Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure

OBJECTIVES: This study was designed to determine whether reductions in morning systolic blood pressure (BP) elicited by treatment of moderate to severe obstructive sleep apnea (OSA) in heart failure (HF) patients are associated with a reduction in sympathetic vasoconstrictor tone. BACKGROUND: Daytime muscle sympathetic nerve activity (MSNA) is elevated in HF patients with coexisting OSA. In our recent randomized trial in HF, abolition of OSA by continuous positive airway pressure (CPAP) increased left ventricular ejection fraction (LVEF) and lowered morning systolic BP. METHODS: Muscle sympathetic nerve activity, BP, and heart rate (HR) of medically treated HF patients (EF <45%) and OSA (apnea-hypopnea index > or =20/h of sleep) were recorded on the morning after overnight polysomnography, and again one month after patients were randomly allocated nocturnal CPAP treatment or no CPAP (control). RESULTS: In nine control patients, there were no significant changes in the severity of OSA, MSNA, systolic BP, or HR. In contrast, in the 8 CPAP-treated patients, OSA was attenuated, and there were significant reductions in daytime MSNA (from 58 +/- 4 bursts/min to 48 +/- 5 bursts/min; 84 +/- 4 bursts/100 heart beats to 72 +/- 5 bursts/100 heart beats; p < 0.001 and p = 0.003, respectively), systolic BP (from 135 +/- 5 mm Hg to 120 +/- 6 mm Hg, p = 0.03), and HR (from 69 +/- 2 min(-1) to 66 +/- 2 min(-1); p = 0.013). CONCLUSIONS: Treatment of coexisting OSA by CPAP in HF patients lowers daytime MSNA, systolic BP, and HR. Inhibition of increased central sympathetic vasoconstrictor outflow is one mechanism by which nocturnal CPAP reduces awake BP in HF patients with moderate to severe OSA.     

Blood pressure effects of CPAP in nonresistant and resistant hypertension associated with OSA: A systematic review of randomized clinical trials

Obstructive sleep apnea (OSA) is a rather common chronic disorder, associated with increased prevalence of hypertension. The pathophysiological mechanisms for hypertension in OSA are at least in part linked to intermittent hypoxia developed during nightly hypopneas and apneas. Hypoxemia stimulates sympathetic overactivity, systemic inflammation, oxidative stress, and endothelial dysfunction. However, it appears that intermittent hypoxemia is not the only factor in the development of hypertension in OSA. Supplemental oxygen therapy that improved oxyhemoglobin saturation to similar levels to those achieved with CPAP treatment did not reduce BP. In this scenario, it could be proposed that hypoxemia acts as a trigger of sympathetic overdrive, which when set is the main factor in the development of hypertension in OSA. This review appraises evidence provided by randomized controlled trials on the BP-lowering effectiveness of continuous positive airway pressure (CPAP) treatment of OSA patients with nonresistant and resistant hypertension. It suggests that CPAP treatment is more effective in treating resistant hypertension than nonresistant hypertension. A possible explanation is that sympathetic overactivity and altered vascular reactivity in OSA could be more severe in resistant hypertension than in nonresistant hypertension. An intricate interaction among compliance, adherence, and their interaction with demographic characteristics, genetic factors, and comorbidities of the population included might explain the differences found between trials on their influence over the antihypertensive effectiveness of CPAP. Further long-term trials are needed in hypertensive OSA patients to assess whether CPAP treatment in OSA patients consistently restores physiological nocturnal BP fall and adjusts resting and circadian heart rate.     

