Baroreceptor Activation Therapy Research Articles

Percutaneous Strategies in Structural Heart Diseases: Focus on Chronic Heart Failure.

Central Illustration : Percutaneous Strategies in Structural Heart Diseases: Focus on Chronic Heart Failure Transcatheter devices for monitoring and treating advanced chronic heart failure patients. PA: pulmonary artery; LA: left atrium; AFR: atrial flow regulator; TASS: Transcatheter Atrial Shunt System; VNS: vagus nerve stimulation; BAT: baroreceptor activation therapy; RDN: renal sympathetic denervation; F: approval by the American regulatory agency (FDA); E: approval by the European regulatory agency (CE Mark). Innovations in devices during the last decade contributed to enhanced diagnosis and treatment of patients with cardiac insufficiency. These tools progressively adapted to minimally invasive strategies with rapid, widespread use. The present article focuses on actual and future directions of device-related diagnosis and treatment of chronic heart failure.

Sympathetic modulation as a goal of antihypertensive treatment: from drugs to devices.

The present study aims to examine the effects of nonpharmacological, pharmacological and devices-based treatment on hypertension-related sympathetic overactivity. This will be done by analyzing the results of different published studies, in which sympathetic activity has been assessed via indirect or direct techniques. After examining the rationale for sympathomodulatory interventions in antihypertensive treatment, the study will discuss the methodological intrinsic limitations of the studies aimed at assessing different therapeutic interventions. The core of the study will be then focused on the effects of nonpharmacological (dietary restriction of sodium intake, physical exercise training, weight reduction), pharmacological (monotherapy, combination drug treatment, new drugs such as sodium glucose co-transport protein-2 inhibitors and angiotensin receptor neprilysin inhibitors), as well as devices-based interventions (renal sympathetic nerves ablation and carotid baroreceptor activation therapy) on the hypertension-related sympathetic overdrive. Finally, the areas worthy of future research as well as the debated issues in the field will be highlighted.

A Comparative Review of Vagal Nerve Stimulation Versus Baroreceptor Activation Therapy in Cardiac Diseases.

Sympathetic imbalance coupled with impairment of baroreceptor control is a key factor responsible for hemodynamic abnormalities in congestive heart failure. Vagal nerve stimulation (VNS) and baroreceptor activation therapy (BAT) are two novel interventions for the same. In this paper, we review the role of sympathovagal alterations in cardiac diseases like heart failure, arrhythmia, hypertension (HTN), etc. Studies like neural cardiac therapy for heart failure (NECTAR-HF), autonomic regulation therapy to enhance myocardial function and reduce progression of heart failure (ANTHEM-HF), and baroreflex activation therapy for heart failure (BEAT-HF), which comprise the history, efficacy, limitations, and current protocols, were extensively analyzed in contrast to one another. Vagal nerve stimulation reverses the reflex inhibition of cardiac vagal efferent activity, which is caused as a result of sympathetic overdrive during the course for heart failure. It has shown encouraging results in certain pre-clinical studies; however, there is also a possibility of serious cardiovascular adverse events if given in higher than the recommended dosage. Attenuated baroreflex sensitivity is attributed to cardiac arrhythmogenesis during heart failure. Baroreceptor activation therapy reverses this phenomenon. However, the surgical procedure for baroreceptor stimulation can have unwarranted complications, including worsening heart failure and hypertension. Considering the effectiveness of the given modalities and taking into account the inconclusive evidence of their adverse events, more clinical trials are needed for establishing the future prospects of these interventional approaches.

Device-based neuromodulation for cardiovascular diseases and patient' s age.

