Vytryhovskyy: Features of Heart Rate Variability in Patients with Coronary Heart Disease and Risk Factors for Cardiovascular Disease According to the SCORE Charts in the Presence of Heart Rate Turbulence



Problem statement and analysis of the recent research

Study of the ECG measurements is closely related to ventricular ectopy, and the analysis of its relationship with the autonomic regulation provides the basis for new methods of diagnosing risk stratification markers of sudden cardiac death [4, 7]. Nowadays, one of the methods to predict sudden cardiac death is the evaluation of heart rate turbulence [11, 16]. It was noted that after ventricular ectopic beats (VEBSs) short-term fluctuations in the cardiac cycle duration (RR-interval) occur. This phenomenon was first described by the research group led by G. Schmidt in 1999; later it became the basis of the definition of “heart rate turbulence” (HRT). Thus, this term is used to describe short-term fluctuations in the duration of the cardiac cycle. Usually, immediately after ventricular ectopic beats the sinus rhythm is more frequent, and then, it slows down, returning to the initial values [10]. The research group led by G. Schmidt offered two HRT indices: turbulence onset (TO) and turbulence slope (TS). TO is a value of sinus rhythm acceleration immediately after VEBs and TS is the intensity of sinus rhythm deceleration, which comes after its acceleration. TO is calculated as the ratio of differences between both the sum of values of the first two sinus RR intervals occurring immediately after VEBs and the next two sinus RR intervals occurring before VEBs to the sum of two sinus RR intervals to VEBs, expressed as a percentage [2]. To calculate TO the following formula is used:

TO (%) = 100 * { ( RR [ 1 ] + RR [ 2 ] ) - ( RR [ -3 ] + RR [ -2 ] ) } / ( RR [ -3 ] + RR [ -2 ] )

