Prognostic Value of Baroreflex Sensitivity in Heart Failure. A 2018 Reappraisal

This article refers to 'Assessment of baroreflex sensitivity has no prognostic value in contemporary, optimally managed patients with mild-to-moderate heart failure with reduced ejection fraction: a retrospective analysis of 5-year survival' by B. Paleczny et al., published in this issue on pages xxx. Arterial baroreflexes represent a key mechanism involved in cardiovascular homeostasis and their impairment is a prominent characteristic of a number of cardiovascular diseases, including hypertension and chronic heart failure (CHF).1-3 Over the last decades, several studies suggested that CHF causes impairment of baroreflex control of heart rate (i.e. an impairment of baroreflex sensitivity, BRS).4-6 Baroreflex dysfunction has been shown to occur not only in patients with severe forms of CHF, with functional impairment quantified by New York Heart Association (NYHA) class III–IV, but also in patients with milder CHF (i.e. NYHA class I–II).2 According to the 2016 European Society of Cardiology classification of heart failure (HF) based on left ventricular ejection fraction (LVEF),7 baroreflex dysfunction mostly occurs in CHF patients with mid-range and reduced systolic function, while limited and apparently opposite data are available for those with preserved left ventricular systolic function. Impaired BRS not only represents one of the mechanisms underlying the pathophysiology of HF,3 but is also associated with a poor cardiovascular prognosis, as consistently shown in patients with established severe HF with reduced ejection fraction (HFrEF) in NYHA class III–IV.4-6 Of note, at least before the introduction of modern recommendations for pharmacologic treatment of HF, reduced BRS was found to have an independent predictive value, regardless of pharmacologic neuroendocrine modulation with beta-blockers and renin–angiotensin–aldosterone system (RAAS) blockers, both of which were shown to improve BRS.6, 8, 9 However, limited evidence does exist on the prognostic value of BRS in contemporary, optimally managed CHF patients, i.e. in patients carefully managed with current modern technological tools and sensitive risk markers, receiving optimized guideline-recommended treatment with beta-blockers and RAAS blockers,7 combined with device therapy whenever appropriate.10 Notably, limited evidence is available in patients with mild-to-moderate HFrEF (NYHA class I–II), as most previous studies demonstrated the prognostic role of reduced BRS in patients with more severe CHF (NYHA class III–IV). In this issue of the Journal, Paleczny and colleagues aimed at filling this gap in knowledge by evaluating the prognostic value of cardiac BRS in a patient population with mild-to-moderate HFrEF (average LVEF 32 ± 6%).11 To this aim, the authors performed a retrospective post-hoc analysis of a subgroup of patients participating in the prospective, observational, multicentre SICA-HF study (Studies Investigating Co-morbidities Aggravating Heart Failure), conducted in a cohort of HF patients with LVEF ≤ 40%.12 It is worth noting that the 97 HFrEF patients recruited in Wroclaw (Poland) and selected for the present retrospective analysis, did not have atrial fibrillation or a permanent pacemaker, underwent autonomic testing, and had a relatively preserved functional capacity, with 96% of them being in NYHA class I–II with mean peak oxygen consumption (VO2) of 20.2 ± 5.2 mL/kg/min at cardiopulmonary stress test. Moreover, by the time study investigations were performed, all patients were on optimal pharmacologic treatment including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers and an aldosterone receptor antagonist (in 85% of cases) as recommended by the HF guidelines available when the study started.13 All patients underwent careful BRS evaluation using three different methods: (i) spontaneous BRS estimation by means of the sequence method,14 (ii) BRS assessment during controlled breathing,15 and (iii) BRS evaluation according to the traditional laboratory approach with an intravenous injection of phenylephrine (BRS-Phe).16 Spontaneous heart rate variability (HRV) analysis was also performed in the time domain.17 The aim of the investigators was to explore the association of BRS impairment with the main clinical outcome of the study, i.e. a composite of 5-year all-cause mortality and appropriate and documented implantable cardioverter-defibrillator (ICD) discharges. The somehow surprising results of the study by Paleczny et al.11 show that assessment of cardiac BRS and HRV in mild-to-moderate HFrEF patients on optimal guideline-recommended treatment, does not provide any prognostically relevant information. Despite the accurate methodological approach to cardiac BRS assessment, the results obtained by Paleczny et al.11 should be interpreted with caution before translating them into a take home message for clinicians, given the characteristics of the study population as well as several methodological issues related to the study design. Regarding the study population, only a relatively small group of rather young, predominantly male, patients (mean age 58 ± 9 years) with mild-to-moderate HFrEF, mostly in NYHA class I–II, were included. Therefore, not only these patients are not representative of the general HF population, but also they differ from those with more severe CHF (NYHA class III–IV)4-6 in whom the prognostic role of impaired BRS was demonstrated. They also differ from those HFrEF patients (NYHA class III) expected to benefit from device therapies aimed at modulating BRS, including baroreflex activation therapy that has recently been shown to improve the clinical conditions of HF