Download Analysis of Heart Rate Variability and Clinical Implications

Analysis of Heart Rate Variability and Clinical Implications
Analysis of Heart Rate Variability
and Clinical Implications
Meldijana Omerbegovic
Clinic for Anesthesia and Reanimation, Clinical Center of University of Sarajevo, Bosnia and Herzegovina
PROFESSIONAL PAPER
Summary
In the last decades analysis of heart rate variability has emerged as a new useful tool for assessing the changes
in autonomic tone that influences cardiovascular function. High variability of oscillations and the integrated
physiologic activities of heart and cardiovascular system is associated with physiologic functioning. Irregularity
of the length of consecutive heart cycles, designated as heart rate variability, reflects the ability of cardiovascular system to adapt to different situations in everyday life. Reduction of these fluctuations of the heart periods
has been shown to be associated with pathological conditions in many experimental and clinical trials. The
extent and consistency of the reduction of heart rate variability in the patients after acute coronary events,
were shown to be related to mortality and cardiovascular dysfunction. In patients with diabetes mellitus who
develop autonomic neuropathy, reduced heart rate variability is quite common. Reduced heart rate variability
was shown in endocrine disorders, neurological and psychiatric diseases, with use of different drugs and many
other conditions. The most common ways of measuring heart rate variability are measuring in time domain
analysis and frequency domain analysis. Parameters calculated from the measurements are related to the
functions of sympathetic and parasympathetic nervous system. Measurements of changes in autonomic function is very important in the follow up in different diseases and for determination of the efficacy of the therapy.
In the field of surgery and anaesthesia, besides preoperative risk stratification, there are many studies on the
effects of different anaesthetics on heart rate variability. In this paper, some aspects of measurement of heart
rate variability and changes of the values of parameters in different pathological conditions and clinical implications are reviewed.
Key words : heart rate variability, noninvasive monitoring, autonomic nervous system, autonomic imbalance
1. INTRODUCTION
Continuos electrocardiographic
monitoring of heart rate in the perioperative period, in the setting of intensive care unit and during labour and
some diagnostic procedures, is considered as a basic standard care. The scope
of this paper is limited to description of
the recently recognized parameters derived from analysis of different duration of the intervals between consecutive heart contractions, which is named
heart rate variability (HRV) and clinical
implications (1).
Inherent automaticity of the depolarization of specialized cells in sino-atrial
node determines heart rate, but it is the
complex interplay of autonomic sympathetic and vagal parasympathetic activity that modulates frequency of the sinoatrial node depolarization . Vagal stimulation produce hyperpolarization of the
cardiac pacemaker cells and reduced rate
of depolarisation, on the contrary sympathetic stimulation causes increasing
of rate of depolarization (2). With every beat of the heart, information about
the state of the circulation, are sent to
the neurons within the medulla oblongata and processed in the milieu of integrative modulating influences from hypothalamus and higher centers. Efferent signals are sent to output regions of
102
the central nervous system and ensure
maintenance of the functioning of the
cardiovascular system at the most appropriate level. Sympathetic preganglionic neurones give major contribution
in the control of heart rate and blood
pressure at the level of spinal cord. Figure 1 represents simplified scheme of the
neural components that influence heart
activity . Interactions between sympathetic and parasympathetic efferent projections involve different modulation of
adenylate cyclase via G-protein-coupled
receptor systems. Catecholamines, released from sympathetic efferent projections or from circulation, influence
myocardial tissue by binding to β1 and
β2 adrenoreceptors,which are coupled
to and stimulate adenylate cyclase via
stimulatory guanine nucleotide-binding protein(Gs). Acetylcholine, released
from parasympathetic efferent postganglionic neurons, binds to cardiomyocyte
M2 muscarinic receptors, which inhibit
adenylate cyclase via inhibitory guanine nucleotide-binding protein (Gi).
Interactions between these two receptor-coupled systems at the adenylate cyclase level determine the formation of
cAMP and influence the function of second messengers in myocyte and subsequently modulate the cell functions (2).
Complex neuronal, reflex and local
Med Arh 2009;63(2) • Stručni članci | Professional papers
control of the frequency of heart rate
is manifested in different length of cardiac cycle in physiological and it is quite
changed in pathological conditions. Acceleration of heart rate is a result of increase in sympathetic activity or decrease in vagal activity with shortening
of cardiac cycles and most effect on diastole duration , while bradycardia is a
result of predominant parasympathetic
activation.