where RR-2 and RR-3 are the first and second sinus RR intervals that precede the ectopic complex; RR1 and RR2 are the first and second sinus RR intervals, which follow immediately after the compensatory pause. To determine TS (mc/RR) the tilt of the RR interval changes is calculated using straight lines of regression for each 5 RR intervals among the next 20 after the compensatory pause RR [1]+RR [5]), RR [2]+RR [6]) ... RR [16]+RR [20] [3]. The value TS is defined as the maximum positive regression slope. The value of TO<0% and TS> 2.5% mc/RR is considered normal, and the value of TO>0% and TS<2.5% mc/RR is considered pathological [15]. The acceleration of sinus rhythm, followed by short-lasting slowdown, is considered as the physiological response to VEBs. The attempt to explain the mechanisms of HRT and their two fixed parameters is the following: TO phenomenon occurs due to the fact that numerous ion channels of cardiomyocytes are not yet fully recovered until the early ectopic contraction resulting in shortening of the action potential (AP). Premature contraction is associated with incomplete diastolic filling of the heart chambers, resulting in reduced systolic output as well as contractility (the Frank-Starling mechanism). It, in turn, lowers the blood pressure, leads to activation of aortic and carotid baroreceptors as well as to an increase in the heart rate (HR) through the baroreflex arc. Ventricular desynchronization in case of VEBs also has some importance [14]. TS phenomenon can be explained as following: immediately after the compensatory pause slow ion channels of cardiomyocytes fully recover leading to the prolongation of the action potential, increased systolic output, increased blood pressure (the phenomenon of post-extrasystolic potentiation), and, in turn, elevated blood pressure reduces heart rate through the baroreflex. Thus, the formation of the HRT can be schematically displayed as follows: the compensatory pause occurs after VEBs resulting in reduced blood pressure, which increases the heart rate and increases the blood pressure through the baroreflex, and later reduces the heart rate through the baroreflex again [5]. G. Schmidt and co-authors in their study used the Holter monitoring records of 100 patients with myocardial infarction and frequent VEBs to determine the normal and abnormal values of HRT (TS = 2.5 ms/s, TO = 0%). The evaluation was performed at least 3 months after acute heart attack. The obtained HRT values were used alongside with the Holter monitoring records of 1,191 patients in the post-infarction period, who participated in 2 large clinical trials: placebo group of the European Myocardial Infarction Amiodarone Trial (EMIAT, n=614) and the Multicenter Post-Infarction Program (MPIP, n=577) [9]. Holter monitoring was performed within the 2nd and 3rd weeks after myocardial infarction. During the observation period (EMIAT - 21 months and MPIP - 22 months), 162 (13.6%) cases of death were recorded. According to the total mortality as the endpoint, the single-factor analysis showed that in EMIAT TS parameter was the strongest risk stratification factor (relative risk - 2.7), while in MPIP the values of TS were second-strength risk stratification factor (relative risk – 3.5) after ejection fraction (EF<30%) [1]. In EMIAT, the multivariate analysis revealed that past myocardial infarction, the values of TO, TS, EF and heart rate> 75 beats/min were independent predictors, and in MRIR independent factors were EF and TS, as opposed to the indicators such as the heart rate, HRV (triangular index<20), advanced age (>65 years), the presence of past myocardial infarction and arrhythmia according to the Holter monitoring VEBs >9 per hour or unstable ventricular tachycardia) [8]. The multivariate analysis showed that the combination of abnormal values of TS and TO were the strongest risk factors for both EMIAT (relative risk of 3.2 in the 95% confidence interval) and in MRIR (relative risk of 3.2 in the 95% confidence interval) [13]. In the EMIAT study, the two-year mortality was 9% in patients with normal values of HRT, 18% in patients with abnormal values of TS and TO, and 34% in patients with pathological combination of TO and TS. Similar values were obtained in the MRIR study (9%, 15%, and 32%, respectively). To study HRT as a predictor of cardiac arrest we used the data of the Autonomic Tone and Reflexes after Myocardial Infarction (ATRAMI). It included the patients who had suffered from myocardial infarction having less risk of cardiac death compared to EMIAT which included patients with ejection fraction <40% and those who underwent thrombolytic therapy [6]. The end point of the ATRAMI study was both fatal and non-fatal cardiac arrest, which was observed in 49 (4.8%) patients. The univariate analysis showed that the value of TS and the combination of TS and TO values significantly increase risk (4.1 and 6.9, respectively, p<0.0001 for both values). On this basis, the combined index for the autonomous function of the heart, including HRT parameters (TS, TO), HRV (SDNN) and sensitivity of the baroreflex was proposed. Patients with abnormal modified combined index were found to suffer from cardiac arrest 16.8 times more frequently than patients who had normal values of these four factors. In another study performed under the supervision of G. Schmidt, the Holter monitoring records of 1,555 patients with past myocardial infarction who underwent reperfusion therapy were evaluated. It was proven that HRT parameters are strong prognostic factors of death in this group of patients [12]. Interesting data were obtained when analyzing HRT according to 10-minute Holter recordings to establish an implantable cardioverter-defibrillator within the protocol of MADIT II, where the primary endpoint was the total mortality. In deceased patients the average values of TS were lower than in surviving ones (2.3 and 4.5 mc/RR, respectively, p<0.05). Literature data show that the predictive sensitivity and accuracy of HRT parameters are higher compared to other non-invasive tests (SCD, ventricular late potentials). In the EMIAT and MRIR studies, in case of the combination of pathological values of TO and TS, the sensitivity was 30%, the specificity was 90% and positive predictive ability was 32%. In other words, by establishing TO and TS within 2.5 mc/RR and 0%, 30% it is possible to detect 30% of patients who will suffer from cardiac arrest. However, the predictive accuracy of other risk factors such as advanced age, past myocardial infarction, low heart rate variability (HRV), arrhythmia, low EF values were within 18-24% in EMIAT and 16-30% in MRIR. According to MRIR the predictive accuracy of EF corresponded to 30% and was close to the value of predictive ability of the combination of TS and TO. EF value had better sensitivity (43%) and predictive ability (85%) than HRT parameters.

