Effect of Losartan and Atenolol on Heart Rate Variability in Newly Diagnosed Essential Hypertensive Patient

Background: Essential hypertension is associated with altered autonomic frrnctionr. Essential hypertension is treated with drugs which modi$r the sympathoparasympathetic balance. Losartan (angiotensin II receptor blocker) and atenolol (beta blocker) is commonly used antihypertensive drugs. Objective: To evaluate the effect of antihypertensive drugs on heart rate variability (HRV) in patients with essential hypertension. Methods: This prospective observational study was carried out in the Department of Physiology, Bangabandhu Sheikfr Mujib Medical University (BSMMLD, Shahbag, Dhaka from July 20l2to June 2013 on 120 newly diagnosed hypertensive patients without any medication (group B, age 30-55 years). They were selected from the Out Patients Department (OPD) of cardiology, BSMMU, Dhaka. Age, sex and BMI matched 60 apparently healthy normotensive subjects were also studied as control (group A). Based on treatment, these study subjects were divided into two groups (Bl and B2). GroupBl" included 60 patients received losartan 50 mg daily and Br" included 60 patients received atenolol 50mg daily .They were observed once before the treatment (B1,&B2"), after 3 months medication (B1b & 82) and after 6 months medication (Bl" & B2"). For assessing HRV, Mean heartrate, Mean R-R interval, Max/Min R-R interval, SDNN, RMSSD were recorded by a polyrite. Data were compared among before treatment, after 3 months teatnent and after 6 months treatment. For statistical analysis ANOVA, independent sample't' test and paired sample 't' test were performed. Results: Mean resting pulse rate, mean heaxt rate, systolic blood pressure, diastolic blood pressure were significantly higher and mean R-R interval, Max/\rfin R-R interval, SDNN, RMSSD were significantly lower in newly diagnosed hypertensive patients in comparison with that of healthy normotensive subjects and after treatunent. In both groups SDNN, RMSSD, mean R-R interval were found significantly higher after 6 months of treatrnent compared to their values after 3 months treatment. Again these values were found close to the values in normotensive subjects. In addition, mean heart rate was found significantly lower in atenolol treated patients than those of controls. Again in atenolol group these values were found significantly higher than the corresponding values in losartan teated patients after 6 months treahnent. Conclusion: Reduced cardiac vagal tone occurs in newly diagnosed hypertensive patients which is improved by both losartan and atenolol and in particular atenolol was found more effective.


Introduction:
Hypertension has been recognrzed as the commonest cardiovascular problems in most of the advanced coun- tries and developing countries.Essential hypertension accounts for 90-95% of all cases of hypertension.Hyper- tension is an emerging health problem in Bangladesh Address for Correspondence: Dr. Shamima Sultana Medical Officer, Department of Physiology, BSMMU.Mobile: 0l7ll 177678 among the cardiovascular diseases.The prevalence rate of hypertension is very high and more than 20% of the adults have hypertension2 .
The autonomic nervous system (ANS)) plays a fundamen- tal role in the control of arterial blood pressure and heart rate.Essential hypertension is associated with altered autonomic functionl.Hypertension is characterized by sympathetic overactivity3 and attenuation of parasympa- thetic modulation of the heart.
The heart rate variability is a powerful noninvasive tool in the assessment of the cardiac autonomic nerve function5.
Among the various HRV measures mean R-R interval, mean heart rate, maximum and minimum R-R ratio, SDNN and RMSSD usually used as marker for cardrac vagal activityll.Essential hypertension is treated with various antihypertensive drugs which modiff the sympathoparasympathetic balanc e''".A prospective randomized trial revealed that losartan signific antly increased parasympathetic activity in hypertensiye patients when compared to placebol3.Few sfudies reported losartan inhibit sympathetic activity in hyperten- sive patientsl4'ls.Another sfudy revealed that losartan had no significant effect on HRV in hypertensive patientsl6'17.Few studies revealed that autonomic balance shifted toward the increased vagal activity treated with atenolol in hypertensive patientslT'l8.On the other hand, one sfudy reported that atenolol had no significant effect on HRV23.Although several investigators observed the effect of losartan and atenolol on HRV separately but no report compared the effect of losartan and atenolol on HRV in newly diagnosed hypertensive patients.Therefore this study aimed to evaluate HRV in untreated hypertensive patients and compare the effect of losartan and atenolol on HRV.