The clinical importance of HRV was
recognized by Hon and Lee, who observed that fetal distress was associated
with significant changes in HRV before
any change in heart rate itself (3).
An important observation was made
by Wolf et al. in 1977 , who found that
a reduced HRV was related to a higher
risk of post-infarction mortality. About
ten years later Kleiger et al. published a
paper on the results of the Multi-Center Post-Infarction Project (MPIP) , what
started a more serious interest in HRV
among cardiologists (4).
Since then a lot of studies have been
performed on the issue of low measures
of HRV which have been linked with different diseases and conditions .
In 1996 Task force of the European
Society of Cardiology and the North
American Society of Pacing and Electrophysiology developed standards of measurements and physiological correlates of
HRV and clinical applications. According
to the guidelines measurement of heart
rate variability (HRV) may provide quantitative information on the modulation
of cardiac sympathetic and parasympathetic nerve activities. The two main applications that could be clinically useful
are the risk stratification after myocardial
infarction and the assessment of diabetic
neuropathy (5). Impaired autonomic nervous activity has been recognized as an
important symptom and is strongly associated with an increased risk of overall
mortality in patients with heart disease.
2. MEASUREMENT OF HRV
The most commonly used methods
of HRV analysis can be categorised into
four groups: time domain measures, frequency domain measures, rhythm analysis and non-linear methods (3).
Two main methods that are used for
evaluation of HRV in clinical practice are
time domain methods and frequency domain methods.
2.1. Time Domain Method
QRS detection is necessary for the
Analysis of Heart Rate Variability and Clinical Implications
HIGHER CENTERS
ARTERIAL
BARORECEPTORS
NODOSE
AFF. SOMA
MEDULA
DRG
AFF.SOMA
SPINAL CORD
LCN
Afferent
soma
S E soma
CIRCULATING
CATECHOLAMINS
ANGIOTENSIN II
EXTRACARDIAC
INTRATHORACIC
GANGLIA
LCN
SE
soma
neurit
neurit
PE
soma
M2
B1
Gs
Gi
Afferent
soma
INTRINSIC
CARDIAC
GANGLIONATED
PLEXUS
neurit
HEART
AC
ATP
cAMP
Figure 1. Schematic representation of neural components that influence
heart activity. Intrinsic cardiac ganglia comprisesympathetic (SE) and
parasympathetic (PE) efferent neurons, local circuit neurons (LCN), and
afferent neurons. Extracardiac intrathoracic ganglia include sympathetic
efferent neurons, local circuit neurons, and afferent neurons. Aff.-afferent;
DRG- dorsal root ganglia; Gs-stimulatory guanine nucleotide-binding
protein; Gi-inhibitory guanine nucleotide-binding protein; AC-adenylate
cyclase; B1- β1-adrenergic receptor; M2-muscarinic receptor.(Modified
from Ardell J.L. Neurohumoral Control of Cardiac Function , ref.2 )
determination of the periods between
adjacent QRS complexes which are
named the N-N (normal-normal) intervals (9).
The simplest calculated measures
are: the mean interval length (meanNN)
and the standard deviation (SDNN).
SDANN is the standard deviation of intervals averaged over 5min sections. The
parameter pNN50 is the proportion of
interval differences of less than 50 ms.
It is a marker for vagal activity. Geometrical measures are based on the density
distribution of NN intervals. The shape
of the histogram can be approximated
by a geometrical shape, such as a triangle, and a measure of that shape can be
used in further assessment (5).
Different calculated variables of time
domain measures are used for analysis of
HRV and they are listed in the Table 1.
2.2. Frequency Domain Method
In the spectral analysis of the tachogram, ECG signal is differentiated into
the frequencies using a mathematical
algorithm (fast Fourier transformation)
,that can be represented on a graph, and
area under the curve is designated as a
spectral power (5).