The autonomic nervous system plays an important role in the pathogenesis of cardiovascular diseases. With aging, autonomic activity changes, and this impacts the physiological reactions to internal and external signals. Both sympathetic and parasympathetic responses seem to decline, reflecting functional and structural changes in nervous regulation. Although some investigators suggested that both the sympathetic and parasympathetic activities were suppressed, others found that only the parasympathetic activity was suppressed while the sympathetic activity increased. In addition, cardiac innervation progressively diminishes with aging. Therefore, one may suggest that neuromodulation interventions may have different effects, and older age groups can express an attenuated response. This article aims to discuss the effect of device-based neuromodulation in different cardiovascular diseases, depending on the patient's age. Thus, we cover renal denervation, pulmonary artery denervation, baroreceptor activation therapy, vagus nerve stimulation, spinal cord stimulation, ganglionated plexi ablation for the management of arterial and pulmonary hypertension, heart failure, angina and arrhythmias. The results of many clinical studies appeared to be unconvincing. In view of the low rate of positive findings in clinical studies incorporating neuromodulation approaches, we suggest the underestimation of advanced age as a potential contributing factor to poorer response. Analysis of outcomes between different age groups in clinical trials may shed more light on the true effects of neuromodulation when neutral/ambiguous results are obtained.

Current and future use of neuromodulation in heart failure.

Autonomic imbalance is a common finding in heart failure (HF) with reduced ejection fraction (HFrEF). Addressing different targets within the autonomic nervous systems has been evaluated in patients with HF, including renal sympathetic denervation, vagal nerve stimulation, and baroreceptor activation therapy (BAT). Although all are pathophysiologically plausible and promising, only BAT shows sufficient evidence for implementation into clinical practice in randomized controlled trials. Baroreceptor activation therapy can be used in patients with symptomatic HFrEF despite optimal guideline-directed medication and device therapy. This article reviews the current and future use of neuromodulation in HF and provides an overview on current guideline recommendations and clinical practice.

Neuromodulatory Approaches for Atrial Fibrillation Ablation.

In this review, the authors describe evolving alternative strategies for the management of AF, focusing on non-invasive and percutaneous autonomic modulation. This modulation can be achieved – among other approaches – via tragus stimulation, renal denervation, cardiac afferent denervation, alcohol injection in the vein of Marshall, baroreceptor activation therapy and endocardial ganglionated plexi ablation. Although promising, these therapies are currently under investigation but could play a role in the treatment of AF in combination with conventional pulmonary vein isolation in the near future.

Neuroscientific therapies for atrial fibrillation.

The cardiac autonomic nervous system (ANS) plays an integral role in normal cardiac physiology as well as in disease states that cause cardiac arrhythmias. The cardiac ANS, comprised of a complex neural hierarchy in a nested series of interacting feedback loops, regulates atrial electrophysiology and is itself susceptible to remodelling by atrial rhythm. In light of the challenges of treating atrial fibrillation (AF) with conventional pharmacologic and myoablative techniques, increasingly interest has begun to focus on targeting the cardiac neuraxis for AF. Strong evidence from animal models and clinical patients demonstrates that parasympathetic and sympathetic activity within this neuraxis may trigger AF, and the ANS may either induce atrial remodelling or undergo remodelling itself to serve as a substrate for AF. Multiple nexus points within the cardiac neuraxis are therapeutic targets, and neuroablative and neuromodulatory therapies for AF include ganglionated plexus ablation, epicardial botulinum toxin injection, vagal nerve (tragus) stimulation, renal denervation, stellate ganglion block/resection, baroreceptor activation therapy, and spinal cord stimulation. Pre-clinical and clinical studies on these modalities have had promising results and are reviewed here.

Autonomic Modulation of Cardiac Arrhythmias: Methods to Assess Treatment and Outcomes.

The autonomic nervous system plays a central role in the pathogenesis of multiple cardiac arrhythmias, including atrial fibrillation and ventricular tachycardia. As such, autonomic modulation represents an attractive therapeutic approach in these conditions. Notably, autonomic modulation exploits the plasticity of the neural tissue to induce neural remodeling and thus obtain therapeutic benefit. Different forms of autonomic modulation include vagus nerve stimulation, tragus stimulation, renal denervation, baroreceptor activation therapy, and cardiac sympathetic denervation. This review seeks to highlight these autonomic modulation therapeutic modalities, which have shown promise in early preclinical and clinical trials and represent exciting alternatives to standard arrhythmia treatment. We also present an overview of the various methods used to assess autonomic tone, including heart rate variability, skin sympathetic nerve activity, and alternans, which can be used as surrogate markers and predictors of the treatment effect. Although the use of autonomic modulation to treat cardiac arrhythmias is supported by strong preclinical data and preliminary studies in humans, in light of the disappointing results of a number of recent randomized clinical trials of autonomic modulation therapies in heart failure, the need for optimization of the stimulation parameters and rigorous patient selection based on appropriatebiomarkers cannot be overemphasized.

