Introduction

Men are in a higher risk group than women for having hypertension₁,₂,₃, coronary artery disease₃, stroke₃, sudden cardiac death₄.

Higher sympathetic tone in men particularly before 60 years of age than women ₅,₆ may increase cardiovascular morbidity and mortality₇. Heart rate recovery (HRR) and chronotropic index (CI) values have been shown to predict cardiovascular morbidity and mortality ₇,₂₆. Thereby, showing the effects of autonomic balance that could be determinative for replying inner or outer stress factors, on HRR, CI and diastolic functions of the heart is valuable for addressing of autonomic effects on cardiac morbidity and mortality. This study aims at assessing the relationship between HRR, CI, diastolic functions and demonstrating how changes on autonomic balance could affect these factors in the group of healthy asymptomatic men

Patients And Methods

Following ethical approval of institutional board and obtaining informed consent, fifty-eight healthy asymptomatic men. Age, height, weight, body mass index, waist and hip circumference, waist/hip ratio were recorded. History, physical examination, routine biochemical tests, complete blood count, thyroid function tests, 12 lead ECG and 24 hour Holter examination (Delmar –Impresario, General Electric, USA) were obtained. Chest X-ray, color Doppler echocardiography (GE-Vivid 7 Pro, General Electric, Florida-USA) and exercise stress test (Quinton 4500 treadmill, Seattle, ABD) were applied to the subjects for differential diagnosis when required. All the tests for each were completed in 15 days.

24 Hour Holter Monitoring, Heart Rate Variability Measurements

Transthoracic Color Doppler Echocardiography

Transthoracic color Doppler echocardiography was done to all of the participants included in the study. Transmitral Doppler flow measurements are taken from the tips of the mitral valve leaflets in apical four chamber view if the patient has normal chamber sizes, no morphologic abnormality, segmental wall motion disorder, hypertrophy or dilatation. E wave velocity, A wave velocity, E/A ratio, mitral E wave deceleration time, isovolumic relaxation time(IVRT), isovolumic contraction time (IVCT), mitral flow period (the period from the beginning of E wave to end of A wave), diastolic period (IVRT + Diastolic filling period :DFP), were measured.

By using tissue Doppler echocardiography Ea, Aa and Ea/Aa ratios were measured. Mainly we used the criteria for evaluation and definition of vary types of diastolic dysfunction that shown in table 6. ₉,₁₀,₁₁ Additionally E/Ea ratio which gives an idea about left ventricular filling pressure is measured and the correlation between other variables is determined ₉,₁₁

Table 6: Definitions of some data used in article and diastolic dysfunction criteria

Figure 1

Exercise Stress Test

Statistical Analysis

Results

Table 1 demonstrates the baseline data of all the participants. In the tables about correlation data, the partial correlation analysis results are shown in order to eliminate the possible effects of age, weight, body mass index, and waist/hip ratio. The positive and negative signs shown before the p values points out the direction of the correlation.

Figure 2

Table 1: Patient characteristics

Table 2 reveals the HRR and chronotropic index data obtained after exercise stress testing and heart rate variability data. HRR was negatively correlated both minimal and mean heart rate that determined 24 hour holter monitoring (p=0.028 and p=0.002 respectively). Otherwise HRR was positively correlated with both the HRR parameters Log LF and Log HF(p=0.01 and p=0.002 respectively) and time based parameters pNN50 and RMSSD(p=0.022 and p=0.032 respectively).HRR was negatively correlated with as a sympathetic tone marker LogLF/LogHF ratio (p=0.034 and p=0.028 respectively)

Figure 3

Table 2: Heart rate variability data, HRR and CI correlations

Table 2 shows the partial correlations between HRR,CI and HRR.

Chronotropic index was also positively correlated with LogLF (P=0.019).Both HRR and CI was positively correlated with total power (p=0.013 and p=0.006 respectively)

Although not being the main purpose of our study HRR data were compared with transmitral flow patterns and tissue Doppler data (Table 3).While autonomic tone values were not correlated with transmitral flow patterns, there was a close correlation with tissue Doppler data. As a sympathetic tone marker, LFn were negatively correlated with Ea and Ea/Aa (p<0.001 and p=0.001 respectively) whereas positively correlated with E/Ea (p=0.037)which is suggested to be positively correlated with diastolic filling pressure(₉,₁₀,₁₁).These correlations were exactly the opposite for the parasympathetic tone marker HFn (table 3). As a symphatetic tone marker, LFn/ HFn mainly correlated same way by LFn with echocardiographic data. LFn/ HFn was negatively correlated with Ea and Ea/Aa (p<0.001 and p<0.001 respectively); positively correlated with E/Ea (p=0.004)

Figure 4

Table 3: The correlations between transmitral and tissue Doppler data and some significant heart rate variability data.

