Chronic heart failure (HF) is a clinical syndrome that affects millions of people worldwide1 and is responsible for high mortality and morbidity and decreased quality of life.2 Although HF affects 1% of the adult population, its prevalence reaches 6-10% of people over the age of 65 years1 and it is responsible for at least 20% of all hospital admissions among the elderly.3 Nearly 30% of patients with HF with decreased ejection fraction also present left ventricular (LV) electrical dyssynchrony that results in a QRS interval greater than 120 ms, most commonly with a left bundle branch block (LBBB) pattern.4 LV electrical dyssynchrony results in decreased diastolic time, anomalous septal motion and increased mitral regurgitation, with an overall reduction in left ventricular ejection fraction (LVEF).1,5

Cardiac resynchronization therapy (CRT) has shown important clinical benefits in the treatment of HF patients with systolic dysfunction (LVEF <35%) and electrical dyssynchrony (QRS >120 ms).4,6 By reducing ventricular electrical dyssynchrony, CRT improves LV systolic function while reducing myocardial oxygen consumption,7 which results in improvement of symptoms and quality of life and in a significant reduction in mortality.4,8,9 However, up to 30% of patients do not respond to CRT (nonresponders).10–12 CRT responders undergo LV reverse remodeling, which is characterized by decreases in intraventricular conduction delay and LV end-systolic volume (LVESV) and reduction in mitral regurgitation area, with a consequent increase in LVEF.8,12,13 LV reverse remodeling is thought to be responsible for the clinical improvement in responders to CRT, but the mechanisms underlying reverse remodeling are not well understood.

The autonomic nervous system (ANS) may play an important role in reverse remodeling. The ANS has an important role in cardiovascular functional and structural regulation,14,15 but ANS function is also recognized as a prognostic marker in HF.16 Furthermore, CRT induces a reduction in mean heart rate (HR) and an increase in heart rate variability (HRV).17–19 Najem et al. also showed that there was an acute increase in cardiac sympathetic activity after biventricular pacing was switched off.20 More recently, an improvement in cardiac sympathetic activity has been demonstrated in responders to CRT, assessed by 123I-MIBG scintigraphy.21,22

Nevertheless, little is known of the impact of CRT on arterial baroreflex function. The arterial baroreflex (with afferents from aortic and carotid baroreceptors) is crucial in the homeostatic regulation of blood pressure (BP).23 It is also a well-established independent prognostic marker in HF; there is evidence that low baroreflex sensitivity is associated with increased cardiovascular morbidity and overall mortality.24 However, it is not known whether baroreflex function before CRT correlates with severity of HF or with the response to cardiac resynchronization. Therefore, the aim of the present study was to assess baroreflex function in HF patients who were candidates for CRT, and to compare it with other clinical and laboratory parameters of HF severity.

Our results show that HF patients who are candidates for CRT have depressed baroreflex function. This is in agreement with the literature, since this population consisted of selected HF patients and HF is a syndrome classically characterized by compensatory chronic neurohormonal hyperstimulation, with hypersympathetic activation and attenuation of the arterial baroreflex.38,39 The extent of the reduction in baroreflex function has important prognostic value in HF, lower values of baroreflex sensitivity being associated with increases in overall mortality, cardiovascular morbidity and mortality and HF hospital admissions.24 Moreover, BEI correlated well with other variables of HF severity. Patients with lower BEI were those with increased cardiac volumes (LVESV and LVEDV), increased BNP and lower functional capacity (peak VO2). BNP and peak VO2 are two independent prognostic markers in HF.28,40 They are widely used in risk stratification of HF patients,40 with important implications for HF clinical management and treatment, including the utility of peak VO2 in stratifying patients for cardiac transplantation.41 Besides the importance of baroreflex function as a prognostic marker in HF,24 our results show that it correlates well with other risk stratification variables including BNP and peak VO2, supporting the idea that baroreflex function itself may be used in HF risk stratification. We found that BEI during tilt could be used to divide patients into low-risk and high-risk HF groups (Figure 3). In our study, patients with BEI lower than 25% had more severe HF. We suggest further studies to use this cut-off value for BEI in order to identify patients selected for CRT that have more significant HF risk.

The importance of the baroreflex in CRT is still not clear as there are few studies on this subject in the literature. However, Braga et al. reported one patient who fully recovered baroreflex function to normal values three months after CRT.39 Moreover, Gademan et al. demonstrated that there was an acute increase in baroreflex sensitivity and HRV after the implantation of a biventricular pacemaker25 and that this increase was predictive of the response to CRT.42 However, in these studies baroreflex function was assessed only after the implantation of a CRT device,25,42 with biventricular pacing switched on and off. It would be valuable to assess baroreflex function before and after CRT device implantation to better understand the autonomic impact of CRT on cardiovascular function. Moreover, the importance of a predictive index is greater when assessed before implantation. Likewise, there are no studies demonstrating that the increase in baroreflex function is sustained chronically, nor if this increase correlates with cardiac reverse remodeling. Further follow-up studies are necessary to better answer all these questions.

Our methodological approach is based on the sequence method,35 which measures baroreflex function through a non-invasive beat-to-beat measurement of HR and SBP. Although the studies that established the prognostic value of the baroreflex used the classic method for measurement of baroreflex sensitivity (the phenylephrine technique),24 there is significant evidence that non-invasive methods give similar results to those obtained through the phenylephrine technique and obviate the use of vasoactive drugs.43,44 The sequence method is used to calculate BEI, a new baroreflex function index that measures the effectiveness with which the HR responds to SBP variations.36,37,45 BEI is less liable to be influenced by ectopic beats, which were quite frequent in our patients, than baroreflex sensitivity. Recently, the assessment of baroreflex function through non-invasive methods by the use of provocative maneuvers has been extended to different clinical entities including reflex syncope,30,37 atrial fibrillation,31 and HF,25 in which it appears to improve specificity. Our work is the first to use a tilt test in HF patients and the results during the orthostatic period provided more consistent data than during the supine basal period, as BEI during tilt correlated with more HF severity variables. Our approach is innovative in the use of tilt testing in patients with HF and our results show that it is a reproducible, consistent and well-tolerated test.

The size of our study group (n=25) is the main limitation of this work. Moreover, the control group also presents some limitations, as it was age-matched but not gender-matched. Furthermore, the fact that all patients were under optimal medical treatment may also be considered a limitation to a work that aims to assess basal baroreflex function, as 96% of patients were taking a beta-blocking agent. Nevertheless, La Rovere et al. have recently shown in a prospective study that there are no significant differences in baroreflex sensitivity between HF patients treated with beta-blockers and those that are not.46

Our work shows the importance of baroreflex assessment in risk stratification of HF patients who are candidates for CRT. In the future, prospective studies with at least a six-month post-CRT follow-up are needed in order to demonstrate the existence of autonomic remodeling associated with CRT and to assess whether baroreflex measurements have predictive value concerning response to CRT.

The authors have no conflicts of interest to declare.