Baroreceptor Activation Therapy: The Importance of Targeting the Right Patient: Who Needs to be Treated? (2015)

There are truths, which are not for all men, nor for all times. (Voltaire) Baroreflex abnormal responses in chronic heart failure (HF) have been reported both in experimental and human studies1 in association with a prolonged exposure to low cardiac output and reduced blood pressure. The exact mechanism of this baroreceptor dysfunction is still debated but it is reversible after optimization of medical treatment or after cardiac transplantation,2 Arterial baroreceptor function (baroreflex sensitivity, BRS) appeared to be a powerful and independent predictor of prognosis in HF patients, both in pre- and post-beta-blockade era.3, 4 The predictive value of BRS stands in the fact that it is a specific individual tract5 and not merely an indicator of cardiac function: it mirrors the complex sympathovagal interaction between afferent receptor information originating from the entire cardiovascular area.6 Pharmacological management of HF relies on principles 30–50 years old and suffers the major limitation of targeting the end-organ consequences of the autonomic imbalance. Very recently the novel approach of direct nerve stimulations has generated great interest. This comprises active stimulation of baroreceptors (BAT) or of the cervical vagus nerve (VS) in an attempt to ameliorate sympathovagal imbalance in the heart.7 The BAT approach presumes that central integration of the afferent signal is preserved and this is proven by the sustained inhibitory action on MSNA. However, to date, very little has been seen in terms of vagal effects on heart rate both with BAT and VS and this might be due to the extensive use of beta-blockers but also to the modality of stimulation resulting in primary afferent activation even in the case of VS. In this prospective, the ongoing multi-centre randomized clinical trial ‘INOVATE-HF’ uses a more physiological heart beat synchronized modality and may provide novel understanding on human vagal stimulation.8 In this issue, Zile et al.9 extended the experience on the effects of BAT in HF patients with reduced left ventricular ejection fraction (LVEF) recently published by the same group10 by testing in a pre-specified analysis any possible differences in patients with and without implanted cardiac resynchronization therapy (CRT). The rationale is that CRT per se may influence the sympathovagal balance to the heart and vessels and thus affect the potential benefit of BAT.11, 12 In the main paper10 the authors randomly assigned 146 HF patients in New York Heart Association (NYHA) class III, LVEF <35%, estimated glomerular filtration rate (eGFR) ≥30 mL/min.1.73 m2, heart rate 60–100 bpm, and systolic blood pressure ≥100 mmHg to guideline-directed medical therapy (GDMT) (n = 70) or to GDMT + BAT (n = 76). Patients assigned to BAT after 6 months follow-up showed improvement in 6-min walking test, Quality of Life score, NYHA class, and N-terminal pro-brain natriuretic peptide (NT-proBNP). No significant difference in LVEF and a positive but non-significant trend in the reduction of HF hospitalization was observed. The safety of BAT was encouraging and it was well tolerated by the patients. Unfortunately, authors could not provide evidence of the modulation of vagal and sympathetic activity by BAT, as heart rate was unchanged and none of the indexes proposed to study autonomic modulation was used. In addition, some important issues such as the use of hospital resources could not be properly assessed, mainly because of a small sample size combined with the relatively low hospitalization rate observed mostly in the US population. Indirectly, the authors speculate, perhaps correctly, that BAT caused a reduction of peripheral sympathetic nerve activity to the vessels and in turn of vascular resistance; this positive effect via an increase in stroke volume may have resulted in the slight increase in systolic blood pressure and pulse pressure observed in treated patients. In HF a similar effect has been described in pharmacological treatment with intravenous vasodilators that, by reducing vascular resistance, improve stroke volume, increase systolic blood pressure and may decrease heart rate. In the proof of concept study by Gronda et al,13, eleven patients were studied by serial measurement of muscle sympathetic nerve activity (MSNA) at baseline and 6 months after BAT. The MSNA decreased from 75 to 45 bursts/100 heartbeats (reduced by one-third), confirming a BAT-induced reduction of the sympathetic outflow to the vessel and of vascular resistance. Patients with CRT were excluded in this study. The rationale that imposes a specific analysis for CRT patients is that resynchronization therapy has been shown to favourably affect autonomic nervous system in HF via different mechanisms: (i) first of all by improving, per se, the haemodynamic performance; (ii) by producing a significant