Dagmara Hering

Renal Denervation in Moderate to Severe CKD

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) < 45 ml/min per 1.73 m(2) is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3-4 CKD (mean eGFR, 31 ml/min per 1.73 m(2)). We used CO(2) angiography in six patients to minimize exposure to contrast agents. Estimated GFR remained unchanged after the procedure, irrespective of the use of CO(2) angiography. Mean baseline BP ± SD was 174 ± 22/91 ± 16 mmHg despite the use of 5.6 ± 1.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were -34/-14, -25/-11, -32/-15, and -33/-19 mmHg, respectively. Night-time ambulatory BP significantly decreased (P<0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3-4 CKD and resistant hypertension.

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.

Gender-Selective Interaction Between Aging, Blood Pressure, and Sympathetic Nerve Activity

The mechanisms mediating the more striking age related increase in cardiovascular disease in women than in men are poorly understood. We tested the hypothesis that aging has a greater impact on sympathetic traffic in women than in men. Muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate were measured in 120 healthy males and 96 healthy females aged 20 to 72 years. MSNA increased with age in both sexes, but age explained 53% of MSNA variance in female subjects and only 8% of MSNA variance in male subjects. Both the slope and intercept of the regression lines were significantly different between male and female groups (P<0.01 and P<0.001, respectively). For each decade of life, women showed an increase of 6.5 bursts/min in comparison to an increase of 2.6 bursts/min in males. Menopause did not explain the age-related increase in sympathetic traffic. For every 10-burst/min increment in MSNA in subjects older than 40, mean blood pressure increased by 2.7 mm Hg in men and by 6.1 mm Hg in women. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, independent of menopausal status. Sympathetic neural mechanisms may contribute importantly to the more marked influence of age on blood pressure and cardiovascular disease in women.

International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

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.

A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension

Elevated blood pressure is the strongest modifiable risk factor for cardiovascular disease worldwide. Despite extensive knowledge about ways to prevent as well as to treat hypertension, the global incidence and prevalence of hypertension and, more importantly, its cardiovascular complications are not reduced—partly because of inadequacies in prevention, diagnosis, and control of the disorder in an ageing world. The aim of the Lancet Commission on hypertension is to identify key actions to improve the management of blood pressure both at the population and the individual level, and to generate a campaign to adopt the suggested actions at national levels to reduce the impact of elevated blood pressure globally. The first task of the Commission is this report, which briefly reviews the available evidence for prevention, identification, and treatment of elevated blood pressure, hypertension, and its cardiovascular complications. The report focuses on how as-yet unsolved issues might be tackled using approaches with population-wide impact and new methods for patient evaluation and education in the broadest sense (some of which are not always strictly evidence based) to manage blood pressure worldwide. The report is built around the concept of lifetime risk applicable to the entire population from conception. Development of subclinical and sometimes clinical cardiovascular disease results from lifetime exposure to cardiovascular risk factors combined with the susceptibility of individuals to the harmful consequences of these risk factors. The Commission recognises the importance of other cardiovascular risk factors—eg, smoking, obesity, dyslipidaemia, and diabetes mellitus—on antihypertensive treatment. However, as a Commission on hypertension, this report focuses mainly on issues and actions related to elevated blood pressure. Previous action plans for improving management of elevated blood pressure and hypertension have not yet provided adequate results. Therefore, the Commission has identified ten essential and achievable goals and ten accompanying, mutually additive, and synergistic key actions that—if implemented effectively and broadly—will make substantial contributions to the management of blood pressure globally. The Commission deliberately has not listed these complementary key actions by priority because the balance between strength of evidence, feasibility, and potential benefit could differ by country.

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.

An independent relationship between muscle sympathetic nerve activity and pulse wave velocity in normal humans.

Objective Carotid–femoral pulse wave velocity (PWV) has been shown to be a powerful predictor of cardiovascular morbidity and mortality. Sympathetic neural mechanisms may have a stiffening influence on arterial mechanical properties. The relationship between direct measures of sympathetic traffic and PWV in healthy humans has not been previously studied. We, therefore, tested the hypothesis that PWV is independently linked to muscle sympathetic nerve activity (MSNA) in normal individuals. Methods We measured MSNA (microneurography), PWV (Complior device), heart rate and blood pressure in 25 healthy male participants (mean age 43 ± 10 years). Results PWV correlated significantly with age (r = 0.63, P < 0.001), SBP (r = 0.43, P < 0.05) and MSNA (r = 0.43, P < 0.05) but not with BMI, waist circumference, waist-to-hip ratio, heart rate, pulse pressure or DBP. Robust multiple linear regression analysis revealed that only age and MSNA were linked independently to PWV (r2 = 0.62, P < 0.001), explaining 39 and 25% of its variance, respectively. After adjustment of PWV for age and SBP, we further divided individuals into ‘excessive’ PWV (i.e. higher than expected from age and SBP) and ‘optimal’ PWV (i.e. lower than expected). BMI and blood pressure were similar in both subgroups. Individuals with excessive PWV had significantly greater MSNA than individuals with optimal PWV (30 ± 10 vs. 18 ± 11 bursts/min, P = 0.01). Conclusion This study provides the first evidence that PWV is linked to MSNA in normal humans. The relationship between MSNA and PWV is independent of age, BMI, waist circumference, waist-to-hip ratio, heart rate, pulse pressure or blood pressure.

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.

Non-dipping pattern of hypertension and obstructive sleep apnea syndrome.

There is growing recognition of cardiovascular consequences of obstructive sleep apnea (OSA). Recurrent episodes of airway obstructions result in hypoxia and hypercapnia increasing sympathetic neural tone, which in turn causes vasoconstriction and marked increases in blood pressure (BP). BP response to OSA may be important in understanding the absence of nocturnal BP fall in the subgroup of hypertensive patients termed ‘non-dippers’. Even mild sleep apnea can increase nocturnal BP through different mechanisms including hypoxemia, sympathetic activation, mechanical changes and disruption of normal sleep. Sleep apnea may be an important factor in determining the increased cardiovascular risk in hypertensive non-dippers. Effective treatment of sleep apnea may attenuate neurohumoral and metabolic abnormalities, improve diurnal BP control and conceivably reduce cardiovascular risk. This review examines the evidence linking OSA to non-dipping pattern of hypertension, and discusses potential mechanisms underlying this link. We will review first, prognostic value of nighttime BP; second, the cardiovascular consequences of sleep apnea; third, the evidence for altered diurnal BP profile in sleep apnea; fourth, the mechanisms contributing to both nocturnal and daytime hypertension in sleep apnea; fifth, the benefits of sleep apnea treatment and finally implications for hypertension management.