Nonpharmacologic Treatment for Heart Failure: A Review of Implantable Carotid Baroreceptor Stimulators As a Therapeutic Option.

There has been significant interest in research for the development of device-based therapy as a treatment option of heart failure (HF), whether it is with reduced or preserved ejection fraction. This is due to the high morbidity and mortality rate in patients with HF despite recent advances in pharmacologic treatment. Following the success of cardiac resynchronization therapy, baroreceptor activation therapy has emerged as another novel device-based treatment for HF. The Barostim neo was developed by CVRx Minneapolis, MN for the treatment of mild to severe HF. The device works by electrically activating the baroreceptor reflex with the goal to restore the maladaptive autonomic imbalance that is seen in patients with HF. Preliminary clinical investigations have given promising results with an encouraging safety profile. Baroreceptor activation therapy as a treatment option is still investigational at this time; however, several trials in different patient populations have already shown benefit with a very good safety profile. In this review, we will summarize the current state of technology and the available literature of the use of baroreceptor activation therapy in patients with different comorbidities, with a focus on this device-based therapy in patients with HF.

Recent advances in understanding and managing resistant/refractory hypertension.

The management of resistant hypertension presents several challenges in everyday clinical practice. During the past few years, several studies have been performed to identify efficient and safe pharmacological and non-pharmacological options for the management of such patients. The Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2) trial demonstrated significant benefits with the use of spinorolactone as a fourth-line drug for the treatment of resistant hypertension over doxazosin and bisoprolol. In addition, recent data support that spironolactone may demonstrate superiority over central acting drugs in such patients, as well. Based on the European guidelines, spironolactone is recommended as the fourth-line drug option, followed by amiloride, other diuretics, doxazosin, bisoprolol or clonidine. Among several device-based approaches, renal sympathetic denervation had fallen into hibernation after the disappointing results of the Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN) 3 trial. However, the technique re-emerged at the epicenter of the clinical and research interest after the favorable results of three sham-controlled studies, which facilitated novel catheters and techniques to perform the denervation. Significant results of iliac anastomosis on blood pressure levels have also been demonstrated. Nevertheless, the technique-related adverse events resulted in withdrawal of this interventional approach. Last, the sympatholytic properties of the carotid baroreceptor activation therapy were associated with significant blood pressure reductions in patients with resistant hypertension, which need to be verified in larger controlled trials. Currently device-based approaches are recommended only in the setting of clinical trials until more safety and efficacy data become available.

Smart Baroreceptor Activation Therapy Strikingly Attenuates Blood Pressure Variability in Hypertensive Rats With Impaired Baroreceptor.

Increased blood pressure (BP) variability (BPV) is an independent risk factor of cardiovascular events among hypertensive patients. The arterial baroreceptor reflex is a powerful regulator of BP and attenuates BPV via a sympathetic negative feedback control. Conventional baroreceptor activation therapy (cBAT) electrically stimulates the carotid baroreceptors with constant stimulation parameters. While cBAT lowers BP, it does not mount a pressure feedback mechanism. We hypothesized that baroreceptor activation therapy with a pressure feedback system (smart BAT [sBAT]) is able to reduce BPV as well as lower BP. We developed sBAT that electrically stimulated baroreceptors at a frequency proportional to the difference between instantaneous BP and a preset reference pressure, and compared its performance with cBAT. In 14-week-old spontaneously hypertensive rats (n=6), we implanted BP telemeter and created impaired arterial baroreceptors by modified sino-aortic denervation. One week after surgical preparation, we administered sBAT, cBAT or no stimulation (sham) for 15 minutes and compared BP and BPV under freely moving condition. Both cBAT and sBAT significantly lowered mean BP (sham, 141.3±12.8; cBAT, 114.3±11.4; and sBAT, 112.0±7.3 mm Hg). Conventional BAT did not affect BPV at all, while sBAT significantly reduced BPV (sham, 15.4±2.6; cBAT, 16.0±5.2; and sBAT, 9.7±3.3 mm Hg). sBAT also prevented transient excessive BP rise and fall. In conclusion, sBAT was capable of reducing BP and attenuating BPV in hypertensive rats with impaired baroreceptor. sBAT is a novel treatment option for hypertensive patients with increased BPV.

