Spontaneous baroreflex sensitivity: towards an ideal index of cardiovascular risk

The article by Lantelme et al. [1] in this issue of the journal comes at a critical time in the longstanding debate on the value of measuring spontaneous baroreflex sensitivity (BRS) in patients. It provides an important argument in favour of measuring the BRS and suggests that it may be useful as a global risk marker for cardiovascular disease. The main approach was to use a large patient group referred for the assessment of hypertension and to determine whether BRS correlated with other known risk factors. The authors found that BRS correlated with age, 24-h systolic blood pressure, heart rate and serum cholesterol in a multivariate analysis, and with left ventricular mass and pulse wave velocity in a univariate analysis. From this, the authors suggested that the BRS may reflect a global index of cardiovascular risk. This is not surprising since BRS reflects some aspects of autonomic function and is strongly influenced by cardiovascular disease. While there are many reasons to support this view, it should be stressed that this was not an outcome study and it does not in any way suggest that BRS is a predictive index of cardiovascular risk. The findings only reveal a correlation of the index with other known risk factors. This is not a criticism as such but, nevertheless, it is an important point to consider as cardiovascular risk was not measured at all, although it features prominently in the article. Indeed, the authors add a question mark to their title, indicative of its slightly provocative nature ‘Spontaneous baroreflex sensitivity: towards and ideal index of cardiovascular risk in hypertension?'. While the evidence is gathering of what BRS really means in terms of risk factor assessment, there are situations where it has clearly been shown to be of considerable value. The ATRAMI study has shown that vagal BRS is a valuable predictor of long-term mortality outcome after myocardial infarction and is independent of the left ventricular hypertrophy, heart rate variability and ventricular dysrhythmias [2]. There is also the suggestion that, in heart failure patients, an assessment of BRS is a useful and independent predictor of long-term survival [3]. A recent study by Ziegler et al. suggests that BRS may be a very sensitive early diagnostic marker in diabetic neuropathy [4]. The issue at hand is whether BRS is a useful index of cardiovascular risk in hypertension. There is strong evidence to suggest that cardiovascular events, such as stroke, myocardial infarction and sudden cardiac death, occur most frequently during the morning hours, which coincides with the rapid rise in blood pressure and heart rate. The baroreflex buffering of the early morning surge in blood pressure does occur and an impaired BRS, leading to greater blood pressure swings during these critical periods, may contribute to the excess events that occur at this time. Very little is known about the importance of BRS in the morning with respect to these events. Thus, the underlying mechanistic studies suggest that BRS may be an independent risk factor. The major question is whether it can be proven by a large scale trial. Is the cost warranted and, if so, is BRS an appropriate target for therapy? How far along this road are we? These are some of the issues that come readily to mind. My aim is not to muddy the waters but hopefully to discuss a number of these issues, although rather briefly. However, several questions should be addressed. First, can BRS ever be an index of cardiovascular risk in hypertension? Perhaps this is a somewhat pessimistic start to the discussion. A potential risk factor that is going to have the most impact on the outcome for patients is one that satisfies the following criteria: (i) it is relatively straightforward to measure; (ii) it is obtainable in a very high percentage of patients; (iii) it is a reasonably reproducible value from one visit to the next; (iv) it can be readily used to stratify patients with well-published and accepted limits for normal and abnormal; and, most importantly (v) it has been shown to be linked to outcome. With the advent of Finapres combined with the sequence and spectral analysis spontaneous methods, it is now much easier to measure BRS. There has also been an explosion of software that will make these determinations much easier, albeit at some considerable cost. For example, a complete system is now available from CNSystems (http://www.cnsystems.at) for non-invasive assessment of the cardiovascular system, including an automated measure of the BRS [5]. Thus, while great strides have been made, I do not think we have reached the stage where we could say that measurement of BRS was available to the wider clinical setting, or is particularly straightforward. It does require a high degree of expertise, usually associated with specialist laboratories. However, this may well change as automated systems become less expensive and more widely available. The second issue relates to how applicable is the technique to a wide spectrum of patients. A recording without artifacts from which the BRS can be calculated cannot always be obtained. In the Lantelme study, successful recordings were made in 90% of patients, which is very close to acceptable. It is perhaps not as good as some risk factors, but it is not the worst when the difficulties encountered in estimating left ventricular hypertrophy by echocardiogram are considered. Those experienced in ambulatory blood pressure recordings will also be well aware of the difficulty of obtaining good recordings and the difficulties of reproducibility. Much can be done to offset these problems in the case of estimating BRS by using a large patient group size, repeating the recording on another occasion, perhaps when the patient is more accustomed to the clinic, and using longer recordings and multiple estimates within the same patient. Importantly, there should be clear guidelines for rejecting artifacts and periods of non-stationarity in the case of spectral methods. This was the approach of Lantelme et al., and indeed of most investigators in the field who used only segments where there is a coherence between blood pressure and heart rate around the 0.1 Hz frequency of at least 0.5. This limit is rather arbitrary and a higher acceptance rate can be achieved by simply lowering the coherence cut-off point. There is also the problem that there is a direct relationship between BRS and the coherence, such that patients with quite low BRS may also have low blood pressure–heart rate coherence and therefore be excluded from the assessment. These are issues that still need to be addressed with appropriate guidelines. Reproducibility within patients is of major concern with respect to BRS assessments. Recently, Dickinson published a letter in this journal which asked the question ‘The baroreflex bandwagon: time to get off?’ [6]. While his arguments on the whole were subject to much criticism, particularly by the accompanying comment by Professor Peter Sleight, Dickinson raised a very valid point when he stated that ‘reproducibility is much over rated'. Indeed there is no question that BRS is quite variable. In the study by Lantelme et al., the coefficient of variation for BRS was 68 and 71% for the two methods of assessment, which was 4.5 times greater than the coefficient for systolic blood pressure. Interestingly, exactly the same results were obtained by Ziegler et al. in a normal healthy population, where the coefficient of variation for BRS was 70%, which was approximately five times greater than that for blood pressure [4]. Some of our studies in conscious rabbits showed that, in a relatively homogenous animal species, the coefficient of variation for BRS estimated by cross spectral analysis was one-half that observed in the above-mentioned clinical studies, (approximately 35%) [7]. Nevertheless, this value was also approximately 4.5 times higher than for systolic blood pressure in the rabbits. Thus, in all three studies mentioned, the coefficient of variation for BRS was 4–5 times that for blood pressure. While this represents a problem in terms of BRS being a candidate risk factor, it is not surprising that this index is much more variable as, after all, it is a ratio of a change in blood pressure and in heart rate. The important question is whether, with such variability, estimates are of any use in predicting outcome. Clearly, this has been established in some clinical situations. The study by Ziegler et al. showed that BRS appeared to be more sensitive as a discrimination factor for autonomic neuropathy than other measures [4]. While the study by Lantelme et al. shows that BRS is related to a number of well-known risk factors in hypertension, there does appear to be a need to conduct an outcome study to establish the potential risk factor of BRS. For a large outcome study to be successful, it would also be necessary to have appropriate guidelines and standards. This process is at a very early stage. A glossary of terms used in the field of cardiovascular variability is available on the Internet (http://www.cbi. polimi.it/glossary/glossary.html). The next meeting of BAVAR (baroreflex and blood pressure variability working group) and the European Society of Hypertension Working Group on Blood Pressure and Heart Rate Variability (http://www.cbi.polimi.it/working-group/12345.htm) will be held in June of this year in Maastricht, with the sole aim of trying to reach a consensus along the lines that have been achieved with heart rate variability. They hope to produce a ‘consensus manuscript, Guidelines on how to determine spontaneous baroreflex sensitivity indices'. The Maastricht meeting has been the result of a continuing and long-standing effort on the part of particular research groups in Europe. Preliminary efforts along this line from same groups have produced a surprising result. Taking the same dataset from a number of patients, each laboratory calculated the BRS and sent their results to the coordinating group in Paris headed by Jean-Luc Elghozi. The results showed an amazing variation in estimates. Thus, a major variant, in addition to the high coefficient of variation in the BRS in a group of patients, can be simply due to the range of methodologies used (algorithms, filters, windowing and other assumptions). The analysis showed there was some clustering of the values, when similar methodologies were used, but the variation was nevertheless quite alarming. I suggest that without such efforts to critically evaluate methodology and reaching appropriate guidelines, there would be little hope for ever establishing BRS as a credible risk factor. The article under discussion by Lantelme et al., addresses some of these issues by using both the sequence method and also the α coefficient, which is an index based on the ratio of relative power spectral densities of blood pressure and heart rate at particular frequencies. The authors also used both assessments during standing and lying. They showed a close correlation between the two methods with virtually identical group estimates, and suggested that some improvement could still be be achieved by recording for longer periods in each patient. Thus, there is still much to do to make BRS a standard assessment in relative risk analysis of a wide population group, or in local clinical practice, which is after all the front line in hypertension management. However, significant steps have been made in many of the areas that need to be addressed. The study by Lantelme et al. is a key study along this path. In addition, the various working groups that have been established, mainly in Europe but with contributions from scientists in other regions, are addressing the issues in a collaborative and constructive way. I do not believe there is a ‘baroreflex bandwagon'. Instead, there is simply an honest desire to extract as much information as possible about the autonomic regulation of blood pressure from a relatively simple continuous measurement of blood pressure for a few minutes in a clinic, or over extended periods using portable blood pressure devices. The understanding of the autonomic nervous system regulation of the heart and kidney, and particularly the assessment of the role of baroreceptor reflexes in the short-term regulation of blood pressure and heart rate variability, may be critical for developing a better strategy to manage cardiovascular risk.