HRR and CI were significantly correlated with echocardiographic and autonomic values.

HRR,CI and diastolic function relations were also examined in our study.(Table 4 )which shows the partial correlation results demonstrates the parasympathetic tone marker HRR(₇) was positively correlated with diastolic period and mitral flow period and negatively correlated with systolic/diastolic period(p=0.002,p=0.025 and p=0.005 respectively). HRR and CI likewise heart rate variability measures were not correlated with transmitral flow patterns (only E/A ratio is correlated with HRR. p=0.048) but correlated with tissue Doppler data. HRR was positively correlated with Ea and Ea/Aa (p=0.050 and p=0.001 respectively) whereas negatively correlated with Aa and E/Ea (p=0.012 and p=0.024 respectively).But the correlation between CI and tissue Doppler data was more significant. CI was positively correlated with Ea and Ea/Aa (p=0.002 and p=0.001 respectively) and negatively correlated with E/Ea (p<0.001)

Figure 5

Table 4: Echocardiographic data, HRR and CI correlations

After performing the exercise stress test the chronotropic indexes were calculated and the participants were divided into two subgroups according to having a CI value of less than or equal to 0.8 or above 0.8. Comparisons about these two subgroups are shown in table 5. As only 4 of 58 participants had the pathologic value of less than 12/minute subgroup analysis was not done. The subgroup having a CI index of less than 0.8 has decreased HF(parasympathetic tone) , total power and SDNN (p=0.023, Z:2.271; p=0.013, Z:2.471; P=0.042, Z: 2.035 respectively), and increased transmitral E/A ratio and E/Ea (p=0.035 Z:2.109; p<0.001 Z:4.625 respectively) decreased Ea wave and Ea/Aa (p<0.001 Z:3.646 ; p<0.001 Z:3.835 respectively)

Figure 6

Table 5: Echocardiographic and heart rate variability data with respect to chronotropic index

Discussion

HRR and chronotropic index both as an autonomic tone marker and having prognostic significance has been the subject of many studies recently₇.Previous studies have shown that HRR is a good marker of parasympathetic activity₇,₁₃,₁₄. The close relation between HRR and heart rate variability and the parasympathetic tonus marker HF is well documented₁₄,₁₅.Our study stated a significant positive correlation between HRR and all the parameters of parasympathetic tone .The correlation between HF and HRR was present also after eliminating the effect of age, weight, waist and hip circumferences (table 2 ).

Not only the HF parameter but also the LF values were positively correlated with HRR. LF value generally defined as a sympathetic tonus marker ₈,₁₆,₁₇ is thought to be related with both sympathetic and parasympathetic tonus, sympathetic and parasympathetic efferent modulation of baroreflex activity, sympathetic modulation of vasomotor activity and increases during the reflex activities with the changes in blood pressure₇,₁₆,₁₇,₁₈,₁₉. There are studies that LF component is not solely related with sympathetic activity₁₉,₂₈.Previous studies has not examined the relation of HRR and LF values in detail. The significant negative correlation between LF and HRR determined by Evrengul et al₂₁ was not noted in our study. But contrarily to our study that study was executed on a population of coronary artery disease. HRR which is an important marker of parasympathetic activity₇ not only had positive correlation with parasympathetic tonus parameters but also with the LF values indicating that the vagal control mechanism is not free from LF value. Martinmaki et al stated decrement of LF and total power besides the HF value after complete vagal blockade ₂₂.LF value is believed to reflect not only sympathetic but also the parasympathetic activity ₇, ₁₉, ₂₂. These results can explain the correlation between HRR and LF values found in our study. The sympathovagal balance marker LF/HF showed a strong negative correlation with HRR as usual. The increase in sympathetic tone results in shortening of the sinoatrial node recovery time. In addition to these HRR is positively correlated with SDNN values which have predictive value for cardiovascular mortality₇. As the predictive value of HRR for cardiovascular morbidity has already been known, it is not surprising for HRR to be correlated with other predictive factors.