Device-device interaction

With a continuous increase in the approval of cardiac implantable electronic devices (CIED), not only pacemakers (PM) and implantable cardioverter defibrillators (ICD) but especially devices for treating chronic heart failure, more and more possibilities of device-device interactions arise, which in isolated cases can lead to death of the patient. Because of the still low numbers of patients overall, there are very few scientific studies and only isolated case reports on this topic. Devices which are at risk of interaction with a previously implanted PM are wearable cardioverter defibrillators (WCD) and subcutaneous ICDs (S-ICD). These two devices both use the surface electrocardiogram (ECG) in their algorithm for detecting ventricular arrhythmia. These surface ECGs seem to be prone to unipolar pacemaker stimulation artefacts. By correct programming of implanted pacemakers in the bipolar stimulation mode it is possible to avoid ECG artefacts and inadequate treatment. In baroreceptor activation therapy (BAT) there seem to be no device interactions so far, even though this device shows substantial highly frequent artefacts in the ECG. The cardiac contractility modulation (CCM) system has also until now not shown interactions with transvenous or subcutaneous ICD devices, even though randomized trials are missing.

Devices and interventions for the prevention of adverse outcomes of tachycardia on heart failure.

Heart failure (HF) is the leading cause of hospitalization in the USA. Despite advances in pharmacologic management, the incidence of HF is on the rise and survivability is persistently reduced. Sympathetic overdrive is implicated in the pathophysiology of HF, particularly HF with reduced ejection fraction (HFrEF). Tachycardia can be particularly deleterious and thus has spurred significant investigation to mitigate its effects. Various modalities including vagus nerve stimulation, baroreceptor activation therapy, spinal cord stimulation, renal sympathetic nerve denervation, left cardiac sympathetic denervation, and carotid body removal will be discussed. However, the effects of these modalities on tachycardia and its outcomes in HFrEF have not been well-studied. Further studies to characterize this are necessary in the future.

Carotid baroreceptor activation therapy for resistant hypertension and heart failure: a report of two cases.

A vast number of drugs and treatment strategies have been approved for treatment of hypertension in the last three decades. However, despite these advances, there is still a reported prevalence of 3 to 30% of treatment-resistant hypertension (TRH) [1]. According to 2013 ESH/ESC guidelines for the management of arterial hypertension, TRH is defined as an office measurement of systolic blood pressure (BP) > 140 mm Hg and/or diastolic BP of > 90 mm Hg despite appropriate life-style measures and antihypertensive treatment including a diuretic (at full dose) and two other antihypertensive drugs of different classes at adequate doses [2]. Following catheter-based renal denervation therapy, the concept of TRH has gained popularity and specific therapies have emerged including carotid baroreceptor activation therapy (BAT). Similar to the concept of TRH, despite enormous advances in surgical and medical treatment of heart failure (HF), 25 to 35% of cases remain in NYHA class III. These patients often experience moderate to severe heart failure symptoms and have a low quality of life, causing increased health care costs. We already know that adrenergic activation and parasympathetic denervation have a role in symptom occurrence and disease progression [3]. With this rationale, carotid BAT has emerged as a therapeutic strategy in treatment of heart failure. Here, we report two cases, one with resistant hypertension and the other with heart failure treated with surgical BAT. Written informed consent was obtained from each patient for submission of the report.

