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Cardiac dysautonomia and arterial distensibility in essential hypertensives
Autonomic Neuroscience: Basic and Clinical 146 (2009) 102–105
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Cardiac dysautonomia and arterial distensibility in essential hypertensives Maurizio Acampa ⁎, Massimo Franchi, Francesca Guideri, Ilaria Lamberti, Fulvio Bruni, Marcello Pastorelli, Giovanni Bova, Anna Laura Pasqui, Luca Puccetti, Alberto Auteri Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy
a r t i c l e
i n f o
Article history: Received 26 March 2008 Received in revised form 7 October 2008 Accepted 13 November 2008 Keywords: Hypertension Autonomic nervous system Heart rate variability QKD interval
a b s t r a c t Introduction: The central nervous system plays an important role in the regulation of blood pressure: the sympathetic nervous system may be a primary contributor to the development of some forms of essential hypertension. Hypertension is also associated with reduced distensibility of large arteries. The aim of our study is the evaluation of a correlation between cardiac dysautonomia (evaluated by means of heart rate variability [HRV]) and altered artery distensibility (evaluated by means of measurement of the time interval from the onset of the QRS wave and the detection of the last Korotkoff sound [QKD interval]). Materials and methods: HRV and QKD interval were evaluated in 23 patients (60.9 ± 8.7 years) with untreated hypertension and in 20 control subjects (53.2 ± 16.8 years). QKD interval and QKD100–60 (that is QKD for a 100 mm Hg systolic blood pressure and 60 bpm heart rate) were measured during a 24-hours blood pressure monitoring. HRV was evaluated by means of a spectral method. Three main spectral components were distinguished: very low frequency (VLF), low frequency (LF) and high frequency (HF) component. Results: Patients with reduced QKD100–60 interval show reduced total power and spectral components values, with higher LF/HF ratio in basal conditions in comparison with control group. In patients with hypertension, QKD100–60 values correlated significantly with LF/HF ratio (Spearman r = −0.551; p = 0.006), HF spectral component (Spearman r = 0.630; p = 0.001) and total power (Spearman r = 0.426; p = 0.004). Conclusions: Our results suggest that sympathetic overactivity may be the contributor of reduced arterial distensibility observed in patients with essential hypertension. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The central nervous system plays an important role in the regulation of blood pressure; several lines of evidence in animal models and in humans suggest that the sympathetic nervous system is a primary contributor to the development and the maintenance of some forms of essential hypertension (Julius, 1991). Sympathetic nervous system overactivity may result from either inappropriately elevated sympathetic drive from brain centers, an increase in synaptically released neurotransmitters in the periphery, or amplification of the neurotransmitter signal at the target tissue (Wyss and Carlson, 2001). Spectral analysis of heart rate variability (HRV) can partially distinguish parasympathetic from sympathetic influences on the heart (Malik et al., 1996) and may provide important insights into the role of the autonomic nervous system in the pathogenesis of essential hypertension: HRV is reduced in men and women with systemic hypertension and autonomic dysregulation is present in the early stages of hypertension (Singh et al., 1998). ⁎ Corresponding author. Dipartimento di Medicina Clinica e Scienze Immunologiche, Sezione di Medicina Interna, Policlinico 'Le Scotte', viale Bracci, 53100 Siena, Italy. Tel.: +39 0 577585741; fax: +39 0 57744114. E-mail address: [email protected] (M. Acampa). 1566-0702/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2008.11.009
Hypertension is also associated with reduced distensibility of large arteries (Gosse et al., 1994; Safar and Frohlich, 1995). Measurements of the time interval from the onset of the QRS wave on the electrocardiogram and the detection of the last Korotkoff sound during blood pressure measurements (QKD interval) are a non invasive method for assessing the physical properties of elastic arteries (Gosse et al., 1994, 1999). A previous study (Kosch et al., 1999) showed a correlation between carotid distensibility, evaluated with echography, and sympathetic imbalance, evaluated by HRV, in basal conditions in subjects with hypertension. The aim of this study was the investigation of arterial distensibility (by means of QKD interval measurement) and of cardiac autonomic nervous system activity (by means of HRV) in basal conditions and after sympathetic stimulation, in patients with hypertension and in control subjects, for a possible correlation between the two parameters. 2. Methods We observed 23 patients (60.9 ± 8.7 years) with hypertension and 20 control subjects (53.2 ± 16.8 years) referred consecutively to our department before any administration of antihypertensive treatment and who had benefited from an ambulatory measurement of the QKD
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Table 1 Patients and control group demographics Hypertensive patients (n = 23) Control group (n = 20) p value Gender Age (years) 24 h SBP (mm Hg) 24 h DBP (mm Hg) 24 h HR (bpm) BMI (Kg/m2) PP (mm Hg) 24 h QKD (ms) 24 h QKD100–60(ms) 24 h QKD100–60 h (%)
13 males, 10 females 60 ± 8 (40–80) 141 ± 13 92 ± 11 78 ± 10 24.7 ± 2.7 48 ± 12 190 ± 20 204 ± 18 96 ± 11
10 males, 10 females 53 ± 16 (31–81) 110 ± 10 79 ± 11 70 ± 11 23.5 ± 2.1 41 ± 4.7 197 ± 15 215 ± 19 100 ± 11
n.s. n.s. 0.01 0.01 0.02 n.s. 0.03 n.s. 0.05 0.02
SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, BMI: body mass index, PP: pulse pressure, QKD100–60 h: value of QKD100–60 as the percentage of height predicted value. Fig. 1. Correlation between QKD100–60 h and LF/HF in 23 patients with essential hypertension. Nonparametric correlation Spearman r analysis (Spearman r = −0.551; p = 0.006).
