Unilateral baroreceptor activation therapy: the beauty of asymmetry

Abstract

With respect to paired internal organs, we commonly think that these are symmetrical and have identical physiological functions. This, however, appears not to be the case. A particular organ where asymmetry comes to expression is the baroreceptor system. Clinical data in patients with resistant hypertension who are treated with device-based baroreceptor activation clearly show that there are functional differences between the left and the right baroreceptor systems. This has implications for our understanding of certain diseases.

Keywords:

• asymmetry
• baroreceptor
• baroreceptor activation therapy
• hypertension
• kidney

Symmetric structures, whether in architecture or in interior design, seem to be appealing to the human mind. Perhaps this is the reason why in science also we love symmetric models. Physicists, for instance, speak of supersymmetry as an alternative to the standard model when they try to explain the interaction between bosons that carry force and fermions as the particles that make up matter. A well-known example of symmetry on the border of science and art is the Vitruvius man, drawn by Leonardo da Vinci. The mirror text that he added was probably meant to illustrate the beauty of symmetry. Indeed, from the outside, the human body looks like it is characterized by perfect symmetry. This notion stimulated the French physician-physiologist Xavier Bichat (1771–1802) to formulate a sort of law about the totally symmetric function of paired organs. His concept survived for several decades until it was seriously challenged by the French anthropologist Paul Pierre Broca (1824–1880) who recognized that, at least in the brain, certain functions differ between the left and right hemispheres. For instance, the brain area that is now known as Broca’s center or Broca’s field and that governs speech is located only in the dominant hemisphere, usually the left one. This is a typical example of anatomic asymmetry with functional consequences.

Interestingly, several observations also point toward asymmetry in bodily functions. For instance, we found earlier that in a substantial proportion of hypertensive patients, a side difference exists between both kidneys [1]. When we measured renal blood flow, in at least half of the cases, blood flow through one kidney differed by 25% or more from that through the other one. An intriguing finding was that in the majority of patients with asymmetric perfusion, the left kidney had the lowest flow. We further established that there is also a side difference in the carotid circulation. The carotid intima–media thickness is significantly greater at the left side than at the right and this is associated with a higher flow velocity at the left side [2]. Most likely, this is caused by the specific anatomy of the local vasculature, which favors a greater energy transfer to the left carotid artery. Further analyses revealed that both atherosclerotic and cardioembolic, but not lacunar strokes occur more frequently in the left hemisphere [2]. This indicates that a functional asymmetry may have clinical implications. Although these data were published already more than 10 years ago, they became important again when we started baroreceptor activation therapy (BAT) in patients with resistant hypertension. BAT is a novel technique which allows electrically stimulating the baroreceptor area. In all likelihood, the electrical stimulus enhances vagal afferent nerve traffic to cardiovascular control centers in the brain with a fall in sympathetic activity as result. With this device-based treatment, it is possible to produce a substantial fall in blood pressure [3,4]. The first generation of this type of device consisted of an implantable pulse generator and two electronic leads that were sutured to both carotid arteries. As this required bilateral surgery, there was a need to explore whether it is possible to achieve acceptable effects on blood pressure with one-sided stimulation. To this end, we analyzed the data from patients who had been stimulated at only one side. Contrary to our expectations, we found that despite similar baseline values, unilateral stimulation caused a significantly greater fall in blood pressure (systolic and diastolic) than bilateral stimulation [5]. Heart rate fell with unilateral stimulation, but did not change with bilateral BAT. In addition, a significantly greater proportion of patients reached their target pressure with unilateral than with bilateral stimulation. These data somehow suggest that the two baroreceptor systems (left and right) do not work in concert, but rather independently from each other. Fortunately, we were also able to compare both sides with respect to their effect on blood pressure and heart rate. Here again, we found asymmetric responses. In most patients, the right side appeared to be the dominant one, that is, to produce the greatest falls. Still, we identified several patients in whom the left side was dominant. What could be the explanation for these phenomena? Of course, we can only speculate about the physiological significance. But it could mean that it serves a protective purpose. If, for example, blood pressure rises suddenly, the baroreceptor system is activated and, through inhibition of the sympathetic nervous system, blood pressure will return to its initial level. If the baroreceptors on the left and right would work in exactly the same way, immediate inhibition of sympathetic activity would produce quite a sudden fall in pressure that may overshoot and that, in turn, has to be compensated for by deactivation of the baroreceptor system. What would follow is an extreme oscillation of pressure until the point where a new steady state is reached. Let us now suppose that a sudden rise in pressure occurs in a person with a right-dominant baroreceptor system. The right system will inhibit sympathetic outflow; but if the left system is less responsive, it will maintain a certain level of sympathetic activity. As a result, the restoration of pressure will slow down a bit so that the fall is pressure is less abrupt. In other words, under these circumstances, the left system acts as a sort of brake. With a sudden fall in pressure, the opposite would occur and, of course, it is vice versa in a person in whom the other side is dominant. From a physiological perspective, this is an entirely plausible mechanism, which makes sense. It would also explain why bilateral BAT is slightly less effective than unilateral BAT because with bilateral stimulation, one activates two opposing mechanisms. So, there is indeed some beauty in asymmetry. It also makes us wonder a bit more about the meaning of paired organs. In the case of external tissues, it seems relatively simple. With two ears we can better locate the origin of a sound and our two eyes allow us to see depth. It is less easy to explain, however, why nature would have equipped us with two, seemingly, identical internal organ systems. In case of kidneys, the argument could be that one kidney acts as a safeguard when the other fails to excrete appropriately. But if that would be the reason, why is there only one liver then? It is striking that we found functional asymmetry in the kidneys and in the baroreceptors, the two systems that, according to classical physiology, are the most important ones for the regulation of blood pressure. Both systems have also repeatedly been implicated in the pathogenesis of hypertension. We know that the side difference is not related to being left- or right-handed, but it would be interesting to explore further whether asymmetric function is an innate phenomenon or develops with aging. Does it have a causal relationship to, for example, hypertension or is it an epiphenomenon? Can certain forms of treatment modify it? What happens in case of situs inversus? We know we can live with one kidney, but what does this mean for its physiological function? These and many other questions open up a new area of research that may provide better insight into how paired organs interact. Since our observations have been obtained in people who are already hypertensive, it is possible that hypertension has caused the asymmetry. In fact, we do not know whether asymmetry also exists in healthy persons and this needs to be urgently explored. Whatever results this type of research will yield, the present state of knowledge makes us already realize that there is a certain beauty in asymmetry.

Financial & competing interests disclosure

PW de Leeuw has received a research grant and consultancy fees from CVRx, Minneapolis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.