4
Is Low Baroreflex Sensitivity only
a Consequence of Essential Hypertension
or also a Factor Conditioning Its Development?
Natasa Honzikova and Eva Zavodna
Masaryk University, Faculty of Medicine, Department of Physiology
Czech Republic
1. Introduction
Baroreflex is the most important nervous regulatory mechanism of blood pressure
homeostasis. Its role in a short-time regulation of blood pressure is very well documented.
On the other hand, the answer to the question whether primary low baroreflex sensitivity
could also be the cause of the development of hypertension remains unresolved. This
question is now topical.
Baroreflex has several branches: reflex control of the peripheral resistance, of the tone of
capacitance vessels, of the heart rate and contractility. Heart rate response to blood pressure
variations is studied most intensively. Heart rate changes caused by stimulation of
baroreceptors are usually quantified as the index of baroreflex sensitivity (BRS), which
corresponds to a prolongation of the cardiac interval due to the increase of blood pressure in
ms/mmHg. This mechanism operates beat-by-beat and is evaluated from recordings of
blood pressure and inter-beat intervals (IBI) lasting for several minutes or several seconds
respectively, depending on the method used. Despite the fact that BRS fluctuates in healthy
subjects at rest, it represents a characteristic individual feature. Baroreflex sensitivity
decreases with age and in different pathological states. This is of major clinical relevance as
a risk factor of sudden cardiac death in patients after myocardial infarction, which is
included among complications of hypertension. Therefore, many studies have paid attention
to this problem providing evidence that metabolic and sympathetic/parasympathetic
changes, especially during obesity, activate mechanisms (for instance thickening of the
carotid wall) causing suppression of BRS. On the other hand, some healthy children and
adolescents have as low BRS as elderly patients with hypertension. Some genetic studies
provided evidence for an inborn disposition to low BRS. This opened the question whether
an inborn low BRS could represent an additive factor disposing to blood pressure elevation.
This is important with respect to epidemic obesity and to an increased prevalence of
hypertension among young people.
We have proved by our own method of a summed-weighted-fuzzified index that low BRS is
an index partially independent of obesity, which is linked with blood pressure elevation in
young population (Krontoradova et al., 2008).
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Genetics and Pathophysiology of Essential Hypertension68
In the methodological part of this Chapter, we describe a cross-spectral method of baroreflex
sensitivity determination and the difference in the signification of this index determined in
ms/mmHg (BRS) as usual, or in mHz/mmHg (BRSf). BRS is inter-beat interval-dependent
and reflects best the total parasympathetic/sympathetic control of the heart rhythm. BRSf is
inter-beat interval-independent and reflects preferably sensitivity of the baroreceptors. This
fact is important when comparing groups of subjects with different mean inter-beat
intervals, for instance, during childhood and adolescence.
2. Baroreflex in short-term and long-term homeostasis of blood pressure
The scientists proceeded from the observation that baroreceptors adapt to an increased
blood pressure and are set to a higher level of blood pressure – the so-called resetting
(Lohmeier et al., 2005). After baroreceptor denervation in experimental animals, blood
pressure is increased by more than 50 mmHg, but during several days it resumes the
original level due to the loss of blood volume by an increased urinary output. The result is
an increase in blood pressure variability with the mean value of blood pressure
corresponding to the value before the denervation. Based on the interpretation of these
experiments it was concluded that the main function of baroreflex is the short-time
regulation of blood pressure (Cowley et al., 1973). Only the recent experiments with chronic
electrical stimulation of the carotid baroreceptor afferent nerve fibres and chronic recording
of the renal sympathetic activity as well as some other experiments demonstrated the role of
baroreceptors in the long-term control of blood pressure (Brooks & Sved, 2005; Cowley et
al., 1992; Thrasher, 2005). The therapy of chronic hypertension resistant to antihypertensive
drugs by stimulation of carotid nerves confirmed that baroreflex is likewise effective in
long-term blood pressure regulation (Filippone & Bisognano, 2007).
2.1 Measurement of heart rate baroreflex sensitivity
The methods used to stimulate baroreceptors include administration of vasoconstrictive or
vasodilative substances. The other possibility of stimulating baroreceptors is the so-called
“neck suction”. Another group of methods applies different mathematical procedures to the
evaluation of recordings of blood pressure and inter-beat fluctuations which last several
minutes. Baroreflex sensitivity calculated by different methods slightly differs (Laude et al.,
2004; Persson et al., 2001).
In our laboratory, we published the first spectral analysis of blood pressure resting
fluctuations in humans (Penaz et al., 1978). We have been using spectral analysis for
baroreflex sensitivity determination since 1992 (Honzikova et al., 1992). Since then, we have
obtained ample methodological experience and we would like to point out some of it.
2.1.1 Cross-spectral method of baroreflex sensitivity determination
At first, we can shortly describe our approach to the determination of baroreflex sensitivity
using one of the options, the cross-spectral method.
The recordings of continuous blood pressure and of inter-beat interval duration (IBI) are
quasi-periodical. Therefore a pre-processing is essential. The recording of blood pressure is
digitized (for instance by a 250 Hz sampling rate and 12-bit resolution), and then stored.
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Is Low Baroreflex Sensitivity only
a Consequence of Essential Hypertension or also a Factor Conditioning Its Development? 69
From the stored signal, the sequences of IBI, systolic blood pressure values (SBP), and
diastolic blood pressure (DBP) are determined. The data acquired represent irregularly
sampled values (concomitantly with variations of IBI) of a continuous time system. They are
interpolated and equidistantly re-sampled.
