aInstitute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
bClinica Medica, University of Milano-Bicocca, Ospedale San Gerardo dei Tintori, Monza, Milan, Italy
Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Tel: +49 511 532 2821; fax: +49 511 532 2750; e-mail: firstname.lastname@example.org
Cardiovascular organ damage takes many years or even decades to ensue. Large epidemiological studies, such as the Framingham Heart Study, have been indispensable in delineating hitherto unknown cardiovascular risk factors. Yet, the sheer size of these studies limits invasiveness and intensity of the physiological characterization. Much of the research applying more sophisticated methodologies in smaller samples has a rather limited time frame. In real life, the data have to be in within a few years to support the next manuscript, grant proposals, or academic promotions. Another approach is to carefully assess patients, to document the findings, and to keep the data in a safe place for the next generation of clinical scientists. Approximately 40 years ago, Swedish scientists laid the foundation for a manuscript published in the present issue of the Journal of Hypertension.
Collén et al. tested the hypothesis that events earlier in life, in this case hypertensive pregnancies, are associated with long-term alterations in sympathetic nervous system activity. The target is well chosen given the pivotal role exerted by neuroadrenergic factors in cardiovascular regulation . Indeed, rare patients at the extreme ends of sympathetic control illustrate the utmost importance of the sympathetic nervous system. Excessive sympathetic activity predisposes to arterial hypertension and cardiovascular organ damage . In fact, an excessive cardiovascular sympathetic drive can acutely damage the heart in rare patients with Takotsubo cardiomyopathy [3,4]. The sympathetically damaged heart often recovers once sympathetic overactivity has resolved. However, sympathetic excitation is also involved, on a chronic basis, in more common organ manifestations of cardiovascular disease. This is the case, for example, in patients with hypertension, in which the sympathetic activation may favor on a chronic basis the development and progression of left ventricular dysfunction, left ventricular hypertrophy as well as vascular structural changes at the level of the large, medium-size and small arterial vessels [2,5–7]. This is also the case in the early clinical phases of the renal damage associated with hypertension, in which the adrenergic overdrive is already present and participates at the disease progression throughout direct and indirect mechanisms . In contrast, patients who are unable to properly engage sympathetic activity due to autonomic failure experience profound blood pressure reductions with minimal hemodynamic challenges. In these patients, standing, meal ingestion, drinking small amounts of alcohol, or taking a hot shower elicits a hypotensive response . Development of novel treatments targeting the sympathetic nervous system, such as electrical carotid sinus stimulation , catheter-based renal sympathetic denervation , and deep brain stimulation , further spurs interest in sympathetic regulation. Given the important effect of the sympathetic mechanisms on cardiovascular function and structure, subtle changes in sympathetic activity could have important health consequences. Yet, the mechanisms setting sympathetic activity in the long run are poorly defined.
Research on sympathetic control mechanisms is complicated by the fact that sympathetic activity can be regulated at various sites. Along the sympathetic efferent branch, transmission and distribution of sympathetic activity can be finely tuned to adjust postganglionic adrenergic nerve activity . Postganglionic adrenergic nerves translate electrical signals into norepinephrine release in peripheral tissues. The released norepinephrine activates postsynaptic α and β adrenoreceptors . In addition, norepinephrine stimulates presynaptic adrenoreceptors, thus, introducing a further layer of complexity. Much of the released norepinephrine is taken up again by adrenergic nerves through the neuronal norepinephrine transporter . Then, norepinephrine is either recycled or enzymatically degraded by monoamine oxidases. Each of the previously mentioned mechanisms strongly affect the strength of the sympathetic stimulus imposed on cardiovascular organs. Thus, reductionist experiments conducted in cells or in isolated organs cannot be simply extrapolated to intact human beings. Instead, sophisticated integrative physiological methodologies, such as recordings of efferent postganglionic muscle sympathetic nerve traffic, are required to address these issues. To obtain muscle sympathetic nerve recordings, thin unipolar tungsten needle electrodes are introduced into peripheral nerves carrying sympathetic activity to muscle resistance vessels.
Collén et al. applied in their study the microneurography technique to test influences of hypertensive pregnancies on sympathetic nervous system activity many years later in life. The rationale for conducting these experiments is compelling. Sympathetic activity is substantially increased during hypertensive pregnancies. In fact, muscle sympathetic nerve activity was almost three-fold increased in women with pre-eclampsia compared with normotensive pregnant women [14–17]. Sympathetic activation appears to precede the manifestation of full-blown pre-eclampsia . Finally, following hypertensive pregnancies, women show an increased cardiovascular risk [19,20]. Collén et al. recruited women who had experienced hypertensive pregnancies between the years 1969 and 1973 at Sahlgrenska University Hospital, Goteborg, Sweden . They divided women with previous hypertensive pregnancies into two groups according to presence or absence of arterial hypertension. In addition, they recruited a control group of normotensive women with previous normotensive pregnancies.
The pooled group of women with previous hypertensive pregnancies did not show increased muscle sympathetic nerve activity compared with women with normotensive pregnancies. In particular, muscle sympathetic nerve activity was normal in currently normotensive women with hypertensive pregnancies. The hypertensive subgroup showed modestly elevated muscle sympathetic nerve activity and larger blood pressure responses to psychological stress induced by the Stroop-colored word test. Furthermore, augmentation index was increased in this group possibly suggesting preclinical vascular damage.