P. Macrarlane compares HRT with the conventional electrocardiographic risk predictors such as HRV, changes in ST-T, QT interval dispersion and receives the following data: the sensitivity, specificity and positive predictive accuracy of reduced HRV (SDNN <100 mc) being 34%, 89% and 34%, respectively, roughly coincides with the indicators for HRT (TO, TS). According to the ATRAM study, the predictive accuracy of the value of TS is equal to 12.5% at 40% sensitivity, thus, being significantly important than the values of baroreflex sensitivity (7.8%). Certainly, the predictive capacity can be increased when considering HRT in combination with other risk factors [9]. At 40% sensitivity pathological value of TS in combination with low HRV gives 20.3% of positive predictive accuracy and in combination with low EF - 17.3%. Almost all research works indicated the relationship between the heart rate and HRT; moreover, HRT was found to reduce in case of high heart rate (> 80 beats/min) [2]. When assessing the impact of the heart rate on HRT, G. Schmidt and colleagues reported that the parameter that determines the slope of the regression line to the heart rate, which they called “The dynamics of turbulence”, has a strong predictive value of death risk. HRT, as a predictor of death, is recommended to be evaluated when the heart rate <80 beats/min [12]. Making a preliminary conclusion, we can state that HRT was studied in patients with acute myocardial infarction, and the study of HRT among healthy individuals or individuals with early manifestations of atherosclerosis, or the initial stages of the cardiovascular system was not performed. On this basis, patients were selected for this study.

Materials and methods

During 2007-2013, there were examined 4,214 patients at the age of 35-85 years who underwent daily monitoring of heart rate variability; 921 patients were diagnosed with the phenomenon of HRT. For this study there were selected 319 patients (198 men and 121 women) in order to study the role of heart rate turbulence in the formation and progression of sudden cardiac death in the cardiovascular continuum. The predominance of men can be explained by the fact that due to moral and religious features of our country, men are more likely to smoke than women. All patients were divided into 4 groups: Group 1 included patients with coronary heart disease without concomitant risk factors such as smoking, obesity, metabolic syndrome; this group consisted of 72 (38 men and 34 women) with signs of HRT.

Group 2 consisted of patients smoking tobacco for more than 2 years; this group consisted of 69 (67 men and 2 women) patients with HRT. Group 3 included patients with metabolic syndrome without existing coronary heart disease or arterial hypertension; in this group there were 69 (51 men and 18 women) patients with HRT. Group 4 consisted of patients with metabolic syndrome and arterial hypertension without coronary heart disease; this group included 69 (17 men and 42 women) patients with the phenomenon of HRT. When randomizing the patients of Group 3 and Group 4 arterial hypertension was seen not as the separate disease, but as a special state of the body or as a separate risk factor for cardiovascular disease. The control group included 50 (25 men and 25 women) patients. The determination of HRT and HRV was performed using the Holter monitoring system “CardioSens 2008”, “CardioSens+V3.0” and “CardioSens CS” (“Medica-Khai”, Kharkiv, Ukraine).

Results of the research

According to the recommendations of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology during the analysis of HRV an expression and equilibrium of various parts of the autonomic regulation, tension of regulatory unit and predominance of regulatory units in patients with the phenomenon of HRT were determined [7, 9]. When analyzing spectral and statistical parameters of HRV in healthy people with symptoms of HRT (the control group) it was found that the rate of acceleration of HRT was TO = -2.53±0.33%, and the rate of deceleration of HRT was TS = 8.39±0.75 mc/bit (throughout the day).

In the active period of the day: In the passive period of the day:
QT=389.70±3.91mc (throughout the day) SI=32.76±3.14
QTc=421.94±3.29mc(throughout the day) TP=4094.76±405.44mc2
SI=40.45±4.06 HF norm=31.53±1.36%
TP 3484.72±324.42mc2 LF norm=68.33±1.35%
HF norm=28.02±1.32% HF=606.25±105.94mc2
LF norm=71.83±1.3% LF=1124.41±118.76mc2
HF=343.11±45.41mc2 VLF=1749.00±175.53mc2
LF=858.41±89.79mc2 LF/HF=2.47±0.15
VLF=1424.00±139.10mc2 IC=6.91±0.55
LF/HF=3.03±0.19
IC=8.65±0.80