The next step is a spectral analysis of these pre-processed data. There are two possibilities of
evaluating the spectra: discrete Fourier transformation (DFT) applied directly on the signals
and DFT applied to the autocorrelation function or the cross-correlation function of the
signals. The latter method allows proving the legitimacy of the results by coherence.
Therefore, we use this second method: the autocorrelation functions of IBI, SBP, DBP, and
the cross-correlation function of IBI and SBP are calculated, and then, in the second step, the
power spectra of the autocorrelation functions IBI, SBP and DBP, and the cross-spectrum of
the cross-correlation function of IBI and SBP are calculated by fast Fourier transformation.
The gain factor between variations in systolic blood pressure and inter-beat intervals
calculated at a frequency of 0.1 Hz is taken as a measure of baroreflex sensitivity (BRS) in
ms/mmHg (Honzikova et al., 1992, 2003; Persson et al., 2001; Zavodna et al., 2006).
The frequency ranges between 0.07 and 0.012, or between 0.05 and 0.15 Hz, respectively, are
used for the determination of BRS. The values of BRS are taken into account only if the
coherence is higher than 0.5 (Fig. 1).
We calculate not only the BRS index in ms/mmHg, but also the BRSf index in mHz/mmHg.
The reason for such approach is explained in detail in part 2.1.2 of this Chapter.
Continuous blood-pressure recordings are taken under different conditions. We use
recordings at rest, in sitting position, during metronome-controlled breathing at a frequency
of 0.33 Hz for about 5 minutes for the determination of the resting value of baroreflex
sensitivity, or recordings at spontaneous breathing during a dynamic test, for instance
workload, when controlled breathing is impossible.
During the testing of long duration, a time-frequency map of the spectra is computed. An
example is given in Fig. 1, representing an experiment lasting 18 minutes: 3 minutes at rest
(controlled breathing 0.33 Hz), 9 minutes of bicycling (0.5 W/kg of body weight,
spontaneous breathing), and 6 min at rest after exercise (Honzikova et al., 2003).
To get such a time course of the system properties the whole signal is processed in segments
step by step from the beginning to the end.
The results of the time-frequency map of spectral analysis presented in Fig. 1 revealed two
characteristic features. First, all calculated parameters - the frequency at which BRS was
determined (f), the maximal power of the product of IBI and SBP spectral component (P),
the selected maximal spectral components in a frequency range between 0.05 and 0.15 Hz of
IBI and SBP (vIBI and vSBP), the time-shift between vIBI and vSBP spectral components in a
frequency range between 0.05 and 0.15 Hz, and baroreflex sensitivity fluctuate in time
course. Second, for some short time intervals, coherence between variability of the signals is
insignificant and so some data are omitted. Therefore, in principle, we never get identical
values of these parameters during repeated measurements. Nevertheless, it was shown in
several studies that there is a significantly lower intra-individual than inter-individual
variability of BRS, SBP or IBI (Dietrich et al., 2010; Honzikova et al., 1990; Jira et al., 2006,
2010a; Penaz et al., 1978).
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Genetics and Pathophysiology of Essential Hypertension70
Fig. 1. An example of the time course of circulatory variables at rest (3 min, controlled
breathing), during exercise (9 min, spontaneous breathing), and during recovery (6 min,
controlled breathing). The individual graphs represent: a) the time course of the following
parameters: systolic and diastolic blood pressure (SBP and DBP); b) inter-beat intervals and
their inverse, heart rate values (IBI and HR); c) fluctuation of the frequency at which BRS
was determined (f) with respect to the maximal power, i.e. the product of IBI and SBP
spectral component amplitudes (P); d) the selected spectral components in the frequency
range between 0.05 and 0.15 Hz of IBI and SBP (vIBI and vSBP); e) the time-shift between
vIBI and vSBP spectral components in the frequency range between 0.05 and 0.15 Hz; f)
baroreflex sensitivity (BRS).
2.1.2 Indices of baroreflex sensitivity calculated in ms/mmHg and mHz/mmHg
Baroreflex sensitivity can be expressed as the change of IBI due to a change of systolic blood
pressure in ms/mmHg (BRS index) or as the change of heart rate (HR) due to a change of
systolic blood pressure in bpm/mmHg (Ackermann et al., 1989) or in mHz/mmHg (Al
Kubati et al., 1997). The BRS index is used in most studies, the second method is not used
frequently, and there is no standard abbreviation for the indication that heart rate was used
for the assessment of baroreflex sensitivity. In our laboratory, we apply calculation of
baroreflex sensitivity in both units, in ms/mmHg and in mHz/mmHg, and we use the
abbreviations BRS and BRSf (f in this abbreviation expresses that we use beat-to-beat values
of heart rate for the calculation). To get the BRSf index (mHz/mm Hg), it is necessary to
calculate the value of a modulus at a frequency of 0.1 Hz in a similar way as in case of the
BRS index using spectral analysis of instantaneous values of the heart rate measured beatby-beat
and the corresponding systolic blood pressure values.
Even though in many dynamic tests or examinations of patients with severely suppressed
baroreflex sensitivity the interpretation of the results is independent of the procedure (units)
used, it is not so in all conditions. For example, examination of BRS and BRSf in 139 patients
7-14 days after the first signs of myocardial infarction had a similar discriminating
significance between patients at risk and not at risk. Both indices were significantly
decreased in patients who died within one year after examination in comparison with the
survivors (Semrad et al., 1998). On the other hand, there is a difference in the age-related
values of BRS and BRSf (Zavodna et al., 2006).