The critical evaluation of the study results is based, as always, on its strengths and limitations. The study merits are the very long follow-up (one of the longest at least in the sympathetic research field) and the use of direct recording of sympathetic nerve traffic, allowing to overcome several limitations of other indirect approaches to assess human adrenergic function . The main study weakness is the small number of women recruited in each group. Another potential limitation is that hypertensive women were evaluated under antihypertensive drug treatment, which may affect sympathetic activity. Despite these caveats, the study results suggest that sympathetic activation during hypertensive pregnancies may recover following delivery. Thus, sympathetic activation may not be the sole mechanism increasing cardiovascular risk in these women. As indicated above, the electrical activity of postganglionic adrenergic nerves is only one albeit important aspect of sympathetic cardiovascular control. We cannot exclude that the coupling between electrical nerve activity and norepinephrine release, the sensitivity of adrenergic receptors, or norepinephrine uptake is disturbed in women with previous hypertensive pregnancies. We cannot also exclude that the behavior of the sympathetic activity, and particularly the adrenergic overdrive, is encompassed over time by other factors involved in cardiovascular risk profile determination. In a nice study published by the Journal of Hypertension few months ago , evidence has been provided that ambulatory blood pressure profile, BMI and insulin resistance might be better markers of cardiovascular risk than endothelial dysfunction, microalbuminuria or sympathetic abnormalities in pregnancy-induced hypertension. The issue, however, remains controversial and unsolved up-to-now, given the fact that in the above-mentioned study, assessment of sympathetic cardiovascular drive was based on the evaluation of the blood pressure and heart rate response to head-up tilting and cold pressor test, that is on indirect markers of adrenergic drive .
The study by Collén et al. provides further insight into the complex interactions between sex and age on the regulation of human sympathetic nervous system activity. Compared with men of similar age, muscle sympathetic nerve activity tends to be lower in premenopausal women. Despite this baseline difference, physiological and psychological stress appears to induce similar sympathetic excitation in women and in men. Women and men show marked increases in muscle sympathetic nerve activity with aging [22,23]. The aging-associated increase in muscle sympathetic nerve activity may be particularly pronounced in women , which could explain the reduction in the protective effect of female sex on cardiovascular risk at an older age. Studies testing cardiovascular responses to near complete pharmacological interruption of sympathetic efferents using ganglionic blockers attest to the functional relevance of these observations. Women exhibited lesser reductions in blood pressure with ganglionic blockade compared with men . In another study, older men showed larger reductions in blood pressure with ganglionic blockade compared with well matched young men . The previously mentioned temporary sympathetic activation during hypertensive pregnancies is another sex-specific response with important health consequences.
The study provides an impetus to ensure access to clinical data for a long time because many clinically and scientifically important questions cannot be resolved in a prospective study lasting only 4–5 years, at best. In fact, some questions cannot be resolved during a scientist's lifetime. We suspect that Collén et al. had to dig through stacks of dusty paper contained in old patient files. Eventually, they succeeded. Now, most of the relevant clinical information is stored electronically. The idea that the information could be retrieved easily with a few mouse clicks is appealing. However, it can be difficult opening files that are only a few years old. Guess what happens when the manufacturer producing the computer program or the computer hardware required to operate this particular program disappears from the face of the earth. Finally, will the electronic data backup really work? We have to deal with all these issues to ensure that the next generations of clinical scientists can utilize our data.
Conflicts of interest
There are no conflicts of interest.
1. Collén A-C, Manhem K, Sverrisdóttir YB. Sympathetic nerve activity in women 40 years after a hypertensive pregnancy. J Hypertens
2. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens
3. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med
4. Raj SR. Too sympathetic? Role of sympathoexcitation in Takotsubo cardiomyopathy. Heart Rhythm
5. Grassi G, Seravalle G, Quarti-Trevano F, Dell’Oro R, Arenare F, Spaziani D, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension
6. Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation
7. Grassi G, Seravalle G, Dell’Oro R, Mancia G. Sympathetic mechanisms, organ damage, and antihypertensive treatment. Curr Hypertens Rep
8. Grassi G, Quarti-Trevano F, Seravalle G, Arenare F, Volpe M, Furiani S, et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension
9. Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G. Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med
10. Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension
11. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet
12. Patel NK, Javed S, Khan S, Papouchado M, Malizia AL, Pickering AE, et al. Deep brain stimulation relieves refractory hypertension. Neurology
13. Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens
14. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia: a state of sympathetic overactivity. N Engl J Med
15. Greenwood JP, Stoker JB, Walker JJ, Mary DA. Sympathetic nerve discharge in normal pregnancy and pregnancy-induced hypertension. J Hypertens
16. Greenwood JP, Scott EM, Stoker JB, Walker JJ, Mary DA. Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans. Circulation
17. Greenwood JP, Scott EM, Walker JJ, Stoker JB, Mary DA. The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia. Am J Hypertens
18. Fischer T, Schobel HP, Frank H, Andreae M, Schneider KT, Heusser K. Pregnancy-induced sympathetic overactivity: a precursor of preeclampsia. Eur J Clin Invest
19. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ
20. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclampsia and the risk of end-stage renal disease. N Engl J Med
21. Mangos GJ, Spaan JJ, Pirabhahar S, Brown MA. Markers of cardiovascular disease risk after hypertension in pregnancy. J Hypertens
22. Ng AV, Callister R, Johnson DG, Seals DR. Age and gender influence muscle sympathetic nerve activity at rest in healthy humans. Hypertension
23. Narkiewicz K, Phillips BG, Kato M, Hering D, Bieniaszewski L, Somers VK. Gender-selective interaction between aging, blood pressure, and sympathetic nerve activity. Hypertension
24. Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men. Circulation
25. Jones PP, Shapiro LF, Keisling GA, Jordan J, Shannon JR, Quaife RA, et al. Altered autonomic support of arterial blood pressure with age in healthy men. Circulation