Baroreflex activation therapy systems: current status and future prospects.

Introduction: Resistant hypertension is characterized by an hyperadrenergic tone and by a neurohumoral activation. In this condition drug therapies are unable to obtain a good control of blood pressure and therefore need a contribution from non-pharmachological approach. To this aim it has been hypothesized that to lower blood pressure this could be obtained through stimulation of carotid baroreceptors and modulation of the adrenergic tone.Areas covered: several studies and trials have evaluated the safety and efficacy of two devices-based therapies and this review will discuss the research obtained mainly in resistant hypertensive subjects.Expert opinion: the studies performed have clearly shown the safety and efficacy of these approaches. The stimulation of carotid baroreceptors induces a significant reduction in blood pressure values associated with a reduction in adrenergic tone. The two systems have same limitations. While baroreflex activation therapy has been upgraded to a more simple system, an upgrade of endovascular baroreflex amplification will be able to reduce the side effects. Due to the fact that neurohumoral activation and hyperadrenergic tone are present in several pathophysiological conditions it is possible to assume a wider use of these systems in the future.

Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report.

BACKGROUND: Baroreflex activation therapy (BAT) exerts in severe heart failure sympathoinhibitory effects, improving clinical variables and reducing hospitalization rate. The current follow-up study was aimed at determining the long-term effects of BAT, assessing whether BAT in heart failure allows to restore physiological levels of sympathetic function. METHODS: Seven patients out of the 11 heart failure patients aged 66.5 ±â€Š3 years (mean ±â€ŠSEM) in New York Heart Association Class III with left ventricular ejection fraction 40% or less and impaired functional capacity recruited in the study survived at the final follow-up (43.5 ±â€Š2.1 months). Measurements included muscle sympathetic nerve activity (MSNA, microneurography) and spontaneous baroreflex-MSNA sensitivity together with hospitalization rate, echocardiography, Minnesota score, New York Heart Association class and standard clinical data. Measurements were collected before and at 6, 21 and 43 months following BAT. Data were compared with those collected in 17 age-matched healthy controls. All assessments were made with the heart failure patient on optimal active therapy. RESULTS: In the seven patients, BAT maintained its beneficial effects over 43.5 ±â€Š2.1 months of follow-up. MSNA values underwent a progressive significant reduction from baseline to 21 and 43 months follow-up following BAT (from 46.2 ±â€Š2.4 to 31.3 ±â€Š3.0 e 26.6 ±â€Š2.0 bursts/min, P < 0.05 at least), becoming almost superimposable to the ones seen in healthy controls (25.5 ±â€Š0.8 bursts/min). Baroreflex-MSNA sensitivity improved, without achieving, however, a full normalization. Blood pressure and heart rate did not change. Left ventricular ejection fraction improved significantly from 32.3 ±â€Š2 to 36.7 ±â€Š3% (P < 0.05). Hospitalization rate decreased substantially when measured as days/year/patients it decreased from 10.3 ±â€Š2.5 preimplant to 1.01 ±â€Š1.4 at the 43.5th month follow-up (P < 0.02). No side effects were reported in the long-term period. CONCLUSION: The current study provides evidence that BAT in heart failure with reduced ejection fraction allows not only to improve hemodynamic and clinical profile but also to exert profound sympathoinhibitory effects, allowing an almost complete restoration of physiological levels of the sympathetic neural function.

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.

Effects of chronic carotid baroreceptor activation on arterial stiffness in severe heart failure.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF. METHODS AND RESULTS: MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3 months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3 months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables. CONCLUSIONS: Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications.

BACKGROUND: The sympathetic nervous exerts a key role in cardiovascular homeostasis control by regulating cardiac output, systemic vascular resistance, heart rate and blood pressure. MATERIALS AND METHODS: Data collected during the past 30 years have unequivocally shown that in a considerable number of cardiovascular as well as noncardiovascular disease there is a marked activation of the sympathetic nervous system which exerts in the long-term period unfavourable haemodynamic, metabolic, cardiovascular and renal effects. RESULTS: This paper will review the current knowledge on the alterations in sympathetic function described in cardiovascular disease, with particular focus on hypertension, heart failure and myocardial infarction. CONCLUSIONS: The consequences of the phoenomenon will be discussed together with its therapeutic implications. This will be done by examining the impact of nonpharmacological as well as pharmacological interventions on sympathetic cardiovascular drive. The effects of new invasive approaches, such as carotid baroreceptor stimulation as well as renal nerves ablation, will be also briefly discussed.

