Spontaneous baroreceptor reflex sensitivity for risk stratification of heart failure patients: optimal cut-off and age effects

Abstract

Baroreflex sensitivity (BRS) is an important prognostic factor as a reduced BRS has been associated with an adverse cardiovascular outcome. The threshold for “reduced” BRS was established by the ATRAMI study at BRS <3 ms/mmHg in patients with a previous myocardial infarction and has shown to improve risk assessment in many other cardiac dysfunctions. The successful application of this cutoff to other populations suggests that it may reflect an inherent property of baroreflex functioning. Hence, our goal is to investigate whether it represents a “natural” partition of BRS values. Since reduced baroreflex responsiveness is also associated with aging, we also investigate whether a BRS estimate below 3 ms/mmHg can be the result of a process of physiologic senescence besides a sign of BRS dysfunction. This study involved 228 chronic heart failure (CHF) patients and 60 age-matched controls. Our novel method combines transfer function BRS estimation and automatic clustering of BRS probability distributions to define indicative levels of different BRS activities. The analysis produced a fit clustering (cophenetic coefficient 0.9 out of 1) and identified one group of homogeneous patients (well separated from the remaining by 3 ms/mmHg) with increased BRS based mortality risk (HR: 3.19 [1.73,5.89], p<0.001). The age dependent BRS cutoff, estimated by 5% quantile regression of log(BRS) with age (considering the age-matched controls), provides a similar mortality value (HR: 2.44 [1.37,4.43], p=0.003). In conclusion, the 3 ms/mmHg cutoff identifies two large clusters of homogeneous HF patients, thus supporting the hypothesis of being a natural cutoff in the HF population. Furthermore, age was found to have no statistical impact on risk assessment, thus suggesting that there is no need to establish age-based cutoffs as 3 ms/mmHg optimally identifies patients at high mortality risk.