reduction in the excitatory afferent input into the central nervous system from the ventricular receptors previously activated by the distorted mechanical activity of the dysfunctional and non-synchronized ventricles; and (iii) by counteracting the remodelling of cholinergic signalling. With this background in mind, Zile and co-authors9 have reanalysed the data of the 146 patients enrolled in the multicentre study according to the presence or absence of CRT (nearly 35%). The final analyses, after considering 10% lost data, were based on a control (non-BAT) group of 54 patients (17 CRT) and on a BAT group of 64 patients (22 CRT) in a study design in which sample size was not estimated as a function of reaching a specific endpoint. At 6 months the trend is in favour of a more pronounced effect of BAT in patients without CRT in some but not in all parameters; the difference was statistically significant in Quality of Life, 6-minute hall walk distance and LVEF, and not significant for NYHA class, NT-proBNP and number of HF hospitalizations. With the information available from the study the data interpretation is cumbersome and speculative but two considerations can be proposed. First is the fact that LVEF was lower in the CRT group, suggesting a condition of non-response and thus a subgroup of patients possibly non-responsive to any additional intervention. Moreover, CRT responders might have achieved maximal reduction in sympathetic drive with no chance of further improvement with BAT. Overall, despite the intrinsic limitations of the data, as in any subanalyses of a randomized trial, the study by Zile et al.9 raises important questions: Do we know those patients who can benefit of active modulation of baroreceptors? Should this invasive technique be proposed for all NYHA class III HF patients with LVEF <35%? The answer, as underlined by Zile et al.'s paper, is definitely ‘no’, but probably the presence of implanted CRT is just one of the possible factors that may influence the response to BAT. We can try to list some of these factors: (i) responders to CRT (and not CRT per se); (ii) beta-blockers, especially carvedilol, at optimized dose; (iii) vasodilators tolerated at high dose; (iv) the presence of another source of sympathetic activation and vagal withdrawal such as ischaemia, anaemia, central or obstructive sleep apnea, or chronic obstructive pulmonary disease; (v) diabetic neuropathy; (vi) hypertrophic cardiomyopathy and many other conditions. Put simply, BAT should not be implanted in all HF patients with depressed LVEF, who are in stable NYHA class III, and in whom a sympathetic hyperactivity is not demonstrated. Can we use surrogated measures of sympathovagal imbalance to the heart and vessels such as mean heart rate, pulse pressure, or plasma catecholamine levels? Again the answer is ‘no’ because heart rate, at least in Europe, may be modulated also by ivabradine and amiodarone, and plasma catecholamines are difficult to measure and not specific for baroreceptor dysfunction. To date, we have the extraordinary opportunity to modulate baroreflex sensitivity but we have to relearn how to measure autonomic imbalance to the heart and vessels in an attempt to identify target patients for this fascinating therapy. Baroreflex sensitivity can be tested by continuous beat-to-beat analysis of heart rate and blood pressure variability, or by measuring, as in the study by Gronda et al.,13 the level of sympathetic withdrawal to muscle neural activity. In conclusion, pharmacologic autonomic interventions, namely angiotensin-converting enzyme inhibitors and beta-blockers are, to date, the pillar of HF therapy. The current therapeutic armamentarium targets the end organ response to the autonomic perturbation associated with HF but nothing can actually intervene in the pathophysiology of this perturbation. Direct stimulation of autonomic nerves appears to be a promising approach to eventually intervening directly in the erroneous signalling that produces the autonomic alteration observed in HF. In this context, BAT has a solid pathophysiological background and the first reports, such as the one presented in the present issue of this journal, are encouraging but there is, however, still a long way to go. Specifically, it is critical to identify, among the whole HF populations, those patients most likely to benefit from BAT. The present study suggests that CRT might already fulfil the therapeutic options in advanced HF patients but does not resolve the issue if this is true for all patients treated independently of their response to therapy. Although BAT requires a relatively modest invasive and safe approach, as for vagal stimulation it requires patients to carry a second device besides implantable cardioverter defibrillator (ICD)/CRT. Thus, for the many reason just presented, a proper selection of patients will be mandatory for the development of this treatment. Conflicts of interest: none declared.