EDITORIAL COMMENT
Cardiac Autonomic Imbalance in Pre-Hypertension and in a Family History of Hypertension*
Daniel A. Duprez, MD, PhD, FACC*
Cardiovascular Division, Medical School, University of Minnesota, Minneapolis, Minnesota.
* Reprint requests and correspondence: Dr. Daniel A. Duprez, Cardiovascular Division, Medical School, University of Minnesota, VCRC-Room 270, 420 Delaware Street Southeast, MMC 508, Minneapolis, Minnesota 55455. (Email: dupre007{at}umn.edu).
The autonomic nervous system plays a crucial role in the pathogenesis of essential arterial hypertension (1). Several studies have demonstrated that hypertensive patients have an impaired cardiac autonomic function (2). Chronic imbalance of the autonomic nervous system is a potent risk factor for adverse cardiovascular events (3). Although not widely recognized by clinicians, this risk factor is easily assessed by measures of heart rate variability during supine position, postural changes, and during deep breathing (4).
Most studies of autonomic function in hypertension have been studied in selected groups with established hypertension and in a limited number of hypertensive offspring. However these studies were not population-based. In this issue of the Journal, Wu et al. (5) compared the cardiac autonomic function in 4 groups, namely normotensive subjects with and without a positive family history of arterial hypertension and pre-hypertensive and hypertensive subjects. The cardiac autonomic function was determined by SD of RR-interval, power spectrum in low frequencies (LF) and high frequencies (HF) and the LF/HF ratio in supine position for 5 min, the ratio between the longest RR-interval at approximately the 30th beat and the shortest RR-interval at approximately the 15th beat after standing (30 max/15 min ratio), and the ratio between the longest RR-interval during expiration and the shortest RR-interval during inspiration (E/I ratio). This study demonstrated that there was a decreased parasympathetic modulation of the heart in normotensive subjects with a positive family history of arterial hypertension, pre-hypertension, and arterial hypertension. Pre-hypertensive subjects manifested a significant impaired parasympathetic activity and enhanced modulation of the heart. The impairment of the cardiac parasympathetic drive existed in hypertension, but the autonomic imbalance with an augmented sympathetic shift was not significantly enhanced.
Sympatho-vagal imbalance has a major impact on blood pressure variability, which is a predictor for cardiovascular morbidity and mortality. It has been shown that sympathetic nerves do not influence variability, because no change was seen with drugs acting on either beta or alpha adrenergic receptors. No correlation was found with plasma catecholamines or sympathetic function tests. By contrast, clear inhibition was demonstrated with atropine, indicating an important role of vagal nerves on blood pressure variability (6). However, in men, inhibition was not complete with atropine; thus other mechanisms also play a role but at present are unknown.
There is limited information regarding the interaction of the autonomic balance and the renin-angiotensin-aldosterone system (RAAS). In a previous study, we examined the changes of the RR-interval and blood pressure variability with power spectral analysis during postural changes in borderline arterial hypertension and a normotensive control group (7). At the same time plasma renin activity, angiotensin II, and aldosterone were sampled. The results indicated that in borderline arterial hypertension, LF and HF of the blood pressure were already significantly increased at rest. Moreover, in borderline hypertension, renin release during postural changes correlated well with the decrease in the power of the HF vagal component of RR-interval variability and with the increase of the LF component of diastolic blood pressure variability. The TROPHY (Trial of Preventing Hypertension) study demonstrated that angiotensin II receptor blockade in pre-hypertension can prevent or postpone the development of stage 1 hypertension (8). Further studies are warranted to unravel the effect of RAAS blockade on the cardiac imbalance in pre-hypertension and its effect to prevent development of hypertension.
Atrial fibrillation and hypertension are 2 prevalent and often coexistent conditions. Several observations suggest that the autonomic nervous system plays an important role in both the initiation and/or the maintenance of atrial fibrillation. Heart rate variability analyses showed that autonomic imbalance is present before the onset of paroxysmal auricular episodes (9). The HARVEST (Hypertension and Ambulatory Recording Venetia) study demonstrated that a persistent high heart rate was an independent predictor of future sustained hypertension, regardless of the initial blood pressure and other confounders (10).
Sympathetic neural factors are involved in energy balance and metabolism as well as in blood pressure control. Therefore, adrenergic overdrive might be implicated in the development and/or progression of the metabolic syndrome (11). Sympathetic nerve overactivity is crucial in the pathogenesis of hypertension in type 2 diabetes (12).