Sleep apnea and heart failure

Sleep apnea is frequently observed in patients with heart failure (HF). In general, sleep apnea consists of two types: obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from upper airway collapse, whereas CSA arises from reductions in central respiratory drive. In patients with OSA, blood pressure is frequently elevated as a result of sympathetic nervous system overactivation. The generation of exaggerated negative intrathoracic pressure during obstructive apneas further increases left ventricular (LV) afterload, reduces cardiac output, and may promote the progression of HF. Intermittent hypoxia and post-apneic reoxygenation cause vascular endothelial damage and possibly atherosclerosis and consequently coronary artery disease and ischemic cardiomyopathy. CSA is also characterized by apnea, hypoxia, and increased sympathetic nervous activity and, when present in HF, is associated with increased risk of death. In patients with HF, abolition of coexisting OSA by continuous positive airway pressure (CPAP) improves LV function and may contribute to the improvement of long-term outcomes. Although treatment options of CSA vary compared with OSA treatment, CPAP and other types of positive airway ventilation improve LV function and may be a promising adjunctive therapy for HF patients with CSA. Since HF remains one of the major causes of mortality in the industrialized countries, the significance of identifying and managing sleep apnea should be more emphasized to prevent the development or progression of HF.     

Blood pressure variability in obstructive sleep apnea: role of sympathetic nervous activity and effect of continuous positive airway pressure

BACKGROUND: Many studies support a link between obstructive sleep apnea (OSA), increased blood pressure (BP) and/or BP variability, and sympathetic nervous system (SNS) activity. We assessed the relationship between SNS activity and 24-h BP variability in patients with OSA, and the effect of continuous positive airway pressure (CPAP) on BP variability. DESIGN: Forty-one patients with a respiratory disturbance index (RDI) > 15 were randomized into CPAP or CPAP placebo groups for a 1-week trial. METHODS: Ambulatory BP, 24-h urine norepinephrine (NE) and polysomnography were measured prior to treatment and after 1 and 7 days of treatment. RESULTS: Neither RDI nor 24-h urine NE levels were related to 24-h mean BP levels. While RDI was associated only with night-time BP variability, daytime urine NE levels were associated with both night-time and daytime BP variability. After treatment, the BP variability decreased significantly but equally in both active and placebo CPAP groups. CONCLUSIONS: Obstructive sleep apnea is more related to BP variability than BP. Sympathetic nervous activity, as inferred from daytime urine NE, is related to changes in BP variability in OSA patients. BP variability is not specifically affected by CPAP.     

Targeting Brain Aminopeptidase A: A New Strategy for the Treatment of Hypertension and Heart Failure

The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI.     

Does Treating Sleep Apnea Reduce Heart Failure Risks?

Sleep-disordered breathing (SDB) is the most common comorbidity in heart failure (HF) patients. SDB, including both central sleep apnea (CSA) and obstructive sleep apnea (OSA), affects up to 70 % of all heart patients. Numerous studies have identified intermittent hypoxia, oxidative stress, and sympathetic activation as the main pathways through which SDB exerts its negative cardiovascular consequences. The etiological relation between SDB and HF is complex and multi-layered. On one level, SDB contributes to the progression of cardiovascular disease (CVD) into HF; on another level, SDB is a consequence of severe advanced HF. At all stages of CVD, SDB likely contributes to the acceleration of disease progression into end-stage process including advanced HF, stroke, and death. Figure 1 describes the role of OSA in the progression of CVD risk status, the role of CSA in end-stage CVD (including HF) and the reciprocal relationship between advanced CVD and SDB. Current evidence supports that SDB treatment improves several physiological parameters and disease markers in patients with CVD and likely decreases the progression into HF. In patients with established HF, available evidence supports that untreated SDB is independently associated with negative consequences in heart failure. However, there are insufficient studies in support of a conclusion that treatment of SDB changes important HF outcomes. In particular, there are no adequately powered randomized controlled trials demonstrating improvement in mortality, admissions, or cardiac function in HF patients with SDB therapy. However, treatment of SDB is largely safe, associated with critical functional benefits, and is increasingly better tolerated, allowing for decision-making processes that favor treatment.     