Resistant Hypertension and Cardiorenovascular Risk

Abstract Studies have documented independent contribution of sympathetic activation to the cardiovascular disease continuum. Hypertension is one of the leading modifiable factors. Most if not all the benefit of antihypertensive treatment depends on blood pressure lowering, regardless how it is obtained. Resistant hypertension is defined as blood pressure that remains uncontrolled in spite of the concurrent use of three antihypertensive drugs of different classes. Ideally, one of the three drugs should be a diuretic, and all drugs should be prescribed at optimal dose amounts. Poor adherence to antihypertensive therapy, undiscovered secondary causes (e.g. obstructive sleep apnea, primary aldosteronism, renal artery stenosis), and lifestyle factors (e.g. obesity, excessive sodium intake, heavy alcohol intake, various drug interactions) are the most common causes of resistant hypertension. Cardio(reno)vascular morbidity and mortality are significantly higher in resistant hypertensive than in general hypertensive population, as such patients are typically presented with a long-standing history of poorly controlled hypertension. Early diagnosis and treatment is needed to avoid further end-organ damage to prevent cardiorenovascular remodeling. Treatment strategy includes lifestyle changes, adding a mineralocorticoid receptor antagonist, treatment adherence in cardiovascular prevention and, in case of failure to control blood pressure, renal sympathetic denervation or baroreceptor activation therapy. The comparative outcomes in resistant hypertension deserve better understanding. In this review, the most current approaches to resistant hypertension and cardiovascular risk based on the available literature evidence will be discussed.

Sustained Reduction of Blood Pressure With Baroreceptor Activation Therapy: Results of the 6-Year Open Follow-Up.

Baroreflex activation therapy is a novel technique for treating patients with resistant hypertension. Although short-term studies have demonstrated that it lowers blood pressure, long-term results have not yet been reported. The aim of the present study is to assess the long-term efficacy and safety of baroreflex activation therapy. Long-term follow-up data were analyzed from all patients who had been included in 1 of the 3 trials that focused on treatment-resistant hypertensive patients. Altogether, 383 patients were available for analysis: 143 of these had completed 5 years of follow-up and 48 patients had completed 6 years of follow-up. In the entire cohort, office systolic blood pressure fell from 179±24 mm Hg to 144±28 mm Hg (P<0.0001), whereas office diastolic pressure dropped from 103±16 mm Hg to 85±18 mm Hg (P<0.0001). Heart rate fell from 74±15 beats per minute to 71±13 beats per minute (P<0.02). The effect of baroreflex activation therapy is greater than average in patients with signs of heart failure and less than average in patients with isolated systolic hypertension. In ≈25% of patients, it was possible to reduce the number of medications from a median of 6 to a median of 3. Temporary side effects, related to either the surgical procedure or the cardiovascular instability, do occur, but they do not require specific measures and resolve over time.After a follow-up of 6 years, baroreflex activation therapy maintains its efficacy for persistent reduction of office blood pressure in patients with resistant hypertension without major safety issues.

Device-Based Therapy for Drug-Resistant Hypertension: An Update.

Drug-resistant hypertension (RH) remains a significant and common cardiovascular risk despite the availability of multiple potent antihypertensive medications. Uncontrolled resistant hypertension contributes substantially to excessive cardiovascular and renal morbidity and mortality. Clinical and experimental evidence suggest that sympathetic nervous system over-activity is the main culprit for the development and maintenance of drug-resistant hypertension. Both medical and interventional strategies, targeting the sympathetic over-activation, have been designed in patients with hypertension over the past few decades. Minimally invasive, catheter-based, renal sympathetic denervation (RDN) and carotid baroreceptor activation therapy (BAT) have been extensively evaluated in patients with RH in clinical trials. Current trial outcomes, though at times impressive, have been mostly uncontrolled trials in need of validation. Device-based therapy for drug-resistant hypertension has the potential to provide alternative treatment options to certain groups of patients who are refractory or intolerant to current antihypertensive medications. However, more research is needed to prove its efficacy in both animal models and in humans. In this article, we will review the evidence from recent renal denervation, carotid baroreceptor stimulation therapy, and newly emerged central arteriovenous anastomosis trials to pinpoint the weak links, and speculate on potential alternative approaches.

Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights

Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

OP-051 Baroreceptor Activation Therapy with Barostim Neo for Treatment of Resistant Hypertension and/or Heart Failure: First Reported 2 Cases in Turkey

OP-051 Baroreceptor Activation Therapy with Barostim Neo for Treatment of Resistant Hypertension and/or Heart Failure: First Reported 2 Cases in Turkey

Clinical Implications

Clinical Implications