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Is Low Baroreflex Sensitivity only
a Consequence of Essential Hypertension or also a Factor Conditioning Its Development? 71
It seems to be useful to explain our approach. The theoretical background is in a non-linear
relationship between IBI and HR (in the scheme below there are big differences in mean IBI
for a better demonstration of the effect discussed). The difference in the values of BRS and
BRSf calculated at a different mean value of IBI is schematically presented in Fig. 2 (left).
Fig. 2. Left: The non-linear relationship between IBI and HR influences BRS and BRSf indices
presented by arrows. Right: The relationship between BRS and BRSf determined in 415
subjects (aged 11-20 years). The correlation coefficient calculated after normalization by a
cube root.
Thus, with the same mean IBI in the two groups tested, the BRS index corresponds to the
baroreflex responsiveness of the heart to blood pressure changes. Such a situation is very
frequent, though mean IBI differs in individuals of such groups.
On the other hand, in a tested group with different mean IBI, the BRSf index should be
preferred. For example, the effect of the development of parasympathetic control of the
heart rate in childhood is manifested by prolongation of the mean IBI (Fig. 2 right). In the
study of Zavodna et al. (2006), 415 healthy subjects at the age of 11-20 years were examined
(under resting conditions, sitting, controlled breathing 0.33 Hz). The BRS and BRSf indices
were determined by the cross-spectral method at a frequency of 0.1 Hz. BRS did not
correlate with age, but BRSf significantly decreased with age. The baroreflex sensitivity
determined as BRS in ms/mmHg was significantly positively dependent on the mean IBI.
This relationship was found not only in the whole group of subjects, but also in the
respective age subgroups. A different situation was encountered in the relationship between
baroreflex sensitivity expressed in mHz/mmHg as BRSf and the mean IBI. BRSf correlated
negatively with IBI in the age range between 11 to 20 years, but in the individual age
subgroups the BRSf index was IBI independent. The greatest impact of IBI on baroreflex
sensitivity was recorded in children aged 11-15 years in whom the mean IBI was prolonged
with age. This means that the BRS index was influenced by the prolongation of mean IBI
reflecting an age-dependent increased tonic vagal nerve activity. On the other hand, it could
be hypothesized that BRSf better expressed the baroreceptor sensitivity.
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Genetics and Pathophysiology of Essential Hypertension72
Some other studies also examined the problem of the relationship between the heart rate
and BRS in children (Allen et al., 2000). It was proposed to standardize the patients’ BRS to a
fixed heart rate of 60 b.p.m. by regression (Abrahamsson et al., 2003). This approach has
some limitation, because the linearity between log-BRS and heart rate is guaranteed only
between the heart rates of 80 and 120 b.p.m. (Wesseling, 2003).
We decided to evaluate a suppression of systolic blood pressure variability by a baroreflex
regulation of the heart rhythm at a frequency of 0.1 Hz using the BRS and BRSf indices
(Honzikova et al., 2007). This study was performed in 58 subjects (20–22 years of age). SBP
variability (SBPv) at 0.1 Hz (LF range) was used for statistical evaluation.
To enable a comparison of the quantitative effects of BRS and BRSf on SBPv, both variables
were expressed as multiples of standard deviations. A negative correlation was found
between SBPv and BRSsd and between SBPv and BRSfsd.
The multiple regression equation
SBPv = 9.43 – 0.0052*IBI/ms + 0.15*BRSsd – 1.85*BRSfsd ; F = 2.92, p<0.05 (1)
revealed a higher regression coefficient of BRSfsd than the regression coefficient of
BRSsd.
In conclusion, this analysis revealed that the inter-beat interval-independent index BRSf
(mHz/mmHg) is a better indicator for evaluation of the efficacy of baroreflex sensitivity
to suppress the SBP variability than the inter-beat interval-dependent index BRS
(ms/mmHg).
3. Physiology of baroreflex sensitivity
3.1 Resting heart rate baroreflex sensitivity as an individual characteristic feature and
the influence of respiration
Baroreflex sensitivity, heart rate, and blood pressure variability are closely interrelated. This
is especially so in the case that all the three variables are determined at a frequency of 0.1
Hz. This is the frequency range of a dominant role of baroreflex suppression of variations in
blood pressure by heart rate changes. If the frequency range of respiration is included in a
measurement or calculation, non-baroreflex factors are involved in respiratory sinus
arrhythmia, such as a central component (Eckberg, 2003; Gilad et al., 2005; Eckberg &
Karemaker, 2009; Tzeng et al., 2009), afferent stimuli from stretch receptors in the lungs and
thoracic wall (Taha et al., 1995), and resonance (van de Vooren et al., 2007). Thus, there is a
difference between BRS values determined at a respiratory frequency and a frequency of 0.1
Hz (Bothova et al., 2010; Fredericks et al., 2000). Bothova et al. (2010) have shown that on
average the determination of BRS by the spectral method at the breathing frequency
overestimates the real BRS. This phenomenon was present only statistically and an opposite
relationship can occur in some subjects. From the point of view of clinicians it is important
that this effect is also present at low BRS values. Therefore, for diagnostic purposes we
recommend the evaluation of BRS at a frequency of 0.1 Hz using metronome-controlled
breathing at a frequency that is substantially higher than 0.1 Hz and is not a multiple of 0.1
Hz to eliminate the respiratory baroreflex-non-related influence and a resonance effect on
heart rate fluctuations.