There was a significant correlation between HRR and diastolic function data. Autonomic system is suggested to be the factor that relates this group of data. The presence of positive correlation with Ea and Ea/Aa and the negative correlation with E/Ea with both HRR and CI suggested that the increase in sympathetic tonus shows the same effect on ventricular muscle and sinus node. Previous studies have emphasized on the close relationship between tissue Doppler data and autonomic tonus.₂₃.Obtained data suggested that the increase in sympathetic tonus decreased the compliance of ventricular myocardium besides decreasing HRR and CI by the effect on sinus node. While there was not a significant correlation between HRR and transmitral flow values, there was a significant correlation between HRR and tissue Doppler data. This may be related to the fact that transmitral flow is highly dependent on other factors affecting volume and transmitral flow₁₀.This study also revealed the significant correlation between tissue Doppler data and autonomic tonus. A decrease in Ea wave and an increase in Aa wave is seen with the increase in sympathetic tonus while the increase in parasympathetic tonus is correlated with the increase in Ea wave. This situation can be explained with the increased sympathetic tone but it is surprising to see this finding in asymptomatic men. This demonstrates that the decrease in ventricular compliance due to sympathetic tonus does not have to occur in a pathologic state. The correlation between the diastolic functions obtained by tissue Doppler and heart rate variability has been demonstrated in previous studies, but this is beyond our study purpose. The strong correlation between HRR and diastolic period that is affected by parasympathetic tonus is an expected result. As it is known, E/Ea is correlated with left ventricular filling pressure. ₉,₁₁HRR is negatively correlated E/Ea in our study. The increase in sympathetic tonus increases left ventricular filling pressure besides decreasing HRR.

Chronotropic index also predicts cardiovascular morbidity and mortality like HRR ₂₀,₂₁,₂₂. CI was positively correlated with LF like HRR. But the insufficiency of the chronotropic adaptability can not be explained with the presence of the parasympathetic component of LF. This partially contrary state may be related with the positive correlation of LF seen with adrenalin but not with noradrenalin ₂₈.Colucci et al. stated desensitization to noradrenalin after a long term sympathetic activation ₂₇.The desensitization formed against beta1 receptors can be bypassed with adrenalin which also stimulates beta2 receptors. The effect of beta2 receptors on the control of heart rate has been documented ₂₇. Adrenalin is thought to control the heart rate by beta2 receptor stimulation when noradrenalin increase in response to exercise ₂₈,₃₀has less effect on heart rate control due to down- regulated beta1 receptors under chronic stimulation ₂₇,₂₉. Adrenalin forms the escape pathway of chronotropic response by the help of desensitized beta2 receptors ₂₉,₃₀,₃₁.At this point of view, the positive correlation of LF value with increased adrenalin and chronotropic index is an expected result. But the study design and the results are not sufficient to comment. Further studies with larger group of subjects are warranted.

The autonomic tonus changes that explains the relation between HRR and tissue Doppler data is also responsible for the same relation between CI and tissue Doppler data. The comparison of the two subgroups of CI grouped according to having values less or equal to 0.8 or greater than 0.8, supports our other results.

The decrease in Ea/Aa ratio which is a marker of the decrease in CI and ventricular compliance and the increase in E/Ea ratio which is related with increased ventricular filling pressure are the results of possible increased sympathetic tonus particularly under the effect of noradrenalin. Although not being tested noradrenalin levels are expected to be high in the group of low CI values ₇,₂₇. . Another interesting result that took attention, contradictory negative correlation was determined transmitral flow E/A ratio and CI. It was interpreted that this result depended on flow dependency of transmitral echocardiographic values. Also it was considered us, increased end diastolic pressure of left ventricle and more restrictive response accompanied increased sympathetic tone even though the group is healthy.

Conclusion

HRR and chronotropic index values which have important predictive value for cardiac morbidity and mortality are associated with the changes in sympathetic tonus and these changes parallels with the diastolic function changes.

Correspondence to

Dr. M .Tolga DOGRU, University of Kirkkale, Kirikkale-Turkey 7100 Tel:+90-3182252485 , +90-5554727096 Fax +90-3182252819 E-mail: mtolgadogru@superonline.com