Sleep‐disordered breathing in heart failure

Sleep‐disordered breathing—comprising obstructive sleep apnoea (OSA), central sleep apnoea (CSA), or a combination of the two—is found in over half of heart failure (HF) patients and may have harmful effects on cardiac function, with swings in intrathoracic pressure (and therefore preload and afterload), blood pressure, sympathetic activity, and repetitive hypoxaemia. It is associated with reduced health‐related quality of life, higher healthcare utilization, and a poor prognosis. Whilst continuous positive airway pressure (CPAP) is the treatment of choice for patients with daytime sleepiness due to OSA, the optimal management of CSA remains uncertain. There is much circumstantial evidence that the treatment of OSA in HF patients with CPAP can improve symptoms, cardiac function, biomarkers of cardiovascular disease, and quality of life, but the quality of evidence for an improvement in mortality is weak. For systolic HF patients with CSA, the CANPAP trial did not demonstrate an overall survival or hospitalization advantage for CPAP. A minute ventilation‐targeted positive airway therapy, adaptive servoventilation (ASV), can control CSA and improves several surrogate markers of cardiovascular outcome, but in the recently published SERVE‐HF randomized trial, ASV was associated with significantly increased mortality and no improvement in HF hospitalization or quality of life. Further research is needed to clarify the therapeutic rationale for the treatment of CSA in HF. Cardiologists should have a high index of suspicion for sleep‐disordered breathing in those with HF, and work closely with sleep physicians to optimize patient management.     

Obstructive sleep apnea and heart failure

Obstructive sleep apnea (OSA) exerts several effects that may be particularly deleterious in patients with heart failure (HF). OSA should be considered especially in HF patients who are obese or have the metabolic syndrome, systemic hypertension, or pulmonary hypertension. HF patients in whom OSA is suspected should undergo a full evaluation by a sleep specialist, including a polysomnogram, to diagnose OSA and differentiate this disease from central sleep apnea. Those found to have OSA should then receive continuous positive airway pressure and/or other interventions, and standard disease management strategies should be used to maximize compliance. Those who cannot tolerate continuous positive airway pressure may be candidates for mandibular advancement devices or surgical therapies including tracheostomy. Standard HF medications should be used to treat HF, and optimization of fluid balance may help minimize OSA severity. However, it is still unknown whether treatment of OSA in HF patients will reduce hospitalizations or mortality.     

Blood pressure changes after automatic and fixed CPAP in obstructive sleep apnea: relationship with nocturnal sympathetic activity

Treatment of obstructive sleep apnea (OSA) by continuous positive airway pressure (CPAP) usually causes a reduction in blood pressure (BP), but several factors may interfere with its effects. In addition, although a high sympathetic activity is considered a major contributor to increased BP in OSA, a relationship between changes in BP and in sympathetic nervous system activity after OSA treatment is uncertain. This study was undertaken to assess if, in OSA subjects under no pharmacologic treatment, treatment by CPAP applied at variable levels by an automatic device (APAP) may be followed by a BP reduction, and if that treatment is associated with parallel changes in BP and catecholamine excretion during the sleep hours. Nine subjects underwent 24-h ambulatory BP monitoring and nocturnal urinary catecholamine determinations before OSA treatment and 2 months following OSA treatment by APAP (Somnosmart2, Weinmann, Hamburg, Germany). Eight control subjects were treated by CPAP at a fixed level. After APAP treatment, systolic blood pressure (SBP) decreased during sleep (p < 0.05), while diastolic blood pressure (DBP) decreased both during wakefulness (p < 0.05) and sleep (p < 0.02). Similar changes were observed in subjects receiving fixed CPAP. Nocturnal DBP changes were correlated with norepinephrine (in the whole sample: r = .61, p < 0.02) and normetanephrine (r = .71, p < 0.01) changes. In OSA subjects under no pharmacologic treatment, APAP reduces BP during wakefulness and sleep, similarly to CPAP. A reduction in nocturnal sympathetic activity could contribute to the reduction in DBP during sleep following OSA treatment.     

Association between difference in blood pressure reduction and risk of cardiovascular events in a type 2 diabetes population: A meta-regression analysis