The frequency domain is divided
into bands, which isolate typical peaks,
as shown in Figure 2. For short-term recordings, the high band (HF) is in range
between 0.15 Hz and 0.4 Hz, the low
band (LF) from 0.04 Hz to 0.15 Hz and
the very low band (VLF) of frequencies
below 0.04 Hz. The measurement of VLF,
LF and HF power components is mostly
in absolute values of power (milliseconds
squared–msec2 ).
Frequency domain methods are appropriate for analysis of short-term recordings and time domain methods are
ideal for the analysis of long-term recordings. Several frequency domain
measures are listed in the Table 2.
3. PHYSIOLOGICAL CHANGES OF
HRV PARAMETERS
In the complex interaction of parasympathic and sympathetic influences,
under resting conditions parasympathetic tone exceeds sympathetic effects
in healthy subjects. The efferent vagal
activity is a major contributor to the HF
component. Sympathetic activation is related to spectral power in the LF band,
but it can also be influenced by vagal activation (5).
The sympatho-vagal balance is expressed in the relation of LF/HF. Spectral analysis of 24-h recordings shows
in normal subjects a circadian pattern
with higher values of LF in the daytime
and higher HF at night. An increase in
LF is observed during 90◦ tilt, standing,
mental stress, and moderate exercise in
healthy subjects (6).
Increased LF power and decreased
HF power, reflect the normal response
to upright tilt movement (5).
Increase in HF components is induced by controlled respiration, cold
stimulation of the face and rotational
stimuli (7).
4. CHANGES OF HRV
PARAMETERS IN DISEASE
variations of RR intervals and LF and HF
components are also present (8).
In the days after the infarction there
is a depression in the time and frequency
domain parameters of HRV with predominance of sympathetic components.
In the later period, after weeks and
months, the HRV could be partially recovered (5). The aim of risk stratification
is to identify the patients with a high risk
of post-infarct mortality.These patients
could have benefit from further treatment, as it was shown in a clinical trial
by Moss and coworkers (9). On the contrary to their findings, the investigators
of DINAMIT trial did not show beneficial effects of implantable cardiac defibrillator in patients with high risk after
acute myocardial infarction (10). The
HRV is independent from other predictors, like depressed left ventricular ejection fraction, increased ventricular ectopic activity.
There is a general consensus that
HRV should be measured a week after
myocardial infarction, as a high proportion of complications may occur in that
period (5). Some recent studies did not
show strong predictive power of HRV in
risk stratification after myocardial infarction, what could be explained with
the use of thrombolysis, early revascularisation and medications like beta
blockers and inhibitors of angiotensinconverting enzyme (11).
It was also shown that HRV could be
an independent prognostic factor in patients with stable angina (12).
Data from meta-analyses indicated
that within the initial two years after
myocardial infarction, patients with
lower HRV demonstrated great increase
in major arrhythmic events like ventricular fibrillation, ventricular tachycardia
or sudden cardiac death (13).
There have been many clinical multicenter trials on the possible beneficial
effects of risk stratification , after myo-
4.1. Cardiovascular diseases
Numerous experimental and clinical studies have shown significant relationship between the autonomic nervous system disorders and cardiovascular diseases.
In the first hours after the myocardial
infarction there is a significant reduction of SDNN. The
Variable
Units Description
vagal stimulation STATISTICAL MEASURES
is decreased and SDNN
ms
Standard deviation of all NN intervals
sympathetic in- SDANN
Standard deviation of the averages of NN intervals in all 5-minute segments of
ms
the recording
fluences predomSDSD
ms
Standard deviation of differences between adjacent NN intervals
inate. The shift
Percent of difference between adjacent NN intervals that are greater than 50
%
in sympatho-va- pNN50
ms
gal balance is ex- GEOMETRIC MEASURES
Total number of all NN intervals divided by the height of the histogram of all NN
pressed in a pre- HRV triangular
index
intervals measured on a discrete scale
dominant LF and a
Baseline width of the minimum square difference triangular interpolation of the
ms
highest peak of the histogram of all NN intervals
reduced HF , with TINN
high LF/HF ratio.