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Is Low Baroreflex Sensitivity only
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3.2 Physiology of baroreflex sensitivity in children and adolescents
Relatively few studies of physiological BRS values in children and adolescents have been
published. These studies indicate that BRS values are similar to those of young healthy
adults and that inter-individual differences are also considerable. Quite different values of
BRS were reported in 1868 children (10-13 years old) by Dietrich et al. (2006) - between 2.3
and 73 ms/mmHg. We found smaller differences in a group of 415 subjects 11-20 years old
(Zavodna et al., 2006), ranging between 3.9 ms/mmHg for the 5th percentile and 18.7
ms/mmHg for the 95th percentile.
These results are surprising and change the view on the role of low BRS as a potentially
primary factor involved in the early elevation of blood pressure. Low values of BRS in some
children (Zavodna et al., 2006; Dietrich et al., 2006) approach the critical value for the risk of
sudden cardiac death in patients after myocardial infarction and correspond to values
present in hypertensive patients. BRS is usually less than 5 ms/mmHg in hypertensive
patients (Labrova et al., 2005) and BRS lower than 3ms/mmHg is a marker of an increased
risk of sudden cardiac death in patients after myocardial infarction (La Rovere et al., 1998;
Honzikova et al., 2000).
Concerning the age-dependent BRS, a decrease was repeatedly described in adults by many
authors (Gribbin et al., 1971; Kardos et al., 2001). Fewer studies on BRS in children were
published (Allen et al., 2000; Lenard et al., 2004; Rudiger et al., 2001). No significant agedependent
baroreflex-sensitivity decrease was found in 400 subjects aged 10 to 19 years, as
long as baroreflex sensitivity was expressed by the BRSf index in mHz/mmHg or after
normalization of BRS on the cardiac interval by multiple regression analysis (Zavodna et al.,
2006). This can be explained by an increase in the parasympathetic tone and a prolongation
of IBI, and this special approach was explained in part 2.1.2 of this Chapter.
3.3 Genetics of BRS
The genetic contribution to a BRS value could involve different components of the
baroreceptor reflex arc, including baroreceptors, central neuronal transmission, reflex
afferent and efferent pathways. In all of these there act numerous ligands, receptors,
channels, etc. A serious understanding of genetically conditioned BRS will be very
complicated because of multiple interactions of these factors.
Baroreceptors are mechanosensory nerve endings that innervate the adventitia of large
arteries – the carotid and aortic sinus. An explanation of the conversion of mechanical
energy into the action potential is still an open question. In the last two decades, a member
of the degenerin family with mechanosensitive properties was detected in baroreceptor
terminals: amiloride-sensitive epithelial Na channels (ENaC) (Drummond et al., 1998). The
ENaC channels are usually under the aldosterone control. We might presume that
aldosterone would increase Na+ current in baroreceptor terminals and improve
baroreceptor sensation of blood pressure rise. In the promotor region of the gene for enzyme
11/18-beta-hydroxylase (CYP11B2) in position -344 it is possible to find the C/T substitution
which may influence the binding of regulatory factors (Lim et al., 2002). The T allele has
been associated with increased plasma and urinary levels of aldosterone (Paillard et al.,
1999; Davies et al., 1999), corresponding to the results of Ylitalo et al. (2000). They found, in a
group of premenopausal women (41-46 years) who were TT homozygotes, increased mean
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Genetics and Pathophysiology of Essential Hypertension74
and inter-individual variability of baroreflex sensitivity. The data are close to our
unpublished data; however, we observed them in a group of young men (20-24 years) but
not in women.
Gollasch et al. (2002) tested several mutations of the potassium large conductance calciumactivated
channel (KCNMB1) and showed that individuals having SNP AA in exon 4b had
greater baroreflex slopes in the high-frequency range than had CA or CC subjects. Their
findings suggest that potassium channel heterogeneity could mainly influence the rapid
baroreflex-mediated adjustment of heart rate by the parasympathetic nervous system. This
idea is also supported by Pedarzani et al. (2000), who documented the presence of very high
levels of -subunit potassium channel mRNA in rat dorsal vagal neurons.
The processing of the baroreceptor input is mediated in the CNS by several
neurotransmitters, especially by angiotensin II. Generally, angiotensin II has a
sympathoexcitatory effect. It was shown that long-term intracerebroventricular infusion of
angiotensin II decreased BRS in rabbits, but therapy with the angiotensin blocker losartan
resulted in BRS increase (Gaudet et al., 2000). We have found in our group of healthy young
subjects (20-24 years) an association between the less frequent homozygotes CC and
decreased baroreflex sensitivity (Jira et al., 2010b).
There are also other studies that were more or less successful in the association of the
mutation in genes with blood pressure variability and its buffering via the baroreflex
pathway, e.g. endothelin (Ormezzano et al., 2005), acid sensing ion channel (Lu et al., 2009),
neuropeptide Y1 receptor (Wang et al., 2009), eNOS (Jira et al., 2011), etc.