The parameters of the sinus cycle acceleration and deceleration that followed premature ventricular contractions (HRT) TO and TS were normal. As presented by the data, in healthy individuals with the phenomenon of HRT, extension of the electrical systole (the QT interval) has not been determined. The tension of overall regulation of the body was high. The stress index in healthy people without HRT phenomenon had a low threshold. In practically healthy individuals in the active period of the day, the subcortical activity of the sympathetic nerve center constituting 40% of the total tension of body regulation prevailed. High-frequency spectrum of HRV being 9.8% of the total tension was very low. When analyzing the power of low-frequency and very low-frequency component of the spectrum, we noted that the activity of the sympathetic circuit was associated with the high psycho-emotional stress and functional state of the cerebral cortex. The value of the stress index was stable throughout the day. In the passive period of the day, there was an increase in the value of the total tension of body regulation, which increased by 17.53% compared to the active period of the day. The ratio of the average values of low-frequency and high-frequency components of HRV (LF/HF) reduced; however, the activity of the sympathetic component prevailed over that of the parasympathetic one LF/HF=2.47±0.15 (N≤1.0). The level of psycho-emotional stress remained high; relative value of VLF range was 42.73%.

When studying HRV in patients with coronary heart disease (postinfarction cardiosclerosis) and HRT without risk factors (Group 1) TCP parameters were as following: TO=-2.23±0.33%, TS=9.23±1.06 mc/bit (throughout the day):

In the active period of the day: In the passive period of the day:
QT=379.82±6.68mc (throughout the day) SI=50.78±6.35
QTc=408.61 ±6.93mc (throughout the day) TP=3660.08±329.76mc2
SI=47.18±4.63 HF norm=31.13±2.44%
TP=4366.98±471.52mc2 LF norm=68.27±1.43%
HF norm=32.01±2.35% HF=543.14±94.22mc2
LF norm=74.44±5.02% LF=1015.38±112.63mc2
HF=707.58±224.01mc2 VLF=1577.08±139.20mc2
LF=1006.50±142.05mc2 LF/HF=2.59±0.14
VLF=1594.11±156.60mc2 IC=7.84±0.50
LF/HF=3.01±0.21
IC=9.71±0.85

The parameters of acceleration (TO) and deceleration (TS) of the sinus cycle in patients with postinfarction cardiosclerosis who were diagnosed with the phenomenon of HRT were within the physiological norm. On the basis of the obtained data, we can say, that in patients with postinfarction cardiosclerosis the QT and QTc intervals were within the physiological norm in the active as well as the passive period of the day. In the active period of the day the total power of variability spectrum was high being the highest among all groups. The stress index corresponded to the lower limit of norm. High-frequency component of the spectrum was high HF norm=16.2% (N=15-25%), which corresponds to the lower limit of norm. When analyzing the ratio of average values of low and high-frequency component of HRV (LF/HF), the predominance of the subcortical activity of the sympathetic nerve center was observed LF/HF=3.01±0.21 (N=1.2-1.8). When analyzing the power of low-frequency and very low-frequency component of the spectrum, there was observed that the activity of the sympathetic circuit was associated with high stress and functional state of the cerebral cortex (VLF=36.51% of the total tension, N=15-30%). The activity of the vasomotor center (LF) corresponded to norm being 23.05% (N=15-40%). The centralization index was the highest in all investigative groups during the active as well as the passive period of the day; in the passive period of the day it reduced by 23.85% compared to the active period of the day. In the passive period of the day, a decrease in the value of the total tension of body regulation by 19.93% was observed compared to the active period of the day. The ratio of the average values of low and high-frequency components of HRV (LF/HF) reduced; however, the activity of the sympathetic component prevailed over that of the parasympathetic one LF/HF=2.59±0.14 (N≤1.0). The level of psycho-emotional stress at night remained high; relative value of VLF range was 43.08% (normal values - 15-30%). The centralization index was within the physiological constants.