AimRecent US recommendations indicate a target blood pressure (BP) of 130/80 mmHg for patients with type 2 diabetes (T2D). Our aim was to characterize the association between risk of cardiovascular events and differences in BP decreases in randomized trials of a T2D population.MethodsA systematic search was made for randomized clinical trials assessing the effects of antihypertensive treatments in T2D patients on mortality, and fatal and non-fatal cardiovascular events, using a meta-regression technique to explore the influence of BP decreases on treatment effects.ResultsA total of 88,503 patients from 44 randomized trials were included. There was no significant association between BP decreases and risk of all-cause or cardiovascular mortality, cardiovascular events or myocardial infarction. However, stroke risk was influenced by BP decreases: compared with no reduction, a 10-mmHg reduction in systolic BP was associated with a relative odds ratio (OR) decrease of 33% (OR: 0.67, 95% CI: 0.54–0.82), and a 5-mmHg diastolic BP reduction was associated with a relative OR decrease of 38% (OR: 0.62, 95% CI: 0.50–0.76). Restricting the analysis to double-blind studies did not change the results for diastolic BP.ConclusionA reduction in BP lowers the risk of stroke, but does not appear to affect the risk of other cardiovascular events in a T2D population.     

Autonomic cardiac modulation in obstructive sleep apnea: effect of an oral jaw-positioning appliance

BACKGROUND: Patients with obstructive sleep apnea (OSA) are characterized by deranged cardiovascular variability, a well-established marker of cardiovascular risk. While long-term treatment with continuous positive airway pressure leads to a significant improvement of cardiovascular variability, little is known of the possibility of achieving the same results with other therapeutic approaches. The aim of our study was to investigate the responses of autonomic indexes of neural cardiac control to another type of OSA treatment based on an oral jaw-positioning appliance. METHODS: In 10 otherwise healthy subjects with OSA (OSA+) and in 10 subjects without OSA (OSA-) we measured heart rate, BP, and indices of autonomic cardiac regulation derived from time-domain and spectral analysis of R-R interval (RRI), before and after 3 months of treatment with the oral device. High-frequency (HF) power of RRI was taken as an index of parasympathetic cardiac modulation, and the ratio between low-frequency (LF) and HF RRI powers as an indirect marker of the balance between sympathetic and parasympathetic cardiac modulation. RESULTS: At baseline, in comparison with OSA- subjects, OSA+ subjects displayed a significantly lower RRI variance (p < 0.02) and reduced HF RRI powers (p < 0.001). After 3 months of treatment with the oral device, the OSA+ group showed a marked reduction in apnea-hypopnea index (p < 0.001), a lengthening in RRI and a significant increase in its variance (p < 0,02), an increased HF RRI power (from 134 +/- 26 to 502 +/- 48 ms2, p < 0.001), and a reduction in LF/HF RRI power ratio (from 3.11 +/- 0.8 to 1.5 +/- 0.5). As a result of these changes, after the 3-month treatment there were no more significant differences between the two groups in these parameters. In both OSA+ and OSA- groups, body weight, heart rate, and BP did not change over time. CONCLUSIONS: Three months of treatment with a specific oral jaw-positioning appliance improves cardiac autonomic modulation in otherwise healthy patients with OSA of mild degree.     

Sleep-disordered breathing in acute decompensated heart failure

Sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and central sleep apnea (CSA), is highly prevalent and frequently unrecognized in patients with chronic heart failure (HF). Untreated SDB may worsen acute decompensation of HF and delay recovery by increasing vascular inflammation and oxidative stress, impeding control of the blood pressure, and promoting arrhythmias. Untreated OSA doubles the risk for developing HF, and patients with HF who develop OSA are thought to have a worse prognosis than patients with HF alone. Similar to the findings in the general population, treatment of OSA appears to reduce cardiovascular morbidity and mortality in HF. The presence of CSA is associated with increased mortality in HF patients. Efficacious suppression of central sleep apnea with continuous positive airway pressure therapy may reduce mortality in HF.     

Chronic Systolic Heart Failure,Guideline-Directed Medical Therapy,and Systemic Hypotension—Less Pressure but Maybe More Risk (Does This Clinical Scenario Need More Discussion?)

Many clinical trials have demonstrated the survival benefit of medication regimens that modulate the neurohormonal activation that occurs with chronic heart failure (HF). These medications, however, also commonly lower systemic blood pressure (BP). Low arterial BP in patients with chronic HF has been shown to be an independent predictor of increased mortality.Given this apparent paradox in therapeutic goals (treat aggressively but keep BP from going too low), how low should we allow systemic BP to go as a result of our medication regimens before we compromise the proven benefits of such drug therapy? Or is the association between the BP-lowering effects of standard therapy and outcomes in HF even meaningful clinically?It is from this perspective that the merits, potential clinical implications, and the relevant published literature pertaining to this patient and practice management issue will be discussed.     