4. Low baroreflex sensitivity as a risk factor
4.1 Significance of low baroreflex sensitivity as a risk factor
The significance of a short-time blood pressure regulation by high BRS as a protection of an
ischemic myocardium from the risk of sudden cardiac death was shown about 15 years ago
and BRS lower than 3ms/mmHg was determined as the critical value of BRS (Honzikova et
al., 2000; La Rovere et al., 1998). At high BRS, a quick prolongation of IBI following a sudden
blood pressure elevation decreases cardiac workload. This is important in an ischemic
myocardium, especially after myocardial infarction, and therefore high BRS prevents
sudden cardiac death.
Myocardial infarction is a frequent complication of essential hypertension. Studies of BRS in
hypertensive patients are important with respect to the potential risk of hypertensive
patients in a possible situation of a later myocardial infarction. BRS is usually lower than 5
ms/mmHg in hypertensive patients (Cowley, 1992; Labrova et al., 2005; Thrasher et al.,
2005). Different comorbidities (diabetes mellitus or heart failure) have an additive effect
either by decreasing BRS, or increasing the risk of myocardial infarction (Mortara et al.,
1997).
Patients at risk of sudden cardiac death profit from implantation of an implantable
cardioverter-defibrillator (ICD). Indication for ICD implantation is done invasively. It would
be desirable to develop a non-invasive approach to risk stratification of patients. Many trials
were carried out to find a combination of non-invasive risk-stratification techniques for
identifying the patients at risk. Although the low left ventricular ejection fraction has been
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Is Low Baroreflex Sensitivity only
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used effectively to select high-risk patients for the application of therapy to prevent sudden
cardiac death, it has a limited sensitivity. Reviews of nearly 15 non-invasive markers of
high-risk patients also include BRS (Bailey et al., 2007; Goldberger et al., 2008).
4.2 Logit and fuzzy models in risk-data analysis
Multiregression analysis is used for evaluation of the influence of different factors on some
functional states, as well as the logistic regression analysis and calculation of the odds ratio
for a group of risk factors. Such approach provides the basic information, for instance for the
understanding of the pathogenesis of any process. Medical practice very often needs not
only identification of risk predictors, but also determination of their critical values,
sensitivity, specificity, and a positive predictive value in the diagnostics or a therapeutic
decision in patients. Calculation of the receiver operating curve (ROC) is used for this
purpose. The improvement of the predictive power of a group of risk factors needs to take
the following physiological assumptions into account. First, the edge between a risky and a
non-risky value of each predictor is not an exact value; secondly, different risk predictors
have different weight.
We have developed fuzzified and weighted models for a sum of risk predictors (Honzik et
al., 2003, 2010). First, ROC and the area under ROC were determined for each single
predictor. The measure of the increasing risk of each single predictor was determined with
one fuzzy set of data with an output range from 0 to 1. The fuzzy weighted method
multiplied each individual risk of each predictor with the predictor’s area under ROC. The
final measure of the risk of each patient was determined as the sum of partial fuzzified
weighted risks of individual predictors. These new individual predictors were also
evaluated by ROC and the area under ROC. For each predictor (measured predictors and a
new fuzzified-weighted-summed predictor) critical values, sensitivity, specificity, and
positive predictive values were calculated. Our new fuzzified-weighted-summed predictor
favourably affected the predictive power of non-invasive risk predictors in individuals. This
approach can be applied in similar decision processes (Krontoradova et al., 2008).
5. Low baroreflex sensitivity due to factors associated with hypertension
5.1 Low BRS and the increased stiffness of the carotid wall
The association between BRS and intima-media thickness (IMT) in the carotid bulb, a
region with high baroreceptor density, was shown as a marker of subclinical
atherosclerosis and essential hypertension (Gianaros et al., 2002; Honzikova et al., 2006a;
Labrova et al., 2005; Zanchetti et al. 1998). Carotid IMT also correlated with age in people
who were not hypertensives (Labrova et al., 2005). Besides intimal thickening due to the
atherosclerotic process, smooth muscle hypertrophy and/or hyperplasia may develop due
to a pressure overload in hypertensive patients. Thus, remodelling of the carotid wall
linked to high blood pressure and an increased stiffness of the carotid sinus leads to lower
distensibility of the baroreceptor carotid region during blood pressure increase. BRS is
also inversely associated with the relative wall thickness and the left ventricular mass
index, and is significantly impaired in hypertensive patients with concentric left
ventricular remodelling (Milan et al., 2007). All these findings suggest that BRS is a target
in arterial hypertension.
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Genetics and Pathophysiology of Essential Hypertension76
As mentioned above, we determined baroreflex sensitivity in hypertensive patients not only
by the BRS index, but also using the BRSf index. Hypertensive patients had thicker IMT and
lower both indices of baroreflex sensitivity, BRS and BRSf, than healthy controls (Labrova et
al., 2005). The positive correlation between age and IMT, the negative correlation between
age and BRS and BRSf, and the positive correlation between IMT and BMI in healthy
subjects were in agreement with the hypothesis that the age-dependent decrease of
baroreflex sensitivity corresponded to the age-related structural changes of the carotid wall.
A different situation appeared in hypertensive patients. We did not see any additive
thickening of their IMT or any decrease of BRS with age, but BRSf decreased significantly
with age. IMT in hypertensive patients was not additively influenced by age or BMI. This
means that the additive influence of age on baroreflex sensitivity in hypertensive patients
could be detected by the BRSf index only. Using two indices of baroreflex sensitivity, BRS
and BRSf, we were able to show that baroreflex sensitivity in hypertensives is lower not only
due to thickening of the carotid wall, but also due to ageing (Labrova et al., 2005; Honzikova
et al., 2006).