patients with these characteristics.18-20 Paleczny et al.11 attributed the lack of differences in survival between patients with reduced vs. preserved BRS to the interfering effect of optimized management, including treatment with beta-blockers and RAAS blockers, and the frequent addition of statins at optimal recommended doses. However, the absence of predictive value for BRS was also likely due to the clinical characteristics of the study population, as suggested by the finding that even VO2 (i.e. a well-established prognostic marker in CHF) was not predictive of outcome in these subjects (Table 3 in Paleczny's et al. paper).11 Some potential methodological limitations of the study by Paleczny et al. are worth mentioning, too. First, indices of BRS and other measures of cardiovascular autonomic modulation were carefully estimated only at baseline. Given that estimates of BRS and HRV, as well as patients' cardiovascular risk, may vary over time, repeated assessments during the 5-year follow-up would have been relevant to meeting the study aim of demonstrating the prognostic value of cardiac autonomic modulation. Second, the authors only focused on indices of reflex vagal cardiac modulation, and were unable to obtain an assessment of baroreflex control of sympathetic nervous activity, which is a well-recognized prognostic marker in HF patients.2 This has prevented them from obtaining a more comprehensive assessment of baroreflex cardiovascular modulation in their patients. Third, baroreflex effectiveness in slowing heart rate in response to systolic blood pressure elevation by phenilephrine injection might have been masked at least in part by the back-up rate of ICD, which might have thus interfered with BRS assessment in case of marked reflex bradycardia, in particular in patients receiving optimal beta-blocker doses. Fourth, the sample size might have been too small, with a risk of type-2 error in achieving a negative result on the prognostic value of BRS. Sample size calculation was based on a post-hoc analysis focused on its ability to have > 95% power to detect a difference in mortality between BRS-Phe < 3.0 and ≥ 3.0 ms/mmHg, but this calculation was made using the mortality rates reported by La Rovere et al.6 for severe CHF patients treated with beta-blockers and having BRS assessed with the phenylephrine method. Such a sample size calculation, however, might not fit the characteristics of the milder CHF patients of the Paleczny's study. It might also not apply to the evaluation of the prognostic value of BRS as assessed by methods other than phenylephrine injection, such as the spontaneous sequence and controlled breathing techniques, thus limiting the reliability of the conclusions on the predictive value of BRS as assessed with these methods. In spite of these limitations, however, the paper by Paleczny et al.11 does provide important information that should stimulate a reappraisal of the prognostic value of BRS in contemporary CHF patients, leading to a more focused use of this tool. The results of their study do indeed suggest that modern management of HF patients may have a considerable impact on overall survival and event-free survival, likely modifying the value of classic prognostic markers such as BRS (Figure 1), a value which might thus need to be re-evaluated. Such a re-assessment, however, should be performed in the frame of properly sized, longitudinal outcome studies, ideally including patients with CHF of varying severity and different disease stages. In fact, a reappraisal of the prognostic value of BRS through a retrospective post-hoc analysis of previous data obtained only in patients with mild-to-moderate CHF may not provide reliable and generalizable data. The conclusions of Paleczny et al.11 should therefore be confined to the type of CHF patients considered in their study. On the contrary, as acknowledged by the authors themselves, this study does not rule out the value of BRS assessment for risk stratification of patients in their initial HF stages, at a time when their management strategy has to be decided. The study by Paleczny et al. also does not rule out the possibility that BRS assessment might have relevance in risk stratification of patients with more severe HF. In fact, data by Paleczny et al. do suggest that in patients with low peak VO2 at cardiopulmonary stress test, reduced BRS (as assessed by the phenylephrine test) did identify individuals at high risk for all-cause death/appropriate ICD discharge. Another issue that remains unexplored, due to the fact that patients with a permanent pacemaker could not be included due to technical reasons, is whether BRS assessment might retain its prognostic value in severe CHF patients also when they receive a device-based treatment, such as cardiac resynchronization therapy, which was reported to significantly improve outcome but also favourably affect BRS in HFrEF patients.10 Overall, the results by Paleczny et al.11 suggest that the prognostic value of BRS evaluation could indeed be different in contemporary, optimally managed CHF patients, but this possibility should be considered as a function of their disease severity. BRS assessment might be less predictive in HFrEF patients with mild-to-moderate reduction in functional capacity, while on the contrary it might still be important as a prognostic marker in patients with more severe CHF, though several issues remain to be clarified in this context. Thus, notwithstanding the methodological care implemented by Paleczny et al. in their BRS estimates, their results should not be extrapolated to HF patients with clinical characteristics that differ from those of their study population. Conflict of interest: none declared.