While studying HRV in patients at high cardiovascular risk according to the SCORE charts (Group 2) with the phenomenon of HRT, the rate of heart rate acceleration was TO= -2.37±0.28%, and the rate of heart rate deceleration was TS=8.42±0.67 mc/bit (throughout the day). The indices of HRV in patients at high cardiovascular risk according to the SCORE charts with ventricular rhythm disorder (ventricular extrasystole) and the phenomenon of HRT were the following:

In the active period of the day: In the passive period of the day:
QT=370.72±4.62mc(throughout the day) SI=51.87±6.37
QTc=408.51±4.33mc(throughout the day) TP=4783.60±493.55mc2
SI=58.61±6.96 HF norm=33.63±1.37%
TP=3915.75±389.2mc2 LF norm=66.58±2.46%
HF norm=33.63±1.50% HF=937.34±197.70mc2
LF norm=65.91±1.62% LF=1383.17±200.13mc2
HF=703.99±131.82mc2 VLF=1808.48±143.30mc2
LF=1101.57±163.85mc2 LF/HF=2.31±0.14
VLF=1496.67±158.68mc2 IC=6.93±0.48
LF/HF=2.77±0.24
IC=8.05±0.66

The parameters of acceleration (TO) and deceleration (TS) of the sinus cycle in patients at high cardiovascular risk according to the SCORE charts were within physiological range. In patients at a high cardiovascular risk according to the SCORE charts with the phenomenon of HRT the extension of the cardiac cycle (the QT interval) was not established as the absolute value of the interval and its corrected indicator. On the basis of the obtained data, we can say that in individuals at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT, the QT and QTc intervals were within the physiological norm in the active as well as the passive period of the day. The stress index in this group of patients was lower than normal values. The tension of the overall regulation of the body was unanimously high. In patients of Group 2 the shift in the ratio of average values of low-frequency and high-frequency components toward the low-frequency ones was observed, although the value of high-frequency component was closer to normal one being 17.98% of the total tension of the body. The value of VLF accounting for 38.22% of the total value indicated that the psycho-emotional stress and functional state of the cerebral cortex play a major role in the pathogenesis of the disease. The centralization index was shifted to the central units of the regulation; during the passive period of the day it reduced by 4.0% only. In the passive period of the day, there was an increase in the absolute level of regulatory system activity by 22.18% compared to the active period of the day. In contrast with the day, there was an increase in the relative value of the vasomotor center (LF) by 20.88%; the activity of the sympathetic branch of the body increased by 25.6%, the activity of the parasympathetic branch of the body increased by 33.33%. Thus, the total tension of body regulation in patients of Group II during the passive period of the day occurs owing to all components of the spectra compared to the active period of the day.

When studying HRV in patients at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT (Group 3) the rate of heart rate acceleration was TO = -1.34±0.26%, and the rate of heart rate deceleration was TS = 9.44±0.56 mc/bit (throughout the day). The indicators of cardiac risk in patients at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT (Group 3) were the following:

In the active period of the day: In the passive period of the day:
QT=400.39±6.62mc(throughout the day) SI=69.79±9.59
QTc=417.57±3.48mc(throughout the day) TP=3880.03±486.71mc2
SI=67.36±6.59 HF norm=34.17±2.48%
TP=3299.92±314.31mc2 LF norm=65.82±1.24%
HF norm=33.83±1.93% HF=741.67±93.82mc2
LF norm=70.49±3.97% LF=1027.38±162.38mc2
HF=609.03±86.87mc2 VLF=1509.83±131.93mc2
LF=686.33±75.29mc2 LF/HF=2.38±0.13
VLF=1171.30±81.28mc2 IC=7.75±0.53
LF/HF=2.72±0.15
IC=9.44±0.76

In patients at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT (Group 3) the parameters of acceleration (TO) were below normal values and the parameters of deceleration (TS) of the sinus cycle were within normal values. Thus, in these people the acceleration of the sinus rhythm immediately after ventricular arrhythmia was below normal, although the intensity of the slowdown corresponded to normal values. The QT interval lengthening was not established as the absolute value of the interval and its corrected indicator. On the basis of the obtained data, we can say that in patients at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT (Group 3) the QT and QTc intervals were within the physiological norm in the active as well as the passive period of the day. The stress index was within normal values being the highest throughout the day compared to other groups. The centralization index indicated that the activity of the central nervous system prevailed over that of the autonomic one. The total tension of body regulation was moderate. The average absolute level of the activity of segmental units of the sympathetic system was slightly above normal values accounting for 35.5% of the total tension. The activity of the parasympathetic circuit of HRV was relatively high being almost equal to the level of the vasomotor center activity. HF spectrum accounted for 18.46% and LF spectrum accounted for 20.8% of TP (the level of the total tension of body regulation). In the passive period of the day, there was an increase in the stress index by 3.6% compared to the active period of the day. The total body tension remained within a moderate level increasing by 17.6% compared to the active period of the day. There was observed an increase in the activity of the parasympathetic (by 21.7%) and sympathetic nervous system (by 28.9%) as well as the vasomotor (49.7%) and the peripheral circuits. The centralization index reduced by 17.09% indicating the predominance of the activity of the central circuit over that of the peripheral one.