The examination of the BRSf index implies the question whether low BRS in hypertensive
patients is only a secondary effect of the mechanisms described above or whether an
individually inborn low BRS could participate in the development of hypertension.
5.2 Obesity, sympathetic activation and hypertension
The relationship between obesity and a higher risk of high blood pressure was established
for both adults and children in dozens of studies, (e.g. Krontoradova et al., 2008; Lurbe et al.,
1998; Rahmouni et al., 2005). The Framingham study brought evidence of the prevalence of
hypertension in obese individuals, which was twice that of individuals of normal weight,
across all ages in men and women (Hubert et al., 1983). It was also reported in several
studies that weight loss in hypertensive subjects lowered blood pressure (Gordon et al.,
1997; Kriketos et al., 2001; Neter et al., 2003), though the results of some studies showed that
blood pressure decrease related to weight loss could be only transient (Laaksonen et al.,
2003). Also, white coat hypertension is more frequent in individuals with overweight
(Helvaci et al., 2007; Honzikova et al., 2006).
Nowadays, the prevalence of obesity increases not only in adults, but also in adolescents. It
is hypothesized that it could be linked with increased prevalence of hypertension in
adolescents and young adults. The data on the epidemics of obesity are alarming. Data from
45 pairs of surveys from 11 countries were analysed in studies by Lobstein & Jackson-Leach
(2006). Annual increases in the prevalence of overweight (including obesity) rose from
typically below 0.5 percentage points in the 1980s to over 1.0 percentage points in the late
1990s. The variations across countries may relate to changes and differences in the key
environmental factors (Wang et al., 2002).
More mechanisms leading to blood pressure increase in obese subjects have been described.
Many studies have documented that sympathetic activation takes part in linking obesity to
hypertension. Particularly, intra-abdominal obesity is a major risk factor for cardiovascular
morbidity and mortality. It seems that leptin plays a key role. Leptin is a hormone secreted
by adipocytes and its blood concentration is proportional to the fat mass content. It acts in
the hypothalamus and, besides controlling the body weight by a suppression of food intake
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Is Low Baroreflex Sensitivity only
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and stimulating the metabolic rate, it also increases sympathetic nervous activity.
Hypertension in obesity is explained by a selective leptin resistance to the appetite reducing
activity, but by preservation of the sympathetic activation and the sympathetic action on the
kidney. Thus, chronic hyperleptinemia in obesity produces hypertension. Sympathetic
activation is linked with an activation of the renin-angiotensin system (RAS) in obesity.
Adipocyte-derived angiotensinogen can act locally to effect adipocyte growth and
differentiation, and thus it can partially attribute to the increased fat mass (Rahmouni et al.,
2005). It can be also secreted into the blood stream (Rahmouni et al., 2005). Rahmouni et al.
(2004) found in mice with obesity induced by high-fat diet greater angiotensinogen gene
expression in the intra-abdominal fat but not in other fat depots or non-adipose tissue. As
regards visceral obesity and hypertension, high circulating levels of free fatty acids in obese
subjects are involved in sympathetic activation. They are released into the portal vein from
lipolysis in visceral fat depots, and this could explain the association between visceral
obesity and sympathetic activation (Rahmouni et al., 2005).
The elevated circulating leptin is associated with impaired baroreflex function. BRS is
reduced in obese children (Lazarova et al., 2009). Leptin receptors are present on vagal
afferent fibres and neurons within the solitary tract nucleus, providing an anatomic
distribution consistent with baroreflex modulation. It was shown in experiments in rats that
leptin microinjection at sites within the solitary tract nucleus impairs the baroreflex
sensitivity for bradycardia induced by increases in arterial pressure (Arnold et al., 2009).
In addition to the effects on homeostasis of body weight and sympathetic activity, leptin has
a broad range of effects in different tissues. The effect on glucose homeostasis supports the
development of type II diabetes mellitus, and this is an additive mechanism related to blood
pressure elevation and BRS decrease.
Endothelial dysfunction such as decreased nitric oxide (NO) responsiveness is also a
common abnormality in obesity. Damage to the endothelium leads to structural changes of
the vessel wall such as thickening of the intima-media of the vessel wall (Rahmouni et al.,
2005). Usually, this mechanism is accepted as a principal one in a decreased BRS because of
a low compliance of the arterial wall where baroreceptors are present. However, it is
necessary to take into account the effect of NO activity involved in low frequency variability
in circulation.
There are data showing that NO is involved in the control of blood pressure variability
(BPV) via release of NO by endothelial cells (Just et al., 1994; Nafz et al., 1997). The greatest
difference in BPV was reported in a frequency range of 0.1 to 0.5 Hz in dogs and 0.2 to 0.6 in
rats, i.e. a frequency range in which the sympathetic nervous system is most effective. NO
buffers blood pressure fluctuations by opposing the sympathetic nervous activity (Stauss et
al., 2000). Moreover, Hogan et al. (1999) demonstrated nitric oxide as a possible factor which
causes a significant reduction in the diastolic and systolic blood pressure low-frequency
power by infusion of the NO donor sodium nitroprusside in humans. In this experiment, the
hypotensive action of sodium nitroprusside was prevented by phenylephrine, but a
reduction in the BP low-frequency power persisted. This corresponds to the fact that in
carriers of less frequent alleles enhanced BPV was observed at a frequency of 0.1 Hz, which
is the frequency of sympathetic activity in humans (Jira et al., 2011).