Table 2 Hypertensive patients demographics Hypertensive patients with Hypertensive patients with p value normal QKD100–60 h (n = 13) low QKD100–60 h (n = 10) Gender Age (years) 24 h SBP (mm Hg) 24 h DBP (mm Hg) 24 h HR (bpm) BMI (Kg/m2) PP (mm Hg)
6 males, 4 females 61.6 ± 11 142 ± 10 91 ± 9 81 ± 9 25.1 ± 2.7 55 ± 10
7 males, 6 females 60.4 ± 7 140 ± 11 94 ± 10 75 ± 9 24.5 ± 2.8 43 ± 11
n.s. n.s. n.s. n.s. n.s. n.s. 0.01
SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, BMI: body mass index, PP: pulse pressure, QKD100–60 h: value of QKD100–60 as the percentage of height predicted value.
interval over 24 h and an evaluation of cardiac autonomic nervous system activity. Patients with left bundle branch block, with cardiac arrhythmias or those fitted with pacemakers were excluded. Patients with known thyroid disorders, history of coronary artery disease, cerebrovascular disease or diabetes mellitus were not recruited. Demographic characteristics of patients and controls are depicted in Tables 1 and 2. HRV, ambulatory 24-hour blood pressure monitoring and QKD interval were measured in all subjects. Informed consent was obtained from each patient before entering the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
for the R wave peak as a reference point. Premature beats, missed beats and artifacts were visually identified using an interactive graphic interface and corrected by the operator. In this way, an RR tachogram was obtained, that is, a discrete series of successive RR intervals as a function of the number of recognized QRS complexes. Algorithm, used for the analysis of the tachogram, was a spectral method (fast Fourier Transformation). Three main spectral components were distinguished in a spectrum calculated from short-term recordings of 5 min: – a very low frequency component (VLF): b 0.04 Hz; – a low frequency component (LF): range 0.04–0.15 Hz – a high frequency component (HF): range 0.15–0.4 Hz. The measurement of VLF, LF, and HF power components and of total power was made in absolute values of power (millisecond squared). The ratio of low to high frequency was calculated, as expression of the sympathovagal balance, in basal condition and after tilt table test, for the evaluation of the response of the heart to the sympathetic stimulation. 2.2. QKD interval
2.1. Heart rate variability The patients were positioned on a tilt table with a foot board to permit weight bearing. After 10 min in the supine position, the patient was tilted to a 70° upright position for 20 min. Blood pressure was monitored at 2 min intervals and 12-lead ECG was continuously monitored and recorded during spontaneous and controlled breathing (12 cycles/min). Commercially available imaging system (Cardioline ECT WS 2000, Remco, Vignate-Milano, Italy) was used. QRS detection and RR interval measurement were automatically performed, looking
We used Diasys Integra device (Novacor, France), which are based in the auscultatory method with ECG correlation. Blood pressure and QKD interval were measured simultaneously. The armband of the device was placed on the left arm, and the device was programmed to take four measurements per hour for 24 h during the normal routine of the patient. Only recordings with at least 80 valid measurements were retained for analysis. The manufacturer's software (Novacor) calculated automatically the mean value of each parameter over 24 h (systolic blood pressure, diastolic blood pressure, heart rate, QKD) and
Table 3 Heart rate variability, spectral components and LF/HF ratio in basal conditions (b) and after tilt table (t) test in control group, in patients with hypertension, with normal and with low QKD100–60
Control group (n = 20) Hypertensive patients (n = 23) Hypertensive patients with normal QKD Hypertensive patients with low QKD
100–60
100–60
(n = 13)
(n = 10)
TP (ms2)
VLF (ms2)
LF (ms2)
HF (ms2)
LF/HFb
LF/HFT
2715 ± 2007 828 ± 656 p = 0.0002 978 ± 650 p = 0.002 649 ± 650 p = 0.0005
1092 ± 1016 381 ± 322 p = 0.006 482 ± 366 n.s. 260 ± 220 p = 0.004
587 ± 463 260 ± 286 p = 0.001 283 ± 249 n.s. 231 ± 341 p = 0.009
822 ± 838 188 ± 220 p = 0.004 236 ± 208 p = 0.02 125 ± 230 p b 0.0001
1.02 ± 0.69 1.99 ± 1.84 p = 0.03 1.23 ± 0.8 n.s. 2.98 ± 2.3 p = 0.001
3.6 ± 1.9 5.6 ± 4.3 n.s. 5.06 ± 3.7 n.s. 6.5 ± 5.1 n.s.
Mann–Whitney test for unpaired data; n.s. = not significant. TP = total power; VLF = very low frequency; LF = low frequency; HF = high frequency.