Table 1. Selected Time Domain Measures of HRV (5)
Reduced circadian
Med Arh 2009;63(2) • Stručni članci | Professional papers
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Analysis of Heart Rate Variability and Clinical Implications
tricular ejection fraction of more than
40% and depressed HRV could benefit
from prophylactic antiarrhythmic treatment with amiodarone, but the need for
further studies in an independent data
set before further recommendations was
emphasized (17). The population of patients with chronic heart failure is growing and there is evidence that autonomic
nervous imbalance plays important role
in the progression of the disease. In the
Figure 2. Power spectral density of the healthy
subject during rest (5)
initial stages of disease increases of LF
and a decrease of HF are detected. In the
cardial infarction. Bigger et al. analysed advanced stages of heart failure both LF
HRV spectral parameters from ECG re- and HF bands are decreased (18).
cordings in 715 participants in the Mul4.2. Respiratory Diseases
ticenter Post Infarction Program (MPIP)
Obstructive sleep apnea syndrome is
during the period of four years and found characterized by repetitive episodes of
strong association between mortality upper airway collapse during sleep. The
and total, ULF, and VLF power. They obstruction of the airway produces vigorous efforts to breathe, leading
Variable
Units Description
Frequency range
to transient arousal and restoraTotal power
ms²
Variance of all NN intervals =< 0,4 Hz
tion of the pattency of the upULF
ms²
Power in ULF range
< 0,003 Hz
per airway. Many data support
VLF
ms²
Power in VLF range
0,003-0,04 Hz
the hypothesis that long-term
LF
ms²
Power in LF range
0,04 -.0,15 Hz
exposure to episodic apnea and
HF
ms²
Power in HF range
0,15 – 0,4 Hz
arousal constitutes an indepenTable 2. Selected Frequency Domain Measures of HRV (5)
dent risk factor for systemic hypertension, heart failure, myofound that adding measures of heart pecardial infarction, and stroke (19). Sevriod variability to previously known preeral studies have shown the usefulness
dictors of risk after myocardial infarcof measuring HRV as a powerful tool for
tion could identify small subgroups with
obstructive sleep apnea syndrome diagtwo and a half year mortality risk of apnosis and follow up of therapeutic proceproximately 50% (14).
dures (19). In patients with mild chronic
In the prospective study Autonomic
obstructive pulmonary disease, cardiac
Tone and Reflexes After Myocardial Indisorders are the leading causes of hosfarction (ATRAMI), in which 55% of
pitalization, accounting for 42 to 48% of
deaths were sudden, it was shown that
all hospitalizations. Monitoring of HRV
within the group of patients after myochanges in the patients with COPD have
cardial infarction who had a depressed
been shown as a possible marker of carleft ventricular ejection fraction, an indiac comorbidities (20).
creased risk of death was associated with
4.3. Endocrine diseases
the presence of autonomic imbalance
Cardiovascular autonomic neurop(15). In the trial named AzimiLide Postathy is one of the most common and
Infarct SurVival Evaluation (ALIVE) a
most investigated complications in panovel class III antiarrhythmic drug, aztients with diabetes mellitus. The earliimilide, was investigated for its effects
est sign , that can be detected in asympon mortality in patients after myocartomatic patients is a depression of heart
dial infarction, and results showed that
rate variability. Primary damage is of
azimilide did not improve or worsen
the branches of vagus nerve, with resulthe mortality of patients after myocartant resting tachycardia. After latency
dial infarction, while low HRV indepenof some years, damage of sympathetic
dently identified a subpopulation at high
nerve fibers changes the sympathovarisk of mortality, what is presented in the
gal balance, but tachycardia remains.
Fig. 3 (16). In the European Myocardial
Later symptoms such as exercise intolInfarct Amiodarone Trial (EMIAT) it
erance, orthostatic hypotension and furwas investigated if the patients with dether decrease of HRV are the manifespressed heart rate variability could have
tations of progressive damage to the aubenefit from amiodarone treatment. Retonomic balance (21). Investigations of
sults showed that patients with left venHRV in patients with hyperthyroidism
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Med Arh 2009;63(2) • Stručni članci | Professional papers
have suggested that thyroid hormone excess may reduce parasympathetic activity (22). Patients with clinical hypothyroidism have a sympatho-vagal imbalance, and the changes of repolarization
times may predispose to the potentially
life-threatening arrhythmias. The assessment of HRV in patients with clinical
hypothyroidism may be a useful tool in
monitoring of the cardiovascular complications (23).
