = 0.55, P = .01). There was a significant reduction in left ventricular mass (139 ± 37 g to 120 ± 29 g, P < .01) and diffuse ventricular fibrosis (T1 partition coefficient 0.39 ± 0.07 to 0.31 ± 0.09, P = .01) on cardiac magnetic resonance imaging. CONCLUSION: BP reduction after renal denervation is associated with improvements in regional and global atrial conduction and reductions in ventricular mass and fibrosis. Whether changes in electrical and structural remodeling are solely due to BP lowering or are due in part to intrinsic effects of renal denervation remains to be determined.

A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.

CONTEXT: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. OBJECTIVE: The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. PARTICIPANTS AND METHODS: A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. RESULTS: PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). CONCLUSIONS: Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension.

Renal denervation (RDN) reduces muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in resistant hypertension. Although a persistent BP-lowering effect has been demonstrated, the long-term effect on MSNA remains elusive. We investigated whether RDN influences MSNA over time. Office BP and MSNA were obtained at baseline, 3, 6, and 12 months after RDN in 35 patients with resistant hypertension. Office BP averaged 166±22/88±19 mm Hg, despite the use of an average of 4.8±2.1 antihypertensive drugs. Baseline MSNA was 51±11 bursts/min ≈2- to 3-fold higher than the level observed in healthy controls. Mean office systolic and diastolic BP significantly decreased by -12.6±18.3/-6.5±9.2, -16.1±25.6/-8.6±12.9, and -21.2±29.1/-11.1±12.9 mm Hg (P<0.001 for both systolic BP and diastolic BP) with RDN at 3-, 6-, and 12-month follow-up, respectively. MSNA was reduced by -8±12, -6±12, and -6±11 bursts/min (P<0.01) at 3-, 6-, and 12-month follow-up. The reduction in MSNA was maintained, despite a progressive fall in BP over time. No such changes were observed in 7 control subjects at 6-month follow-up. These findings confirm previous reports on the favorable effects of RDN on elevated BP and demonstrate sustained reduction of central sympathetic outflow ≤1-year follow-up in patients with resistant hypertension and high baseline MSNA. These observations are compatible with the hypothesis of a substantial contribution of afferent renal nerve signaling to increased BP in resistant hypertension and argue against a relevant reinnervation at 1 year after procedure.

Renal nerve ablation reduces augmentation index in patients with resistant hypertension.

OBJECTIVE: Renal denervation (RDN) has been demonstrated to reduce muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant hypertension. Whether alterations of arterial stiffness may contribute to BP-lowering effects of RDN is unknown. METHODS: We measured office BP and arterial stiffness using fingertip tonometry-derived augmentation index (EndoPAT2000) at baseline and at 3-month follow-up in 50 consecutive patients with resistant hypertension. Forty patients received RDN and 10 patients served as controls. MSNA was obtained in 20 RDN and 10 non-RDN patients. RESULTS: Baseline BP averaged 170/92 ± 19/15 mmHg (RDN) and 171/93 ± 14/8 mmHg (non-RDN) despite the use of 4.9 ± 1.9 and 4.4 ± 2.0 antihypertensive drugs, respectively. RDN significantly reduced SBP (170  ± 19 vs. 154 ± 25 mmHg; P < 0.001) and DBP (92 ± 15 vs. 84 ± 16 mmHg; P<0.001), augmentation index (30.6  ± 23.8 vs. 22.7 ± 22.4%; P=0.002), AI@75 corrected for heart rate (22.4 ± 21.6 vs. 14.4 ± 20.7; P=0.002) and MSNA (80 ± 15 vs. 71 ± 18  bursts/100 heartbeats; P<0.01). Changes in AI@75 with RDN were unrelated to SBP (r=0.043; P = 0.79), and DBP (r = 0.092; P = 0.57) and MSNA changes (r = -0.17; P = 0.49). No changes in BP, augmentation index, AI@75 or MSNA were observed in the non-RDN group. CONCLUSION: RDN results in a substantial and rapid reduction in augmentation index, which appears to be independent of BP and MSNA changes. These findings are indicative of a beneficial effect of RDN on arterial stiffness in patients with resistant hypertension and may contribute to the sustained BP-lowering effect of RDN.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.

BACKGROUND AND OBJECTIVES: Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. RESULTS: Average office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. CONCLUSIONS: RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension.

Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in patients with resistant hypertension. The mechanisms underlying sympathetic neural inhibition are unknown. We examined whether RDN differentially influences the sympathetic discharge pattern of vasoconstrictor neurons in patients with resistant hypertension. Standardized office BP, single-unit MSNA, and multi-unit MSNA were obtained at baseline and at 3-month follow-up in 35 patients with resistant hypertension. Twenty-five patients underwent RDN, and 10 patients underwent repeated measurements without RDN (non-RDN). Baseline BP averaged 164/93 mm Hg (RDN) and 164/87 mm Hg (non-RDN) despite use of an average of 4.8 ± 0.4 and 4.4 ± 0.5 antihypertensive drugs, respectively. Mean office BP decreased significantly by -13/-6 mm Hg for systolic BP (P<0.001) and diastolic BP (P<0.05) with RDN but not in non-RDN at 3-month follow-up. RDN moderately decreased multi-unit MSNA (79 ± 3 versus 73 ± 4 bursts/100 heartbeats; P<0.05), whereas all properties of single-unit MSNA including firing rates of individual vasoconstrictor fibers (43 ± 5 versus 27 ± 3 spikes/100 heartbeats; P<0.01), firing probability (30 ± 2 versus 22 ± 2% per heartbeat; P<0.02), and multiple firing incidence of single units within a cardiac cycle (8 ± 1 versus 4 ± 1% per heartbeat; P<0.05) were substantially reduced at follow-up. BP, single-unit MSNA, and multi-unit MSNA remained unaltered in the non-RDN cohort at follow-up. RDN results in the substantial and rapid reduction in firing properties of single sympathetic vasoconstrictor fibers, this being more pronounced than multi-unit MSNA inhibition. Whether the earlier changes in single-unit firing patterns may predict long-term BP response to RDN warrants further exploration.

Health-related quality of life after renal denervation in patients with treatment-resistant hypertension.

Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure (BP) in patients with resistant hypertension. The effect of renal denervation on health-related quality of life (QoL) has not been evaluated. Using the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, we examined QoL before and 3 months after renal denervation in patients with uncontrolled BP. For baseline comparisons, matched data were extracted from the Australian Diabetes, Obesity, and Lifestyle database. Before renal denervation, patients with resistant hypertension (n = 62) scored significantly worse in 5 of the eight 36-Item Short-Form Health Survey domains and the Mental Component Summary score. Three months after denervation (n = 40), clinic BP was reduced (change in systolic and diastolic BP, -16 ± 4 and -6 ± 2 mm Hg, respectively; P<0.01). The Mental Component Summary score improved (47.6 ± 1.1 versus 52 ± 1; P = 0.001) as a result of increases in the vitality, social function, role emotion, and mental health domains. Beck Depression Inventory scores were also improved, particularly with regard to symptoms of sadness (P = 0.01), tiredness (P<0.001), and libido (P<0.01). The magnitude of BP reduction or BP level achieved at 3 months bore no association to the change in QoL. Renal denervation was without a detrimental effect on any elements of the 36-Item Short-Form Health Survey. These results indicate that patients with severe hypertension resistant to therapy present with a marked reduction in subjective QoL. In this pre- and post-hypothesis generating study, several aspects of QoL were improved after renal denervation; however, this was not directly associated with the magnitude of BP reduction.