Many genetically hypothetic mechanisms could be involved in the pathophysiology of the
individual disposition for an increase of blood pressure in dependence on obesity. However,
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Genetics and Pathophysiology of Essential Hypertension78
they seldom show a linkage between obesity and variability in circulation in a frequency
range of 0.1 Hz or baroreflex sensitivity.
Fatso/fat mass and obesity associated gene (FTO gene) was established as contributing to
obesity. It is expressed in the hypothalamus and influences energy metabolism. Since
hypothalamus is also involved in blood pressure regulation, the relationship of
polymorphism of the FTO gene to blood pressure control was studied (Pausova et al., 2009).
It was found in this study, carried out nearly in 500 adolescents, that individuals with the
FTO-risk genotype, compared with those who lacked it, demonstrated greater adiposity,
including the amount of intra-abdominal fat, higher systolic blood pressure, and a higher
sympathetic modulation of the vasomotor tone evaluated as a variability of diastolic blood
pressure in a frequency range of 0.1 Hz by spectral analysis. It was hypothesized that sex
differences and inter-individual differences in linking intra-abdominal obesity to
hypertension could be explained by mechanisms of action of androgens. Voluminous intraabdominal
fat, higher blood pressure, and a prominent sympathetic modulation of the
vasomotor tone (evaluated as a variability of diastolic blood pressure in a frequency range
of 0.1 Hz by spectral analysis) were found in boys aged 12 to 18 years, who had a low CAGrepeat
number in the androgen-receptor gene in comparison with those with a high CAGrepeat
number. No such differences were seen among girls. This study documented not only
that this gene represents a genetic risk factor for linkage between intra-abdominal obesity
and hypertension, but also that sympathoactivation may be an underlying link between
these states (Pausova et al., 2010).
6. Low BRS as a factor causing blood pressure elevation in adolescents
6.1 Prevalence of hypertension and white coat hypertension in children and
adolescents
The concept of white coat hypertension is used in situations when blood pressure measured
at a causal office examination is elevated, but is within the physiological range during its
repeated measurement or a 24-hour blood-pressure measurement. Some authors believe that
white coat hypertension does not require pharmacological therapy (Cavallini et al., 1995),
but an increased risk of cardiovascular diseases was reported in other studies (Gustavsen et
al., 2003; Lande et al., 2008).
Prevalence of white coat hypertension is relatively high in different countries in both adults
and children. Prevalence of white coat hypertension was higher in obese children, but
differences as to age or sex were insignificant (Stabouli et al., 2005). Dozens of studies have
brought similar results. Elevation of blood pressure mainly concerns its systolic value. The
difference measured in diastolic blood pressure could be conditioned by the technical
difficulty of its measurement, especially in small children (Hornsby et al., 1991). Nowadays,
ambulatory blood pressure measurement is a standard for the diagnostics of white coat
hypertension.
6.2 Primary low baroreflex sensitivity as an additive factor of blood pressure elevation
in children and adolescents
Recently, several studies have shown that an increase in the body mass index (BMI)
correlates significantly with the elevation of blood pressure and a decrease of BRS.
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Is Low Baroreflex Sensitivity only
a Consequence of Essential Hypertension or also a Factor Conditioning Its Development? 79
Differences in the BMI, BRS/BRSf indices, mean IBI, and systolic blood pressure variability
were compared in healthy controls, adolescents with white coat hypertension, and
hypertensive adolescents (Honzikova et al., 2006b). The stepwise blood pressure elevation in
these groups was associated with a stepwise increase of BMI and a stepwise decrease of
both indices of baroreflex sensitivity, BRS and BRSf; the mean IBI was unchanged. Systolic
blood pressure variability was increased in hypertonic adolescents only.
Such a finding may correspond with the idea that subclinical atherosclerosis and a
remodelling of the vascular wall may develop very early, though the finding of a similarly
lower BRS in children, adolescents and young adults with white coat hypertension suggests
a contradicting interpretation. This group of young subjects with white coat hypertension
has a physiological blood pressure over 24 hours and there is no reason for remodelling the
vascular wall. Nevertheless, they have lower BRS than healthy controls and BRSf as well.
These results suggest the only interpretation, namely that low BRS precedes blood pressure
elevation (Honzikova et al., 2009).
Fig. 3. Receiver operating curves of baroreflex sensitivity (BRS, thin line), body mass index
(BMI, dashed line), and a combination of both factors (full line). Optimal critical values
determined as values at which the maximum achievable combination of sensitivity and
specificity was reached: 7.08 ms/mmHg for BRS (triangle), 22.20 kg/m2 for BMI (square),
and 0.439 normalized units for a combination of BMI and BRS (point). Reproduced with
permission of Physiological Research.
Direct evidence that low baroreflex sensitivity is a partially independent risk factor for the
development of essential hypertension was provided by Krontoradova et al. (2008). In this
study hypertonic subjects had a significantly lower BRS and a significantly higher BMI (the
BRSf index was not evaluated with respect to the same mean IBI in controls and
hypertonics). On the other hand, no correlation was found between BMI and BRS either in
the group of hypertonics or in controls. The predicting power of BMI, BRS, and a
combination of both factors determined by logistic regression analysis for hypertension was
evaluated by sensitivity and specificity. The optimal critical values were determined by the
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Genetics and Pathophysiology of Essential Hypertension80
receiver operating curves (ROC), i.e. a plot of sensitivity versus specificity for moving
critical values in steps. Also, the area under the ROC curve was calculated. The approach
described in part 4.2 of this Chapter was applied for the evaluation of association of
decreased BRS and increased BMI with a risk of hypertension. The sensitivity, specificity
and area under ROC were increased for a combination of both factors, BRS and BMI, in
predicting hypertension (see Fig. 3).
