Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: firstname.lastname@example.org
Scientists interested in arterial hypertension indulge in novel cellular mechanisms, complex genetic association studies, state-of-the-art clinical trials, or other exciting issues. Life in the hypertension clinic tends to be less glamorous. In many patients, blood pressure is not even measured. No surprise, these patients may not receive treatment for a long time. False measurements due to technical shortcomings, such as improper cuff size, are another important problem. On the contrary, this simple measurement stood the test of time. Clinical trials proving that antihypertensive treatment ameliorates cardiovascular morbidity and mortality relied on brachial blood pressure measurements. Given that a blood pressure measurement with a brachial cuff is such a big deal, should we even bother thinking about new diagnostic techniques? We will provide a few arguments why sometimes more detailed cardiovascular physiological profiling, particularly baroreflex testing, may be warranted. Cardiovascular physiological profiling could help filling the gap between real life patient care and science.
Technology to noninvasively assess hemodynamics, central blood pressure, vascular properties, and cardiovascular reflex regulation became available in recent decades. Subsequently, these technologies were refined and miniaturized such that they are not restricted to specialized research laboratories anymore. In fact, measurements assessing vascular function and cardiovascular reflex regulation are increasingly incorporated in larger scale epidemiological and interventional studies [1,2]. Vascular assessments including determination of pulse wave velocity or augmentation index are also increasingly applied in the clinic. Standardization of these methodologies across devices and definition of reference ranges could provide a further boost. However, information obtained from different methods is rarely integrated. Instead, ‘isolated’ physiological measurements serve as cardiovascular risk biomarkers. Noninvasive hemodynamic profiling as a means to guide pharmacological treatment of arterial hypertension is a notable exception . In this issue, Lucini et al. remind us that hemodynamics, cardiovascular reflexes, and vascular properties are interrelated and provide complementary information.
The authors noninvasively assessed carotid artery mechanical properties using high resolution ultrasound equipped with a wall tracking system in 191 otherwise healthy individuals. When wall displacement and blood pressure are followed throughout the cardiac cycle, carotid elasticity and compliance can be calculated. The authors also assessed baroreflex sensitivity based on spontaneous blood pressure and heart rate fluctuations. A disadvantage of noninvasive baroreflex assessment is that full sigmoid baroreflex curves cannot be computed; pharmacological baroreflex testing using phenylephrine and nitroprusside covers a wider blood pressure range, thereby providing more detailed insight in baroreflex regulation. Yet, pharmacological testing is difficult to conduct in the clinic or in larger scale clinical studies.
The investigators observed that carotid arteries became stiffer, whereas intima–media thickness progressively increased with age. The youngest proband quintile with an average age around 20 years exhibited approximately two-fold better carotid elasticity and compliance compared with the oldest quintile with a mean age around 60 years. Baroreflex indices also substantially deteriorated with age. Finally, carotid artery structure and function and baroreflex sensitivity were correlated with each other even when age was adjusted for. Thus, vascular structure and function explained a significant albeit small proportion of the variability in baroreflex heart rate regulation. The study is a good example how physiological measurements can be tied together to obtain deeper insight in cardiovascular regulation. In the following paragraphs, we will provide a few reasons why reviving integrated cardiovascular physiology may pay off.
Traditionally, students memorize all the physiological reflex mechanisms involved in cardiovascular regulation early in medical school. Later on, much of the information is erased as students enter clinical rotations. Our beloved brachial blood pressure cuff may be the villain because students and young physicians get used to the idea that blood pressure is a static measurement. It is hard to understand mechanisms of action and potential side-effects of antihypertensive medications without a solid cardiovascular and renal physiology background. Now, noninvasive methodologies, particularly beat-by-beat blood pressure and heart rate recordings are utilized in some institutions to teach students cardiovascular physiology. The beauty of noninvasive monitoring techniques is that human cardiovascular physiology, particularly baroreflex mediated responses, can be observed instantaneously. Looking at your own spontaneous changes in heart rate and blood pressure while you get up from squatting to standing beats the best physiology text on baroreflex mechanisms. Even better, the same test could be repeated later on in a patient with impaired baroreflex function.