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QKD100–60, that is the value at 100 mm Hg systolic blood pressure and 60 bpm heart rate from the linear relationship QKD = K − aSBP-bHR obtained over a hundred measurements in each recording. This was designed to eliminate the part of the variation in the QKD stemming from the linear dependence of preejection time on heart rate. For comparison of different populations, the QKD100–60 was also expressed as the percentage of the height predicted value (QKD100–60 h) (Gosse et al., 1999). 2.3. Statistical analysis Data were expressed as mean ± standard deviation. Statistical analysis included comparison of untreated hypertensive patients with control subjects and of patients with low and high QKD100–60 values with control subjects, by means of nonparametric Mann– Whitney test for unpaired data. To determine whether there was a relationship between QKD100–60 values and each heart rate variability parameter (VLF, LF, HF, LF/HF, total power) in patients with hypertension, a nonparametric correlation Spearman r analysis was performed using Graphpad Instat (version 3.06 for Windows) computer software. A p value below 0.05 was considered statistically significant. 3. Results 3.1. 24 hour blood pressure and QKD measurements Hypertensive patients had significantly elevated systolic and diastolic blood pressure values (Table 1) in comparison with healthy subjects. In 43% (10/23) of hypertensive patients QKD100–60 values were reduced in comparison with normal values (Table 1). 3.2. Heart rate variability In patients with hypertension total power of HRV and spectral components, evaluated in basal conditions, were reduced in comparison with control group; LF/HF ratio, expression of sympathovagal balance, in basal condition was higher in hypertensive patients in comparison with control group, but after tilt test similar values were observed in the two groups (Table 3). Patients with reduced QKD100–60 interval show reduced total power and spectral components values, with higher LF/HF ratio in basal conditions in comparison with control group (Table 3). However, patients with normal QKD100–60 showed no differences in respect to LF/HF ratio, VLF and LF components, in comparison with control group.
Fig. 2. Correlation between QKD100–60 h and LF/HF in 10 patients with essential hypertension and with reduced QKD100–60 interval. Nonparametric correlation Spearman r analysis (Spearman r = −0.6585; p = 0.04).
Patients with reduced QKD100–60 interval showed higher LF/HF ratio in comparison with patients with normal QKD100–60 (Table 3). In patients with hypertension, QKD100–60 h values correlated significantly with LF/HF ratio (Spearman r = −0.551; p = 0.006) (Fig. 1), with HF spectral component (Spearman r = 0.630; p = 0.001) and with total power (Spearman r = 0.426; p = 0.004). Furthermore, in patients with reduced QKD100–60 interval, QKD100– 6060 h values correlated significantly with LF/HF ratio (Spearman r = −0.6585; p = 0.04) (Fig. 2) and with HF spectral component (Spearman r = 0.8196; p = 0.005). In patients with normal QKD100–60 interval, no correlation was found between QKD 100–60 h values and HRV parameters. 4. Discussion Arterial stiffness evaluated by measurement of the QKD interval is considered an independent predictor of cardiovascular events (Gosse et al., 2005). In hypertensive patients, the buffering function of large arteries is constantly altered, due to modifications in the viscoelastic properties of the arterial wall (Levy, 1996); arterial stiffness is largely determined by two influences: those related to the arteries themselves (wall structure and function and lumen size) and the mean distending arterial blood pressure (Payne and Webb, 2006; Wilkinson and McEniery, 2004). Furthermore, there is strong evidence that specific gene expression profile is associated with aortic stiffness determining the amount and density of stiff wall material and the spatial organization of the material (Laurent et al., 2005; Yasmin and O'Shaughnessy, 2008). Arterial-wall properties are also found to be influenced by the sympathetic nervous system in animals and humans (Boutouyrie et al., 1994; Mangoni et al., 1997). It was suggested that sympathetic activity may influence the mechanical properties of the arterial wall through complex interactions involving increases in arterial smooth muscle tone and distending blood pressure (Basghaw and Peterson, 1972). Several studies have suggested that sympathetic neural control affects not only small resistance arteries (Dobrin, 1984), but also mechanical properties of large arteries (Bergel, 1961). For example, pharmacological or electrical activation of the sympathetic nervous system has been shown to reduce distensibility of small and mediumsize arteries in animals (Cox, 1976; Gerova and Gero, 1969) and there is evidence that in animals, small-artery distensibility is increased by the removal of sympathetic influences (Baumbach et al., 1989) and that in humans, radial artery distensibility increases after transient anesthesia of the brachial plexus (Grassi et al., 1995). This suggests that the sympathetic nervous system may increase arterial wall stiffness not only phasically, but also tonically. A previous study (Mangoni et al., 1997) provides an unequivocal