Hypertension in Patients with Heart Failure with Reduced Ejection Fraction

Hypertension (HTN) is a well-known health problem associated with considerable morbidity and mortality and it is an important risk factor for the development of heart failure (HF). These findings support the need for optimizing the antihypertensive strategies to prevent the progression to HF. Interestingly, the progression from HTN to HF, among other things, may be a consequence of inappropriate over-activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system (SNS), and the natriuretic peptide system (NPS). In the present review, we will discuss the pathophysiological aspects of the progression from HTN to HF with reduced ejection fraction (HFrEF) and we will focus on the evolution of different pharmacological therapies which are reported to be effective in reducing BP and improving HF outcomes, paying particular attention to the recent trials that have demonstrated the efficacy of the combined therapy of RAAS blockade and Neprilysin (NEP) inhibitor in lowering BP and mediating several beneficial actions within cardiovascular tissues, such as avoiding the worsening of HF.     

Sleep Apnea in Heart Failure

Purpose of review

In this review, we discuss the current treatment options for sleep-disordered breathing (SDB) in patients with heart failure (HF). We address the role of positive airway pressure (PAP) devices and other emerging therapies. The review includes discussion of recent trials that reported negative consequences for the PAP devices in patients with heart failure.

Recent findings

Optimal guideline-directed medical therapies of HF and PAP devices have been the mainstay treatments for HF patients with SDB. Recently, randomized controlled trials (RCTs) evaluated the effect of PAP on clinical outcomes in patients with cardiovascular (CV) disease and heart failure and found no benefit in decreasing fatal and non-fatal CV events. The Sleep Apnea Cardiovascular Endpoints (SAVE) trial evaluated continuous positive airway pressure (CPAP) ventilation in patients with CV disease and obstructive sleep apnea (OSA) and did not observe any improvement in CV effect. In patients with HF and central sleep apnea (CSA), adaptive servo-ventilation (ASV) was hypothesized to help HF outcomes, but the Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure (SERVE-HF) trial did not show any mortality benefit. Instead, the trial suggested an increase in all-cause and CV mortality in the treatment arm.

Summary

currently, studies have not shown the use of PAP therapy to improve any risks of CV outcomes or death in HF patients with sleep apnea, but some associations with improvements in symptoms from OSA have been observed.

     

Advances in the management of sleep-disordered breathing in heart failure

Obstructive (OSA) and central sleep apnea (CSA) are very common in patients with congestive heart failure (CHF). This is clearly a risk factor for worsening the prognosis of patients. Treatment of sleep apnea in these patients may stop disease progression. Modern therapy, primarily central sleep apnea, is provided by adaptive servoventilation (ASV). Short-term randomized trials have demonstrated that treatment with ASV increased ejection fraction (EF), reduces sympathetic activity and blood pressure. Unfortunately, there is not enough data on whether there are effects on mortality and morbidity. Studies of this issue, such as SERVE-HF and ADVENT-HF, are currently in progress and results are expected. There are other forms of therapy of OSA like CPAP, oxygen, theophylline, acetazolamide, heart synchronisation therapy and transplantation. In patients with a predominance of OSA, in addition to previous methods, there are other recommended forms of therapy like appropriate weight loss, orthodontic appliances and surgical treatment.     

Ca channel blocker and heart failure

Ca channel blocker (CCB) inhibits the entry of calcium ion through L-type calcium channel in the vascular smooth muscle, and possesses the blood pressure lowering action. It was expected that CCB might be useful for the treatment of heart failure (HF) because of its vasodilating action. However, the prospective, randomized, double-blind, crossover studies have shown that the short-acting CCBs rather increase morbidity and mortality in patients with chronic HF during the long-term follow-up. It would be due to the fact that CCBs increase the sympathetic nerve activity and cause tachycardia in response to their acute vasodilating effects. Amlodipine, the long-acting CCB, has been shown to have a neutral effect on morbidity and mortality in patients with HF. Recently, new CCBs, which do not increase heart rate, have been developed. These drugs exert the inhibitory action for N- or T-type Ca channel or directly prevent sympathetic nerve activity. Furthermore, some CCBs may act protectively in HF by stimulating nitric oxide production and/or inhibiting oxidative stress. Newly developed CCBs promise to be useful for the treatment of chronic HF.     