Sometimes, risk assessment may not be enough to diagnose or treat a patient in the hypertension clinic. Extreme examples of patients requiring more comprehensive physiological assessment are those with impaired baroreflex function. Baroreflex failure ensues, when baroreceptors or baroreflex afferent nerves are severely damaged . Lack of baroreflex restraint is associated with extreme blood pressure surges with psychological or physiological stress. Autonomic failure is caused by interruption of the efferent baroreflex arc, comprising parasympathetic and sympathetic nerves. The leading clinical feature in these patients is severe orthostatic hypotension. However, many autonomic failure patients also feature sometimes severe supine hypertension, thus complicating their clinical management [6,7]. Although history taking and a physical examination, including supine and upright measurements of heart rate and blood pressure, are usually sufficient to recognize these rather severe conditions, additional testing is usually conducted to differentiate autonomic disorders and to follow disease progression over time. More subtle changes, such as the aging-associated decline in baroreflex function, may go undetected. Advanced methodologies, such as those applied by Lucini et al., may be helpful in this setting.
Comprehensive cardiovascular autonomic assessment could guide antihypertensive treatment. As baroreflex buffering strongly affects the sensitivity to vasoactive medications , these tests could also identify elderly patients at risk for an extreme and potentially dangerous hypotensive response to antihypertensive medications. In patients with poor baroreflex function, antihypertensive treatment could be started at lower doses. Autonomic testing could also be considered in patients not responding to first-line antihypertensive medications. Indeed, the autonomic nervous system has been rediscovered as treatment target. Attenuation of sympathetic activity through electrical carotid sinus stimulation and catheter-based renal nerve ablation has been tested as treatments of resistant arterial hypertension [9–11]. Whereas some patients respond to these treatments, others do not. A significant proportion of nonresponders is difficult to accept given the costs and invasiveness of these techniques. More comprehensive cardiovascular autonomic assessment before the intervention could identify patients more or less likely to respond. In a patient whose hypertension is not related to sympathetic activation, sympathetic inhibition may not be the best treatment. Animal studies support this point of view as sympathetically driven obesity-associated hypertension responds much better to electrical carotid sinus stimulation compared with hypertension elicited by angiotensin II infusion [12,13]. Pharmacological strategies modulating cardiovascular autonomic tone also enter the clinic. Ivabradine, which modulates autonomic influences on the sinoatrial node through pacemaker current inhibition, is a prime example . New treatment involving autonomic cardiovascular control may emerge in the future. For instance, regulator of G-protein signaling 4 (RGS4) may modulate parasympathetic influences on the sinoatrial node . Cardiac sympathetic innervation has been proposed as another treatment target .
More detailed cardiovascular autonomic phenotyping should be considered for future genetic studies. Genetic technologies evolved at a breathtaking speed. Now, genome-wide association studies are conducted in increasingly large samples and there is more to come [17,18]. In these studies, hitherto unknown gene loci likely involved in blood pressure control have been uncovered. Yet, only a relatively small portion of the variability in blood pressure regulation can be explained so far. Although the depth of the genetic information increases exponentially, phenotyping in many genetic studies on arterial hypertension is surprisingly superficial. Other cardiovascular phenotypes ought to be considered as well. For example, baroreflex heart rate regulation is highly heritable . Recent studies confirmed this finding and also suggested that mechanosensory functions including hearing, touch sensation, and baroreflex regulation may be in part regulated by common genes . We conclude that thanks to technical advances in recent years, noninvasive methodologies can be utilized to obtain comprehensive insight in human cardiovascular control. Thus, integrated cardiovascular physiology, or should we call it physionomics, can be and should be incorporated in teaching, patient care, and clinical research. Go for the cardiovascular physionom.
Conflicts of interest
There are no conflicts of interest.
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