demonstration that in the anesthetized rat the sympathetic nervous system tonically restrains large-artery distensibility and that the restraint involves both elastic and muscle-type vessels, suggesting that diseases that increase sympathetic activity (as in congestive heart failure) (Giannattasio et al., 1995a; Cohn et al., 1984) and therapeutic interventions that reduce it (Giannattasio et al., 1995b) may be accompanied by modifications not only in the arterioles, but also in large conduit arteries, with potential implications for arterial impedance and cardiac load. Furthermore, the sympathetic nervous system exerts a marked tonic restraint of arterial distensibility, also in subjects with peripheral artery disease and this stiffening influence may increase the traumatic effect of intravascular pressure on the vessel wall and favour atherosclerosis (Failla et al., 1999). These findings are particularly important in certain condition such as aortic aneurysm: in fact experimental studies showed that the stresses are much higher at inflection points in aneurysm model than in non-aneurysm model, and the stresses at media in stiffened wall are higher than in unstiffened wall. This observation explains why the
M. Acampa et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 102–105
patients with aortic aneurysm, especially aortic arch aneurysm, are prone to have aortic dissection (Gao et al., 2008). In particular, increased stiffness significantly increased peak wall stress, which was located at the inflection point rather than at the maximum diameter (Flora et al., 2002). According to these observations, our study shows that in untreated essential hypertensive patients there is a correlation between sympathovagal balance and arterial distensibility; in particular sympathetic overactivity, low vagal activity and reduced HRV are associated with an altered value of QKD100–60, that is with a reduced artery distensibility. Hypertensive patients with reduced QKD100–60 show a sympathetic overactivity in basal conditions and not after tilt table test in comparison with patients with normal QKD100–60: this observation suggests that, in a group of hypertensive patients, sympathetic overactivity in basal condition (and not sympathetic response to external stimulations) contributes to a reduction of large artery distensibility. These findings confirm the results of previous studies showing a link between parasympathetic modulation of pulse transit time (an essential component of QKD interval) variability and spectral component HF of HRV (Ma and Zhang, 2006). Our results show also that only 43% of hypertensive patients have reduced QKD100–60 values: the reason of these finding could be that the patients studied had no coronary artery disease, cerebrovascular disease or diabetes mellitus and their hypertension was of recent onset. The results of our study may give a contribution to understand, at least in part, the mechanisms involved in the reduced artery distensibility in subjects with hypertension. From a clinical perspective, the relevance of these results suggests also, in selected patients with sympathetic overactivity, the possibility to reduce the alterations of mechanical properties of large arteries by means of specific treatment with beta-blockers, according to recent studies showing that beta-blockers reduce aortic stiffness in hypertension (Mahmud and Feely, 2008). References Basghaw, R.J., Peterson, L.H., 1972. Sympathetic control of the mechanical properties of the canine carotid sinus. Am. J. Physiol. 222, 1462–1468. Baumbach, G.L., Heistad, D.D., Siemens, J.E., 1989. Effects of sympathetic nerves on composition and distensibility of cerebral arterioles in rats. J. Physiol. 416, 123–140. Bergel, D.H., 1961. The dynamic elastic properties of the arterial wall. J. Physiol. 156, 458–469. Boutouyrie, P., Lacolley, P., Girerd, X., Beck, L., Safar, M., Laurent, S., 1994. Sympathetic activation decreases medium sized arterial compliance in humans. Am. J. Physiol. 267, H1368–H1377. Cohn, J.N., Levine, T.B., Olivari, M.T., Garnerg, V., Lura, B.S., Francis, G.S., Simon, A.B., Rector, T., 1984. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311, 819–823. Cox, R.H., 1976. Effects of norepinephrine on mechanics of arteries in vivo. Am. J. Physiol. 231, 420–425. Dobrin, P.B., 1984. Mechanical behavior of vascular smooth muscle in cylindrical segments of arteries in vitro. Ann. Biom. Eng. 12, 497–510.
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Failla, M., Grappolo, A., Emanuelli, G., Vitale, G., Fraschini, N., Bigoni, M., Greco, N., Denti, M., Giannattasio, C., Mancia, G., 1999. Sympathetic tone restrains arterial distensibility of healthy and atherosclerotic subjects. J. Hypertens. 17, 1117–1123. Flora, H.S., Talei-Faz, B., Ansdell, L., Chaloner, E.J., Sweeny, A., Grass, A., Adiseshiah, M., 2002. Aneurysm wall stress and tendency to rupture are features of physical wall properties: an experimental study. J. Endovasc. Ther. 9, 665–675. Gao, F., Ohta, O., Matsuzawa, T., 2008. Fluid–structure interaction in layered aortic arch aneurysm model: assessing the combined influence of arch aneurysm and wall stiffness. Australas. Phys. Eng. Sci. Med. 31, 32–41. Gerova, M., Gero, J., 1969. Range of the sympathetic control of the dog femoral artery. Circ. Res. 24, 349–359. Giannattasio, C., Failla, M., Stella, M.L., Mangoni, A.A., Cargo, S., Pozzi, M., Grassi, G., Mancia, G., 1995a. Alterations in radial artery compliance in patients with congestive heart failure. Am. J. Cardiol. 