4.4. Renal diseases
Autonomic nervous system dysfunction is a prominent characteristic of the
uremic state and analysis of HRV has
demonstrated striking changes of cardiac autonomic nervous system in patients with chronic renal failure. It has
also been associated with sudden death
in patients undergoing hemodialysis, especially in those with coronary stenosis
and nocturnal myocardial ischemia (24).
4.5. Psychiatric diseases
Depression has significant adverse
effects on the course and outcome of
coronary heart disease and it has been
suggested to be associated with about a
three fold increase in cardiac mortality
(25). Physiological studies have demonstrated compromised modulation of the
sympathetic and parasympathetic nervous system in psychosis. The fact that
many antipsychotics could have potentially dangerous cardiac side effects led
to investigations with atypical antipsyhotics, which have been demonstrated
to have beneficial side effects profile (26).
Power spectrum analysis demonstrated significant reduction of HRV, vagal tone activity and augmented sympathetic activity in the patients with posttraumatic stress disorder (PTSD) who
had no medications in comparison to
healthy subjects. Significant autonomic
dysregulation of patients with PTSD at
rest, could be corrected with administration of selective serotonin reuptake
inhibitors (27).
5. CHANGES OF HRV
PARAMETERS UNDER
MEDICATION
Heart rate variability could be significantly changed by different groups
of drugs, and it could also be used as a
parameter to quantify the effects of the
drugs in some diseases. Beta-blockers,
calcium channel blockers and different
antiarrhythmics have been studied in
the patients with CVS diseases (16,17).
Beta- adrenergic blockers prevent
Analysis of Heart Rate Variability and Clinical Implications
toring of sympatho-vagal balance
during induction and maintaining
of anesthesia are in focus of many
current trials of HRV in perioperative period (33).
7. CONCLUSION
Heart rate variability reflects
the response of the heart to a variety of influences. Substantial reFigure 3. Kaplan-Meier curve of all-cause mortality in placebo patients in
ductions of HRV are seen in the
high risk group (HRV< 20U) and low risk group (HRV>20U). (From Camm
AJ et al. Mortality in Patients After a Recent Myocardial Infarction, ref.16 )
setting after acute cardiac events,
like acute myocardial infarction,
the rise in the LF component observed
and it was shown as an indepenin the morning hours. Carvedilol ther- dent predictive factor of mortality in
apy in patients with chronic heart fail- the patients after acute coronary event.
ure significantly increased HRV with Reduced HRV is an early finding in pabeneficial effects on hemodynamics (28). tients with cardiac diabetic autonomic
The trials with antihypertensive agents neuropathy before development of clinihave shown better effects of angiotensin cal symptoms. In many other endocrine
II receptors antagonists in regard to an- disorders, neurological and psychiatric
gitensin converting enzyme inhibitors diseases, monitoring of changes in HRV
(29). Among other medications, antiep- enables following of the effects of therileptics are known to impair cardiac au- apy and the state of the disease.
Perioperative period is another imtonomic function, and it is known that
carbamazepine increases sympathetic portant issue, as monitoring of preopand parasympathetic tone, which could erative HRV could be of great imporbe very important in the overall mor- tance for the risk stratification of the
bidity and mortality (30,31). Most anti- patients with cardiovascular diseases
psychotic drugs have cardiac effects as and predicting possible complications.
a consequence of their pharmacological Large prospective and standardized triactions, and it was shown that HRV was als could give more information on relereduced. Studies with olanzapine and vance of this noninvasive monitoring of
amilsupride also showed that amilsu- autonomic nervous system function in
pride had a more vagotonic effect, sug- the perioperative period. Development
gesting greater cardiovascular safety in of the technique of monitoring, analycomparison to olanzapine (32).
sis and standardization of procedures of
measurement of the heart rate variability
6. HRV CHANGES IN
(HRV) could give a useful tool in evalPERIOPERATIVE PERIOD
uating of autonomic changes and autoGeneral anaesthesia and surgery pro- nomic imbalances in the specific disease
duce significant changes in autonomic states and perioperative period.
nervous system function. Most studies
that investigated the effects of different References
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Corresponding author: Meldijana Omerbegović, MD. Klinika
za anesteziju i reanimaciju, Klinički Centar Univerziteta u
Sarajevu. Email: [email protected]
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