The study of Wu et al. (5) focused only on a Chinese population. Other studies have shown that race can have a potential influence on heart rate variability (13). Therefore, further longitudinal studies are needed in other ethnic populations to examine the predictive value of cardiac autonomic function in relation to development of arterial hypertension. Another important point is the gender difference on heart rate variability. There is evidence that women have greater heart rate variability than men, even after controlling for a large number of potential confounders (14).
Normotensive subjects with a family history of hypertension are known to be characterized by altered cardiovascular morphology and reactivity (15). Although the reason for this has not yet been completely clarified, it has been suggested that an imbalance in the autonomic nervous system might play an important role. Pitzalis et al. (16) studied whether autonomic control of heart rate and cardiac structure and function are impaired early in the offspring of hypertensive families. Their main findings were that arterial blood pressure, autonomic control of heart rate, and diastolic function were significantly different in normotensive subjects with a positive family history of hypertension from those without. They speculated that the mechanisms controlling cardiovascular function were already modified in the pre-hypertensive state and that these changes were strictly related to the male gender. These results strongly suggested once more that the role of gender should be taken into account whenever studies of hypertensive offspring are being evaluated.
The future challenge is to investigate whether nonmedical and medical regimens can restore the equilibrium of the cardiac autonomic balance in normotensive subjects with a positive family history of hypertension and in subjects with pre-hypertension in order to prevent or delay the development of hypertension and its cardiovascular damage.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Mark AL. The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure J Hypertens 1996;14(Suppl):S159-S165.[Web of Science]2. Liao D, Cai J, Barnes RW, et al. Association of cardiac autonomic function and the development of hypertension: the ARIC study Am J Hypertens 1996;9:1147-1156.[CrossRef][Web of Science][Medline] 3. Gillman MW, Kannel WB, Belanger A, D'Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study Am Heart J 1993;125:1148-1154.[CrossRef][Web of Science][Medline] 4. Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology Heart rate variability standards of measurement, physiological interpretation, and clinical use Circulation 1996;93:1043-1065.[Free Full Text] 5. Wu J-S, Lu F-H, Yang Y-C, et al. Epidemiological study on the effect of pre-hypertension and family history of hypertension on cardiac autonomic function J Am Coll Cardiol 2008;51:1896-1901.[Abstract/Free Full Text] 6. Clement DL, De Pue N, Jordaens LJ, Packet L. Adrenergic and vagal influences on blood pressure variability Clin Exp Hypertens A 1985;7:159-166.[CrossRef][Web of Science][Medline] 7. Duprez DA, De Sutter JH, De Buyzere ML, et al. Renin-angiotensin-aldosterone system, RR interval, and blood pressure variability during postural changes in borderline arterial hypertension Am J Hypertens 1995;8:683-688.[CrossRef][Web of Science][Medline] 8. Julius S, Nesbitt SD, Egan BM, et al. Trial of Preventing Hypertension (TROPHY) Study Investigators Feasibility of treating prehypertension with an angiotensin-receptor blocker N Engl J Med 2006;354:1685-1697.[Abstract/Free Full Text] 9. Bettoni M, Zimmermann M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation Circulation 2002;105:2753-2759.[Abstract/Free Full Text] 10. Palatini P, Dorigatti F, Zaetta V, et al. HARVEST Study Group Heart rate as a predictor of development of sustained hypertension in subjects screened for stage 1 hypertension. The HARVEST Study. J Hypertens 2006;24:1873-1880.[Web of Science][Medline] 11. Rahmouni K, Correia ML, Haynes WG, Mark AL. Obesity-associated hypertension: new insights into mechanisms Hypertension 2005;45:9-14.[Abstract/Free Full Text] 12. Perin PC, Maule S, Quadri R. Sympathetic nervous system, diabetes, and hypertension Clin Exp Hypertens 2001;23:45-55.[CrossRef][Web of Science][Medline] 13. Lampert R, Ickovics J, Horwitz R, Lee F. Depressed autonomic nervous system function in African Americans and individuals of lower social class: a potential mechanism of race- and class-related disparities in health outcomes Am Heart J 2005;150:153-160.[CrossRef][Web of Science][Medline] 14. Snieder H, van Doornen LJ, Boomsma DI, Thayer JF. Sex differences and heritability of two indices of heart rate dynamics: a twin study Twin Res Hum Genet 2007;10:364-372.[CrossRef][Web of Science][Medline] 15. Muldoon F, Terrel DF, Bunker CH, Manuck SB. Family history studies in hypertension research. Review of the literature. Am J Hypertens 1993;6:76-88.[Web of Science][Medline] 16. Pitzalis MV, Iacoviello M, Massari F, et al. Influence of gender and family history of hypertension on autonomic control of heart rate, diastolic function and brain natriuretic peptide J Hypertension 2001;19:143-148.[CrossRef][Web of Science][Medline]
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