This means that low BRS may serve as an independent risk factor for the development of
essential hypertension. What mechanism of blood pressure elevation due to individually
low BRS could be taken into consideration? Stressing situations increase the sympathetic
nervous activity as well as blood pressure. Blood pressure elevation is partially blunted by
the heart rate baroreflex response. This suppression of blood pressure increase is insufficient
in children with low BRS; therefore, white coat hypertension occurs and frequent
vasoconstrictive reactions could lead to the development of essential hypertension after a
longer time.
7. Conclusion
Baroreflex sensitivity is, to a certain extent, an individually characteristic index. It fluctuates
spontaneously even at rest and therefore, regardless of how it is further processed
mathematically, a particular value measured represents an approximate estimate of its size.
On the other hand, low values of baroreflex sensitivity are highly repeatable in some
individuals, and it is just the low BRS values that pose a risk for the development of
hypertension and its complications. Bearing in mind the fact that essential hypertension is a
disease of higher age, the majority of studies done in previous years were naturally focused
on baroreflex sensitivity in older population. The increased arterial stiffness, increased IMT,
and sympathetic activation in obesity represent indubitable factors which lead to
hypertension and, consequently, result in a decrease of BRS. The hypothesis ensuing from
these studies, which states that the drop in baroreflex sensitivity accompanies the
development of hypertension as a secondary manifestation of the disease, is proved by these
studies. Low baroreflex sensitivity is then a risk factor in further complications of the
disease, particularly after myocardial infarction. Also, the pathophysiological mechanism of
protection of the myocardium from ischemia through high baroreflex sensitivity is obvious.
Quick prolongation of IBI following a sudden blood pressure elevation decreases cardiac
workload.
On the other hand, measurements of BRS in children and adolescents and the first genetic
studies on the inborn conditionality of BRS have provided enough evidence that some
individuals possess congenitally low baroreflex sensitivity. This condition does not mean
any risk for a healthy organism. Without a targeted study, we cannot even speculate on how
this assumption will manifest itself in advanced age in terms of increased risk of sudden
cardiac death, since in the meantime the long-term pathological influence of other
mechanisms lowering baroreflex sensitivity will have presented itself in the other risky
patients.
However, low baroreflex sensitivity apparently represents a risk. It is probably a further
factor which disposes an individual towards blood pressure elevation. Low baroreflex
sensitivity will manifest itself as blood pressure hyperreactivity. It may lead to white coat
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Is Low Baroreflex Sensitivity only
a Consequence of Essential Hypertension or also a Factor Conditioning Its Development? 81
hypertension in adolescents as a step in the development of essential hypertension.
Therefore, congenitally low baroreflex sensitivity may be considered as another risk factor
for the development of essential hypertension. This is the reason why in the young
population, including children and adolescents with low baroreflex sensitivity, increased
emphasis should be put on the prevention of obesity and sufficient physical activity as on
easily influenceable stimuli which additively increase blood pressure.
Measuring baroreflex sensitivity is a simple, in no way stressful, non-invasive method. It
requires just a couple of minutes taking non-invasive record of blood pressure by means of a
pressure cuff applied on a finger and subsequent mathematical processing. However, if a
BRS determination is to provide the presumed relevant clinical information, it is not that
easy. BRS evaluation in the young may only be carried out on the basis of repeated
measurements. In child age and adolescence, it is appropriate to take into account the
average heart rate when quantifying BRS. One of the possibilities is the BRSf index or some
other adequate method. This area of research is therefore substantial from the point of view
of the study of baroreflex sensitivity, prevention of hypertension and its severe
complications, and may be of significance for preventative medicine.
8. Acknowledgement
This study was supported by grant MSM 0021622402 from the Ministry of Education, Youth
and Sports of the Czech Republic. We gratefully acknowledge A. Krticka for help with the
methodology part.
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Genetics and Pathophysiology of Essential Hypertension
Edited by Prof. Madhu Khullar
ISBN 978-953-51-0282-3
Hard cover, 236 pages
Publisher InTech
Published online 09, March, 2012
Published in print edition March, 2012
InTech Europe
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This book, authored by renowned researchers in the field of Hypertension Research, details the state of the art
knowledge in genetics, genomics and pathophysiology of Essential hypertension, specifically the genetic
determinants of hypertension and role of gene variants in response to anti-hypertensive therapy. Two chapters
describe mitochondrial mutations in Essential hypertension and in hypertension associated Left ventricular
hypertrophy, one chapter reviews in detail the global gene expression in hypertension, and an up to date
treatise on pathophysiology of resistant hypertension is detailed in another chapter. Other topics included in
the book are end organ damage, baroreceptor sensitivity and role of music therapy in essential hypertension.
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Natasa Honzikova and Eva Zavodna (2012). Is Low Baroreflex Sensitivity only a Consequence of Essential
Hypertension or also a Factor Conditioning Its Development?, Genetics and Pathophysiology of Essential
Hypertension, Prof. Madhu Khullar (Ed.), ISBN: 978-953-51-0282-3, InTech, Available from:
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sensitivity-only-a-consequence-of-essential-hypertension-or-also-a-factor-conditio