阻塞性睡眠呼吸暂停患者持续正压通气治疗前后自主神经 …

目的 研究阻塞性睡眠呼吸暂停（ＯＳＡ）患者夜间睡眠时自主神经功能的状态，以及有效的持续正压通气治疗对自主神经张力的影响。方法 对５６例重度ＯＳＡ患者持续正压通气（ＣＰＡＰ）治疗前和治疗中进行夜间７小时多导睡眠图（ＰＳＧ）及动态心电图监测，另择３０名正常受试者作为对照。采用心率功率谱分析法（ＨＲＰＳＡ）定量分析ＯＳＡ患者治疗前后夜间自主神经功能的变化。结果 ＯＳＡ组夜间睡眠时伴随着反复的呼吸暂停和低     

Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients.

Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Several randomised controlled trials have shown that continuous positive airway pressure (CPAP) treatment of OSA reduces blood pressure (BP). This randomised, sham-placebo controlled crossover trial assesses whether CPAP produces a similar clinically significant fall in BP in hypertensive OSA patients, but without hypersomnolence. Thirty-five, nonsleepy, hypertensive patients with OSA were treated with CPAP for 1 month, randomised first to either therapeutic or sham-placebo (subtherapeutic CPAP, about 1 cmH(2)O pressure). The second months' alternative treatment followed a 2-week washout period. BP was measured over 24 h, before and at the end of the two treatment periods: mean 24-h BP was the primary outcome variable. There was no overall significant difference in mean 24-h BP: the change in mean 24-h BP on therapeutic CPAP was -2.1 mmHg (sd 8.1), and -1.1 mmHg (sd 8.1) on subtherapeutic CPAP, with a difference of 0.7 mmHg (95% confidence interval (CI) +2.9- -4.4). There was a small significant fall in Epworth Sleepiness Score, therapeutic (-1.4) versus sham (-0.3), and difference -1.2 (95% CI -2.0- -0.4), but no change in objective sleepiness. In nonhypersomnolent hypertensive patients with obstructive sleep apnoea, there is no significant fall in mean 24-h blood pressure with continuous positive airway pressure, in contrast to the fall seen in hypersomnolent patients with obstructive sleep apnoea.     

Renal Denervation for Treating Hypertension: Current Scientific and Clinical Evidence

Initial studies of catheter-based renal denervation (RDN) for uncontrolled HTN using radiofrequency ablation in the main renal arteries showed that RDN was effective in lowering office blood pressure (BP). However, the first randomized sham-controlled trial, SYMPLICITY-HTN-3, did not show significantly lower office or 24-h ambulatory systolic BP compared with sham treatment. Subsequent studies in both animals and humans demonstrated the potential importance of more distal and branch renal artery radiofrequency ablation, and a second-generation multielectrode system became available. Two recent randomized sham-controlled trials in patients not taking antihypertensive drugs (SPYRAL HTN-OFF MED) or continuing to take drugs (SPYRAL HTN-ON MED) performed RDN with the second-generation radiofrequency ablation system using an ablation protocol that included treatment of the distal renal artery as well as the branch renal arteries. These studies showed that RDN significantly reduced office and 24-h ambulatory BP compared with sham treatment. Another recent randomized sham-controlled trial in patients not receiving medications showed that RDN with catheter-based ultrasound (RADIANCE-HTN SOLO) applied in just the main renal arteries significantly lowered daytime ambulatory and office BP compared with sham treatment. These trials have renewed clinical and scientific interest in defining the appropriate role of RDN in hypertension treatment. In addition, other important issues will need to be addressed in the future such as the development of tests to determine the extent of RDN at the time of the procedure and the potential of renal nerve fibers to regain their patency at some later stage following the ablation procedure.