Long-term chronic baroreflex activation: persistent efficacy in patients with heart failure and reduced ejection fraction.

AIMS: Baroreflex activation therapy (BAT) has recently been shown to reduce muscle sympathetic nerve activity and hospitalization rate while improving clinical variables through 6 months of therapy in patients with heart failure and reduced ejection fraction (HFrEF). The objective of the present study is to extend the information on this patient cohort over a long-term follow-up. METHODS AND RESULTS: Eleven patients were enrolled in the study and presented with optimized, stable medical therapy, New York Heart Association Class III HFrEF with left ventricular ejection fraction 40% or less, impaired functional capacity and no active cardiac resynchronization therapy. For the present report, muscle sympathetic nerve activity, baroreflex sensitivity data and hospitalization rate together with standard clinical data were collected at 12 and 21.5 ±â€Š4.2 months following BAT activation. Two patients died during long-term follow-up. The remaining nine patients maintained the improvements observed at 6 months, including reduced sympathetic activity and rates of hospitalization. CONCLUSION: BAT provides long-term chronic reductions in sympathetic activity and utilization of hospital resources in patients with HFrEF. General clinical presentation, quality of life and functional capacity are likewise improved and maintained. The temporal association of BAT with sympathetic drive diminution and improvement in objective clinical measures suggests a cause-and-effect relationship that will be verified in future randomized controlled trials of outcome.

Carotid Baroreceptor Stimulation in Resistant Hypertension and Heart Failure.

A significant number of hypertensive subjects fail to achieve adequate blood pressure control despite adherence to maximal doses of several antihypertensive drugs. In the same way although medical and device therapies continue to improve the clinical course of heart failure patients, morbidity, mortality and healthcare costs remain high. Electrical stimulation of the carotid sinus is a new interesting approach for the treatment of resistant hypertension and heart failure. The purpose of this paper is to overview the argument starting from physiological background and evaluating the clinical results obtained with this approach in these pathophysiological conditions.

Similarities and differences between renal sympathetic denervation and carotid baroreceptor stimulation.

The two novel approaches recently introduced for the treatment of resistant hypertension, i.e. carotid baroreceptor stimulation and renal denervation, share a number of similarities but are also characterized by important differences. The similarities include the evidence that both interventions have as common pathophysiological background the state of sympathetic overdrive characterizing essential hypertension. In addition both procedures 1) are invasive, 2) exert in the short-term period clearcut blood pressure lowering effects and 3) still face a number of open questions, particularly related to the long-term blood pressure lowering effects, impact on end-organ damage and on cardiovascular events. The differences include the fact that two procedures act on distinct targets that trigger sympathetic activation and consequently blood pressure increase. In addition, only in the case of carotid baroreceptor stimulation the blood pressure effects can be easily assessed immediately following the implantation. Finally, the economic costs, metabolic effects and impact on vagal modulation of heart rate are different between the two interventions. This paper will provide a comparison of the background, effects and outcome of renal denervation and carotid baroreceptor stimulation, stressing whenever possible the clinical implications of the main features of the two interventions.

Novel antihypertensive therapies: renal sympathetic nerve ablation and carotid baroreceptor stimulation.

Therapeutic interventions aimed at reducing high blood pressure still encompass a number of difficulties and limitations. This is the case particularly in resistant hypertension, i.e. a condition characterized by a very high cardiovascular risk. Carotid baroreceptor stimulation and renal sympathetic nerves ablation represent new approaches in the treatment of this condition. This paper will provide a comparison of the effects of the two procedures, highlighting their effects on blood pressure, metabolic profile, target organ damage, safety and tolerability profile.

