Impaired baroreflex sensitivity as a potential marker of cardiovascular risk in hypertension

Baroreflex heart rate control in hypertension Baroreflex mechanisms contribute importantly to short-term regulation of heart rate, sympathetic tone and consequently blood pressure. The arterial baroreflex normally acts to oppose increases in blood pressure by inhibiting sympathetic activity, causing vasodilation and slowing heart rate. The traditional concept holds that arterial baroreflex is abnormal in hypertension [1,2], with a higher threshold for activation and a reduction in sensitivity; furthermore, these alterations result from chronic increases in arterial pressure. An important mechanism that allows sympathetic and arterial pressure to increase is baroreflex resetting [2]. Baroreflex resetting refers to a shift in the relationship between blood pressure changes and the efferent autonomic response (e.g. sympathetic nerve activity or heart rate). Sustained increases in pressure trigger a resetting of the operating point of the reflex to a higher level of pressure; that is, the baroreflex loses much of its ability to buffer the rise in pressure and actually functions to maintain pressure at the higher level. Hypertension-induced resetting of the baroreflex may be elicited by both ‘baroreceptor resetting’ (shift in pressure–afferent baroreflex activity relationship) and by ‘central resetting’ (shift in afferent baroreflex–efferent autonomic relationship) [3,4]. In recent years, three new concepts have emerged regarding alterations in arterial baroreflexes in hypertension. First, there is growing evidence [5–7] that the baroreflex may be more important in long-term blood pressure regulation than is commonly thought. Second, it has been found that such alterations may represent a hereditary component in the pathogenesis of essential hypertension and could precede an increase in arterial pressure [8–10]. Third, it is now well established that abnormalities in baroreflex control of parasympathetic activity (heart rate) do not necessarily predict alterations in baroreflex control of sympathetic nerve activity and vascular resistance [5]. Indeed, there is evidence from both experimental studies on animals and humans that baroreflex control of sympathetic activity, vascular resistance and arterial pressure may be preserved in hypertension despite impairment of baroreflex control of heart rate [11,12]. Arterial baroreflex and cardiovascular risk Impaired arterial baroreflex sensitivity has been associated with cardiac mortality and nonfatal cardiac arrests after a myocardial infarction [13]. More recently, baroreflex sensitivity has been shown to predict all-cause mortality and sudden death in hypertensive patients with chronic renal failure [14]. Although there is increasing evidence that the baroreflex is implicated in the pathogenesis of essential hypertension, the prognostic value of baroreflex sensitivity in hypertensive patients without overt cardiovascular disease still remains undefined. In the current issue of Journal of Hypertension, Ormezzano et al. [15] report that baroreflex impairment might contribute to the risk of future cardiovascular events. They assessed the prognostic value of baroreflex sensitivity in a cohort of 451 hypertensive patients, which was followed-up for an average of 6.2 ± 2.8 years. Baroreflex sensitivity was assessed by the sequence technique [16,17] in which the slope of the regression line between the spontaneous increases or reductions in systolic blood pressure (SBP) and the related lengthening or shortening in the pulse interval is calculated over spontaneous sequences of three or more consecutive beats. Deaths and major adverse cardiovascular events were associated with a reduction in baseline baroreflex sensitivity (both SBP+/pulse interval+ and SBP−/pulse interval− sequences). In the multivariate analysis, the reduction in baroreflex sensitivity, as assessed by SBP+/pulse interval+ sequences, was associated with total mortality rate and increased relative risk of deaths and major adverse cardiovascular events. The authors conclude that reduction in baroreflex sensitivity is an independent predictor of total mortality and cardiovascular morbidity in hypertensive patients. These novel and important findings raise some questions. First, what are the potential mechanisms linking baroreflex impairment with cardiovascular risk? Second, is the reported impairment a true independent risk factor or rather a risk marker? Third, will baroreflex testing become a tool to stratify the hypertension-associated risk in a clinical setting? Current guidelines on hypertension issued by the European Society of Hypertension and the European Society of Cardiology (ESH/ESC) [18] stress the concept of global risk assessment and identify a number of factors that might enhance the cardiovascular risk, including the presence of target organ damage. Cardiovascular functional and structural alterations accompanying high blood pressure such as left ventricular diastolic dysfunction and hypertrophy, vascular remodelling and hypertrophy are associated with altered reflex cardiovascular control [19,20]. Target organ damage was not assessed in the study by Ormezzano et al. [15]. Therefore, it would be important to evaluate the relative contribution of target organ damage to the observed link between baroreflex impairment and cardiovascular events. Another potential limitation of the study, acknowledged by the authors, refers to the lack of information on antihypertensive drug treatment during follow-up, as these drugs may have different effects on adrenergic neural drive [21]. This appears to be the case also for nonpharmacological interventions, given the evidence that dietary sodium restriction, physical activity, and body weight control may all favourably interfere with baroreflex function and, more in general, with autonomic cardiovascular control [22]. Two final issues should be addressed. First, the study by Ormezzano et al. [15] did not plan to perform ambulatory blood pressure monitoring and thus was not designed to assess whether and to what extent the different patterns of the 24-h blood pressure profile are described in hypertension (i.e. the dipping, nondipping, extreme dipping and reverse dipping behaviour) plays a role in the relationships between baroreflex sensitivity and cardiovascular risk. It is however likely that the behaviour of the day–night blood pressure pattern has a role, given the close relationships the nondipping and the reverse dipping have with cardiovascular events [23]. Second, the group of patients characterized by a more pronounced impairment in baroreflex sensitivity displayed a body mass index above the normal range and thus presumably an abnormal profile of insulin sensitivity. Given the adverse effects of insulin resistance on autonomic cardiovascular control [24], the hypothesis can be advanced that metabolic factors are also of importance in determining the baroreflex alteration and its impact on prognosis. In conclusion, the study by Ormezzano et al. [15] provides the first evidence that baroreflex impairment may be of prognostic significance in hypertensive patients without overt cardiovascular disease. Future studies should address the following questions: What is the ‘added’ value of baroreflex testing beyond the risk factors already included in the current guidelines? Does treatment-related improvement in baroreflex function directly translate into less ‘hard’ endpoints, like in case of left ventricular regression and reduction in microalbuminuria? If so, is this effect independent of blood pressure changes? Is there any substantial difference between various classes of antihypertensive drugs? Addressing these questions is crucial for future role of noninvasive baroreflex testing in the clinical assessment of the hypertensive patients.