76, 381–385. Giannattasio, C., Failla, M., Stella, M.L., Mangoni, A.A., Turrini, D., Cargo, S., Pozzi, M., Grassi, G., Mancia, G., 1995b. Angiotensin-converting enzyme inhibition and radial artery compliance in patients with congestive heart failure. Hypertension 26, 491–496. Gosse, P., Guillo, P., Ascher, G., Clementy, J., 1994. Assessment of arterial distensibility by monitoring the timing of Korotkoff sounds. Am. J. Hypertens. 7, 228–233. Gosse, P., Jullien, V., Jarnier, P., Lemetayer, P., Clementy, J., 1999. Ambulatory measurements of the timing of Korotkoff sounds in a group of normal subjects: influence of age and height. Am. J. Hypertens. 12, 231–235. Gosse, P., Lasserre, R., Minifié, C., Lemetayer, P., Clementy, J., 2005. Arterial stiffness evaluated by measurement of the QKD interval is an independent predictor of cardiovascular events. Am. J. Hypertens. 18 (4 Pt 1), 470–476. Grassi, G., Giannattasio, C., Failla, M., Pesenti, A., Peretti, G., Marinoni, E., Fraschini, N., Vailati, S., Mancia, G., 1995. Sympathetic modulation of radial artery compliance in congestive heart failure. Hypertension 26, 348–354. Julius, S., 1991. Autonomic nervous system dysregulation in human hypertension. Am. J. Cardiol. 67, 3B–7B. Kosch, M., Hausberg, M., Barenbrock, M., Kisters, K., Rahn, K.H., 1999. Studies on cardiac sympathovagal balance and large artery distensibility in patients with untreated essential hypertension. J. Hum. Hypertens. 13, 315–319. Laurent, S., Boutouyrie, P., Lacolley, P., 2005. Structural and genetic bases of arterial stiffness. Hypertension 45, 1050–1055. Levy, B.I., 1996. The mechanical properties of the arterial wall in hypertension. Prostaglandins, Leukot. Essent. Fat. Acids 54, 39–43. Ma, H.T., Zhang, Y.T., 2006. Spectral analysis of pulse transit time variability and its coherence with other cardiovascular variabilities. Conf. Proc. I.E.E.E. Eng. Med. Biol. Soc. 1, 6442–6445. Mahmud, A., Feely, J., 2008. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am. J. Hypertens. 21, 663–667. Malik, M., Bigger, J.T., Camm, A.J., Kleiger, R.E., Malliani, A., Moss, A.J., Schwartz, P., 1996. Heart rate variability. Circulation 93, 1043–1065. Mangoni, A.A., Mircoli, L., Giannattasio, C., Mancia, G., Ferrari, A.U., 1997. Effect of sympathectomy on mechanical properties of common carotid and femoral arteries. Hypertension 30, 1085–1088. Payne, R.A., Webb, D.J., 2006. Arterial blood pressure and stiffness in hypertension. Is arterial structure important? Hypertension 48, 366–367. Safar, M.E., Frohlich, E.D., 1995. The arterial system in hypertension. Hypertension 26, 10–14. Singh, J.P., Larson, M.G., Tsuji, H., Evans, J.C., O'Donnell, C.J., Levy, D., 1998. Reduced heart rate variability and new-onset hypertension. Hypertension 32, 293–297. Wilkinson, I.B., McEniery, C.M., 2004. Arterial stiffness, endothelial function and novel pharmacological approaches. Clin. Exp. Pharmacol. Physiol. 31, 795–799. Wyss, J.M., Carlson, S.H., 2001. The role of the nervous system in hypertension. Curr. Hypertens. Rep. 3, 255–262. Yasmin, O'Shaughnessy, K.M., 2008. Genetics of arterial structure and function: towards new biomarkers for aortic stiffness? Clin. Sci. (Lond.) 114, 661–677.
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Cardiac dysautonomia and arterial distensibility in essential hypertensives Maurizio Acampa ⁎, Massimo Franchi, Francesca Guideri, Ilaria Lamberti, Fulvio Bruni, Marcello Pastorelli, Giovanni Bova, Anna Laura Pasqui, Luca Puccetti, Alberto Auteri Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy
a r t i c l e
i n f o
Article history: Received 26 March 2008 Received in revised form 7 October 2008 Accepted 13 November 2008 Keywords: Hypertension Autonomic nervous system Heart rate variability QKD interval
a b s t r a c t Introduction: The central nervous system plays an important role in the regulation of blood pressure: the sympathetic nervous system may be a primary contributor to the development of some forms of essential hypertension. Hypertension is also associated with reduced distensibility of large arteries. The aim of our study is the evaluation of a correlation between cardiac dysautonomia (evaluated by means of heart rate variability [HRV]) and altered artery distensibility (evaluated by means of measurement of the time interval from the onset of the QRS wave and the detection of the last Korotkoff sound [QKD interval]). Materials and methods: HRV and QKD interval were evaluated in 23 patients (60.9 ± 8.7 years) with untreated hypertension and in 20 control subjects (53.2 ± 16.8 years). QKD interval and QKD100–60 (that is QKD for a 100 mm Hg systolic blood pressure and 60 bpm heart rate) were measured during a 24-hours blood pressure monitoring. HRV was evaluated by means of a spectral method. Three main spectral components were distinguished: very low frequency (VLF), low frequency (LF) and high frequency (HF) component. Results: Patients with reduced QKD100–60 interval show reduced total power and spectral components values, with higher LF/HF ratio in basal conditions in comparison with control group. In patients with hypertension, QKD100–60 values correlated significantly with LF/HF ratio (Spearman r = −0.551; p = 0.006), HF spectral component (Spearman r = 0.630; p = 0.001) and total power (Spearman r = 0.426; p = 0.004). Conclusions: Our results suggest that sympathetic overactivity may be the contributor of reduced arterial distensibility observed in patients with essential hypertension. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The central nervous system plays an important role in the regulation of blood pressure; several lines of evidence in animal models and in humans suggest that the sympathetic nervous system is a primary contributor to the development and the maintenance of some forms of essential hypertension (Julius, 1991). Sympathetic nervous system overactivity may result from either inappropriately elevated sympathetic drive from brain centers, an increase in synaptically released neurotransmitters in the periphery, or amplification of the neurotransmitter signal at the target tissue (Wyss and Carlson, 2001). Spectral analysis of heart rate variability (HRV) can partially distinguish parasympathetic from sympathetic influences on the heart (Malik et al., 1996) and may provide important insights into the role of the autonomic nervous system in the pathogenesis of essential hypertension: HRV is reduced in men and women with systemic hypertension and autonomic dysregulation is present in the early stages of hypertension (Singh et al., 1998). ⁎ Corresponding author. Dipartimento di Medicina Clinica e Scienze Immunologiche, Sezione di Medicina Interna, Policlinico 'Le Scotte', viale Bracci, 53100 Siena, Italy. Tel.: +39 0 577585741; fax: +39 0 57744114. E-mail address: [email protected] (M. Acampa). 1566-0702/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2008.11.009
Hypertension is also associated with reduced distensibility of large arteries (Gosse et al., 1994; Safar and Frohlich, 1995). Measurements of the time interval from the onset of the QRS wave on the electrocardiogram and the detection of the last Korotkoff sound during blood pressure measurements (QKD interval) are a non invasive method for assessing the physical properties of elastic arteries (Gosse et al., 1994, 1999). A previous study (Kosch et al., 1999) showed a correlation between carotid distensibility, evaluated with echography, and sympathetic imbalance, evaluated by HRV, in basal conditions in subjects with hypertension. The aim of this study was the investigation of arterial distensibility (by means of QKD interval measurement) and of cardiac autonomic nervous system activity (by means of HRV) in basal conditions and after sympathetic stimulation, in patients with hypertension and in control subjects, for a possible correlation between the two parameters. 2. Methods We observed 23 patients (60.9 ± 8.7 years) with hypertension and 20 control subjects (53.2 ± 16.8 years) referred consecutively to our department before any administration of antihypertensive treatment and who had benefited from an ambulatory measurement of the QKD
M. Acampa et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 102–105
103
Table 1 Patients and control group demographics Hypertensive patients (n = 23) Control group (n = 20) p value Gender Age (years) 24 h SBP (mm Hg) 24 h DBP (mm Hg) 24 h HR (bpm) BMI (Kg/m2) PP (mm Hg) 24 h QKD (ms) 24 h QKD100–60(ms) 24 h QKD100–60 h (%)
13 males, 10 females 60 ± 8 (40–80) 141 ± 13 92 ± 11 78 ± 10 24.7 ± 2.7 48 ± 12 190 ± 20 204 ± 18 96 ± 11
10 males, 10 females 53 ± 16 (31–81) 110 ± 10 79 ± 11 70 ± 11 23.5 ± 2.1 41 ± 4.7 197 ± 15 215 ± 19 100 ± 11
n.s. n.s. 0.01 0.01 0.02 n.s. 0.03 n.s. 0.05 0.02
SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, BMI: body mass index, PP: pulse pressure, QKD100–60 h: value of QKD100–60 as the percentage of height predicted value. Fig. 1. Correlation between QKD100–60 h and LF/HF in 23 patients with essential hypertension. Nonparametric correlation Spearman r analysis (Spearman r = −0.551; p = 0.006).
Table 2 Hypertensive patients demographics Hypertensive patients with Hypertensive patients with p value normal QKD100–60 h (n = 13) low QKD100–60 h (n = 10) Gender Age (years) 24 h SBP (mm Hg) 24 h DBP (mm Hg) 24 h HR (bpm) BMI (Kg/m2) PP (mm Hg)
6 males, 4 females 61.6 ± 11 142 ± 10 91 ± 9 81 ± 9 25.1 ± 2.7 55 ± 10
7 males, 6 females 60.4 ± 7 140 ± 11 94 ± 10 75 ± 9 24.5 ± 2.8 43 ± 11
n.s. n.s. n.s. n.s. n.s. n.s. 0.01
SBP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, BMI: body mass index, PP: pulse pressure, QKD100–60 h: value of QKD100–60 as the percentage of height predicted value.
interval over 24 h and an evaluation of cardiac autonomic nervous system activity. Patients with left bundle branch block, with cardiac arrhythmias or those fitted with pacemakers were excluded. Patients with known thyroid disorders, history of coronary artery disease, cerebrovascular disease or diabetes mellitus were not recruited. Demographic characteristics of patients and controls are depicted in Tables 1 and 2. HRV, ambulatory 24-hour blood pressure monitoring and QKD interval were measured in all subjects. Informed consent was obtained from each patient before entering the study. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki.