Sympathetic nervous system: role in hypertension and in chronic kidney disease.

PURPOSE OF REVIEW: A number of cardiovascular disease have been shown to be characterized by a marked increase in sympathetic drive to the heart and peripheral circulation. This is the case for essential hypertension, congestive heart failure, obesity, metabolic syndrome and chronic renal failure. This review focuses on the most recent findings documenting the role of sympathetic neural factors in the development and progression of the hypertensive state as well as of target organ damage. It also reviews the participation of sympathetic neural factors in the development of the earlier stages of renal failure. RECENT FINDINGS: A marked increase in sympathetic neural discharge, as assessed via the microneurographic technique, has been shown to occur in the predialytic stage of chronic renal failure. Recent evidence, however, indicates that also in the earlier clinical phases of kidney disease, sympathetic activation is detectable. Further data show that sympathetic neural mechanisms participate in renal and/or hypertensive disease progression, favouring the development of target organ damage. Finally, recent findings indicate that the metabolic disarray frequently complicating the high blood pressure state (metabolic syndrome, dislipidemia, insulin resistance) may have as pathophysiological background a sympathetic overdrive. Altogether these data represent the rationale for employing in hypertension (and particularly in resistant hypertension) therapeutic interventions such as carotid baroreceptor stimulation and renal denervation, capable of exerting sympathoinhibitory effects. SUMMARY: The sympathetic nervous system represents a major pathophysiological hallmark of both hypertension and renal failure and is an important target for the therapeutic intervention.

Blood pressure control in resistant hypertension: new therapeutic options.

Resistant hypertension, namely the hypertensive state characterized by the inability of multiple antihypertensive drug interventions to lower blood pressure to goal levels, represents a condition frequently detected in clinical practice. Its main features are represented by its heterogeneous etiology as well as its very high cardiovascular risk. This latter peculiarity has implemented the research for new approaches to the treatment of the disease. This article will focus on two of them, namely carotid baroreceptor electric stimulation and the renal denervation procedure. Clinical studies and large-scale clinical trials are presently ongoing with the aim of defining the long-term efficacy and safety profile of the two interventions.

Differential sympathetic activation in muscle and skin neural districts in the metabolic syndrome.

The present study was designed to determine whether and to what extent the activation of the sympathetic nervous system reported in the metabolic syndrome is generalized to the whole cardiovascular system or if it is rather confined to selected vascular districts. In 16 untreated patients with metabolic syndrome, 12 essential hypertensive subjects, 12 obese subjects, and 14 lean healthy normotensive controls, we measured blood pressure (Finapres, Englewood, CO), heart rate (electrocardiogram), venous plasma norepinephrine (high-performance liquid chromatography), and postganglionic sympathetic nerve traffic in the skeletal muscle and in the skin districts (microneurography). The muscle and skin nerve traffic measurements were obtained in a randomized sequence. Measurements also included skin sympathetic nerve responses to an arousal (acoustic stimulus). The 4 groups of subjects had superimposable ages. Muscle sympathetic nerve traffic values were significantly higher in subjects with hypertension and in those with obesity than in controls (51.2 +/- 2.8 and 52.0 +/- 3.0 vs 37.2 +/- 3.3 bursts per 100 heart beats, respectively; P < .01 for all). A further significant increase in muscle sympathetic nerve traffic was detected in subjects with the metabolic syndrome (61.0 +/- 3.2 bursts per 100 heart beats, P < .05). In contrast, skin sympathetic nerve traffic was not significantly different in the 4 groups of individuals (13.0 +/- 0.7, 14.3 +/- 1.3, 12.5 +/- 0.8 vs 15.4 +/- 1.0 bursts per minute, respectively; P = not significant). The skin sympathetic responses to an acoustic stimulus were also similar in the different groups. The present data provide the first direct evidence that in the metabolic syndrome the sympathetic activation is not uniformly distributed over the cardiovascular system. This may depend on the fact that muscle and skin sympathetic nerve activities are regulated by mechanisms that are affected in a different fashion by the various components of the disease.