Discussion of the results

Thus, in healthy people with the phenomenon of HRT high activity of the sympathetic branch was observed during the passive period of the day. Hypersympathicotonia associated with high psycho-emotional stress was typical for people with postinfarction cardiosclerosis and the phenomenon of HRT; the central mechanism of regulation prevailed over the autonomic ones. In people with coronary heart disease (postinfarction cardiosclerosis) the psycho-emotional stress and functional state of the cerebral cortex played an important role in the pathogenesis of the disease. In people with past myocardial infarction and the phenomenon of HRT – the parameters of acceleration (TO) and deceleration parameters (TS) of the sinus cycle were within physiological norms. Based on the obtained data, we can say, that in people with this pathology the QT and QTc intervals were within physiological norm in the active as well as the passive period of the day. In people with the phenomenon of HRT, coronary heart disease and past myocardial infarction high activity of the sympathetic branch was observed remaining to be high in the active as well as in the passive period of the day and throughout the day it was not variable in absolute terms. Hypersympathicotonia and high activity of the vasomotor center at night explain the high incidence of complications and exacerbations of coronary artery disease in the passive period of the day. In individuals at very high cardiovascular risk according to the SCORE charts with the phenomenon of HRT the QT interval lengthening was not observed. These people had high level of tension of body regulatory, which in the passive period of the day increased proportionally due to all spectra of HRV. Hypersympathicotonia was typical for these people. Thus, the feature of this group was the moderate total tension of HRV in the active period of the day and its rise to the highest limits during the passive period of the day, which was associated with low activity of all spectra. The stress index in patients at very high cardiovascular risk according to the SCORE charts in the passive period of the day reduced compared to the active period of the day. There was no significant dynamics in the ratio of average values of low-frequency and high-frequency components of HRV during the day. The indices of acceleration and deceleration of the sinus rhythm in patients at very high cardiovascular risk according to the SCORE charts were within normal limits. In individuals at high cardiovascular risk according to the SCORE charts with the phenomenon of HRT the parameters of HRT acceleration were below normal limits; the parameters of deceleration were normal; shortening of the QT interval was not observed. The total tension of HRV in patients of this group was moderate in the passive period of the day; in the passive period of the day it increased mainly due to the sympathetic component and the activity of the vasomotor center. The stress index was high in patients at high cardiovascular risk according to the SCORE charts and the phenomenon of HRT compared to other groups.

There are many methods for early detection of patients with susceptibility to sudden cardiac death (medical history, a high-resolution (24 bits) or 12-channel ECG study, echocardiography, testing with exercises, heart probing, electrophysiological study); however, the most available and a highly specific method is the study of HRV and HRT. This method allows detecting larger contingent of patients with predictors of sudden cardiac death, in addition to already known pathology:

  • after past myocardial infarction with low EF and ventricular ectopia;

  • recurrent syncope of unknown origin;

  • dilated or hypertrophic cardiomyopathy with co-existent syncope or ventricular tachycardia;

  • arrhythmogenic right ventricular dysplasia;

  • sudden death survivors;

  • changes in the length of the QT interval.

The advantages of the method:

  • wide availability;

  • affordability;

  • it is not difficult to interpret the results;

  • it is easy to repeat for dynamic observation.

Despite some limitations, such as atrial fibrillation or premature ventricular contractions, the determination of HRT is an original way to assess the heart function of the autonomous system in patients with heart disease and associated risk factors. In the predictive accuracy HRT is slightly better than other known markers of sudden death, but it is quite simple and non-invasive method to assess the risk without cancellation of ß-blockers.

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