for the R wave peak as a reference point. Premature beats, missed beats and artifacts were visually identified using an interactive graphic interface and corrected by the operator. In this way, an RR tachogram was obtained, that is, a discrete series of successive RR intervals as a function of the number of recognized QRS complexes. Algorithm, used for the analysis of the tachogram, was a spectral method (fast Fourier Transformation). Three main spectral components were distinguished in a spectrum calculated from short-term recordings of 5 min: – a very low frequency component (VLF): b 0.04 Hz; – a low frequency component (LF): range 0.04–0.15 Hz – a high frequency component (HF): range 0.15–0.4 Hz. The measurement of VLF, LF, and HF power components and of total power was made in absolute values of power (millisecond squared). The ratio of low to high frequency was calculated, as expression of the sympathovagal balance, in basal condition and after tilt table test, for the evaluation of the response of the heart to the sympathetic stimulation. 2.2. QKD interval
2.1. Heart rate variability The patients were positioned on a tilt table with a foot board to permit weight bearing. After 10 min in the supine position, the patient was tilted to a 70° upright position for 20 min. Blood pressure was monitored at 2 min intervals and 12-lead ECG was continuously monitored and recorded during spontaneous and controlled breathing (12 cycles/min). Commercially available imaging system (Cardioline ECT WS 2000, Remco, Vignate-Milano, Italy) was used. QRS detection and RR interval measurement were automatically performed, looking
We used Diasys Integra device (Novacor, France), which are based in the auscultatory method with ECG correlation. Blood pressure and QKD interval were measured simultaneously. The armband of the device was placed on the left arm, and the device was programmed to take four measurements per hour for 24 h during the normal routine of the patient. Only recordings with at least 80 valid measurements were retained for analysis. The manufacturer's software (Novacor) calculated automatically the mean value of each parameter over 24 h (systolic blood pressure, diastolic blood pressure, heart rate, QKD) and
Table 3 Heart rate variability, spectral components and LF/HF ratio in basal conditions (b) and after tilt table (t) test in control group, in patients with hypertension, with normal and with low QKD100–60
Control group (n = 20) Hypertensive patients (n = 23) Hypertensive patients with normal QKD Hypertensive patients with low QKD
100–60
100–60
(n = 13)
(n = 10)
TP (ms2)
VLF (ms2)
LF (ms2)
HF (ms2)
LF/HFb
LF/HFT
2715 ± 2007 828 ± 656 p = 0.0002 978 ± 650 p = 0.002 649 ± 650 p = 0.0005
1092 ± 1016 381 ± 322 p = 0.006 482 ± 366 n.s. 260 ± 220 p = 0.004
587 ± 463 260 ± 286 p = 0.001 283 ± 249 n.s. 231 ± 341 p = 0.009
822 ± 838 188 ± 220 p = 0.004 236 ± 208 p = 0.02 125 ± 230 p b 0.0001
1.02 ± 0.69 1.99 ± 1.84 p = 0.03 1.23 ± 0.8 n.s. 2.98 ± 2.3 p = 0.001
3.6 ± 1.9 5.6 ± 4.3 n.s. 5.06 ± 3.7 n.s. 6.5 ± 5.1 n.s.
Mann–Whitney test for unpaired data; n.s. = not significant. TP = total power; VLF = very low frequency; LF = low frequency; HF = high frequency.
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QKD100–60, that is the value at 100 mm Hg systolic blood pressure and 60 bpm heart rate from the linear relationship QKD = K − aSBP-bHR obtained over a hundred measurements in each recording. This was designed to eliminate the part of the variation in the QKD stemming from the linear dependence of preejection time on heart rate. For comparison of different populations, the QKD100–60 was also expressed as the percentage of the height predicted value (QKD100–60 h) (Gosse et al., 1999). 2.3. Statistical analysis Data were expressed as mean ± standard deviation. Statistical analysis included comparison of untreated hypertensive patients with control subjects and of patients with low and high QKD100–60 values with control subjects, by means of nonparametric Mann– Whitney test for unpaired data. To determine whether there was a relationship between QKD100–60 values and each heart rate variability parameter (VLF, LF, HF, LF/HF, total power) in patients with hypertension, a nonparametric correlation Spearman r analysis was performed using Graphpad Instat (version 3.06 for Windows) computer software. A p value below 0.05 was considered statistically significant. 3. Results 3.1. 24 hour blood pressure and QKD measurements Hypertensive patients had significantly elevated systolic and diastolic blood pressure values (Table 1) in comparison with healthy subjects. In 43% (10/23) of hypertensive patients QKD100–60 values were reduced in comparison with normal values (Table 1). 3.2. Heart rate variability In patients with hypertension total power of HRV and spectral components, evaluated in basal conditions, were reduced in comparison with control group; LF/HF ratio, expression of sympathovagal balance, in basal condition was higher in hypertensive patients in comparison with control group, but after tilt test similar values were observed in the two groups (Table 3). Patients with reduced QKD100–60 interval show reduced total power and spectral components values, with higher LF/HF ratio in basal conditions in comparison with control group (Table 3). However, patients with normal QKD100–60 showed no differences in respect to LF/HF ratio, VLF and LF components, in comparison with control group.
Fig. 2. Correlation between QKD100–60 h and LF/HF in 10 patients with essential hypertension and with reduced QKD100–60 interval. Nonparametric correlation Spearman r analysis (Spearman r = −0.6585; p = 0.04).
Patients with reduced QKD100–60 interval showed higher LF/HF ratio in comparison with patients with normal QKD100–60 (Table 3). In patients with hypertension, QKD100–60 h values correlated significantly with LF/HF ratio (Spearman r = −0.551; p = 0.006) (Fig. 1), with HF spectral component (Spearman r = 0.630; p = 0.001) and with total power (Spearman r = 0.426; p = 0.004). Furthermore, in patients with reduced QKD100–60 interval, QKD100– 6060 h values correlated significantly with LF/HF ratio (Spearman r = −0.6585; p = 0.04) (Fig. 2) and with HF spectral component (Spearman r = 0.8196; p = 0.005). In patients with normal QKD100–60 interval, no correlation was found between QKD 100–60 h values and HRV parameters. 4. Discussion Arterial stiffness evaluated by measurement of the QKD interval is considered an independent predictor of cardiovascular events (Gosse et al., 2005). In hypertensive patients, the buffering function of large arteries is constantly altered, due to modifications in the viscoelastic properties of the arterial wall (Levy, 1996); arterial stiffness is largely determined by two influences: those related to the arteries themselves (wall structure and function and lumen size) and the mean distending arterial blood pressure (Payne and Webb, 2006; Wilkinson and McEniery, 2004). Furthermore, there is strong evidence that specific gene expression profile is associated with aortic stiffness determining the amount and density of stiff wall material and the spatial organization of the material (Laurent et al., 2005; Yasmin and O'Shaughnessy, 2008). Arterial-wall properties are also found to be influenced by the sympathetic nervous system in animals and humans (Boutouyrie et al., 1994; Mangoni et al., 1997). It was suggested that sympathetic activity may influence the mechanical properties of the arterial wall through complex interactions involving increases in arterial smooth muscle tone and distending blood pressure (Basghaw and Peterson, 1972). Several studies have suggested that sympathetic neural control affects not only small resistance arteries (Dobrin, 1984), but also mechanical properties of large arteries (Bergel, 1961). For example, pharmacological or electrical activation of the sympathetic nervous system has been shown to reduce distensibility of small and mediumsize arteries in animals (Cox, 1976; Gerova and Gero, 1969) and there is evidence that in animals, small-artery distensibility is increased by the removal of sympathetic influences (Baumbach et al., 1989) and that in humans, radial artery distensibility increases after transient anesthesia of the brachial plexus (Grassi et al., 1995). This suggests that the sympathetic nervous system may increase arterial wall stiffness not only phasically, but also tonically. A previous study (Mangoni et al., 1997) provides an unequivocal demonstration that in the anesthetized rat the sympathetic nervous system tonically restrains large-artery distensibility and that the restraint involves both elastic and muscle-type vessels, suggesting that diseases that increase sympathetic activity (as in congestive heart failure) (Giannattasio et al., 1995a; Cohn et al., 1984) and therapeutic interventions that reduce it (Giannattasio et al., 1995b) may be accompanied by modifications not only in the arterioles, but also in large conduit arteries, with potential implications for arterial impedance and cardiac load. Furthermore, the sympathetic nervous system exerts a marked tonic restraint of arterial distensibility, also in subjects with peripheral artery disease and this stiffening influence may increase the traumatic effect of intravascular pressure on the vessel wall and favour atherosclerosis (Failla et al., 1999). These findings are particularly important in certain condition such as aortic aneurysm: in fact experimental studies showed that the stresses are much higher at inflection points in aneurysm model than in non-aneurysm model, and the stresses at media in stiffened wall are higher than in unstiffened wall. This observation explains why the
M. Acampa et al. / Autonomic Neuroscience: Basic and Clinical 146 (2009) 102–105
patients with aortic aneurysm, especially aortic arch aneurysm, are prone to have aortic dissection (Gao et al., 2008). In particular, increased stiffness significantly increased peak wall stress, which was located at the inflection point rather than at the maximum diameter (Flora et al., 2002). According to these observations, our study shows that in untreated essential hypertensive patients there is a correlation between sympathovagal balance and arterial distensibility; in particular sympathetic overactivity, low vagal activity and reduced HRV are associated with an altered value of QKD100–60, that is with a reduced artery distensibility. Hypertensive patients with reduced QKD100–60 show a sympathetic overactivity in basal conditions and not after tilt table test in comparison with patients with normal QKD100–60: this observation suggests that, in a group of hypertensive patients, sympathetic overactivity in basal condition (and not sympathetic response to external stimulations) contributes to a reduction of large artery distensibility. These findings confirm the results of previous studies showing a link between parasympathetic modulation of pulse transit time (an essential component of QKD interval) variability and spectral component HF of HRV (Ma and Zhang, 2006). Our results show also that only 43% of hypertensive patients have reduced QKD100–60 values: the reason of these finding could be that the patients studied had no coronary artery disease, cerebrovascular disease or diabetes mellitus and their hypertension was of recent onset. The results of our study may give a contribution to understand, at least in part, the mechanisms involved in the reduced artery distensibility in subjects with hypertension. From a clinical perspective, the relevance of these results suggests also, in selected patients with sympathetic overactivity, the possibility to reduce the alterations of mechanical properties of large arteries by means of specific treatment with beta-blockers, according to recent studies showing that beta-blockers reduce aortic stiffness in hypertension (Mahmud and Feely, 2008). References Basghaw, R.J., Peterson, L.H., 1972. Sympathetic control of the mechanical properties of the canine carotid sinus. Am. J. Physiol. 222, 1462–1468. Baumbach, G.L., Heistad, D.D., Siemens, J.E., 1989. Effects of sympathetic nerves on composition and distensibility of cerebral arterioles in rats. J. Physiol. 416, 123–140. Bergel, D.H., 1961. The dynamic elastic properties of the arterial wall. J. Physiol. 156, 458–469. Boutouyrie, P., Lacolley, P., Girerd, X., Beck, L., Safar, M., Laurent, S., 1994. Sympathetic activation decreases medium sized arterial compliance in humans. Am. J. Physiol. 267, H1368–H1377. Cohn, J.N., Levine, T.B., Olivari, M.T., Garnerg, V., Lura, B.S., Francis, G.S., Simon, A.B., Rector, T., 1984. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311, 819–823. Cox, R.H., 1976. Effects of norepinephrine on mechanics of arteries in vivo. Am. J. Physiol. 231, 420–425. Dobrin, P.B., 1984. Mechanical behavior of vascular smooth muscle in cylindrical segments of arteries in vitro. Ann. Biom. Eng. 12, 497–510.
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