Methods:
This prospective observational study was carried out to observe the HRV by assessing time domain measures in L20 newly diagnosed hypertensive patients with ranged from 30-55 years in the Department of Physiology, Bang- abandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka from July 2012 to June 2013.Age, sex and BMI matched 60 apparently healthy nonnotensive subjects were also studied as control (group A).Based on treatment, these study subjects were divided into two groups(8l and B2).GroupBlu included 60 patients received losartan 50mg daily and 82, included 60 patients received atenolol 50mg daily .They were 162 observed once before the treatment (B 1 u & B2^) after3 months medication(B 1o & B2b) and after 6 months medi- cation ( 81"&B.2^).These patients were selected from the Out Patient Department of Cardiology, BSMMU.
Then the subject was prepared for Autonomic Nerve Function Test.The subject was kept in complete bed rest in supine position for 15-20 minutes in a cool and calm environment.Then all preparations for recording of the Heart rate variability parameters were made by connecting the channels of ECG and a 5 minutes recording was taken in resting position.Time domain parameters of the HRV like Mean heart rate, Mean R-R interval, Max/Min R-R interval, SDNN, RMSSD were measured by polygraph.
Then all the patients were requested to attend the Department of Physiology of BSMMU, again after 3 months and after 6 months of antihypertensive medication, to have the assessment of the above mentioned study variables.For statistical analysis ANOVA, independent sample't' test and paired sample 't' test were performed.

Table-I
Anthopometric data of all subjects are given in.

Age (years) BMI (kglmz)
A (n-60)    The exact mechanisms involved for the decreased HRV and BRS in hypertension and improvement after treatment with losartan and atenolol in hypertensive groups of present study can not be elucidated from this type of study.However, it is assumed that all the above mentioned mechanisms may influence the degree of deterioration of these variables in hypertension patients and improvement aftw treatment with losatan and ateno- 1o1.From the result though the improvement of cardiac autonomic nerve function was marked after 3 months of treatmebt but data after 6 months of treatment showed further improvement.This is suggestive of positive relation and duration of treatment with antihypertenstve drugs with improvement of HRV.
t66 Conclusion: Impairment of cardiac autonomic nervous activity occurs in newly diagnosed hypertensive patients which is improved by both losartan and atenolol and in particular atenolol was found more effective.The rute of improve- ment of impaired cardtac autonomic function releated to their duration of treatment.

Table - II
Baseline measures in dffirent groups(n-120)Mean values of mean heart rute were significantly higher in group B,u and Br, than that of group A and this values were significantly decreased in group Bro andgroup 8,.in comparison to their baseline value.In addition this value showed no significant difference when compared between groupA and group B,..Mean heart rate in group Iable-III Simple time domain measures of HRV in dffirent groupsThe mean values of SDNN, RMSSD were signific arfily lower in group B,u and Bruthan that of group A and this values were significantly increased in group B,o, B,., Bro and Br" than that of their baseline.But these values showed no statistically significant difference between group A and group B1c.(TableIV).
B,o vs B,.n B,u vs B,rt {n group B,u and Bru than that of group A and this values were significantly increased in group B,o, 8,., Bro and Br" in compared to baseline value.(TableIII).
Different investigators suggested various mechanisms for the improvement of HRV in hypertensive patients after treatment with losartan and atenolol.It has been suggested that blocking the type-I receptor (AT,) of Angiotensin II by losartan would release the baroreceptor from the suppresor effect of high level of Angiotensin II leading to increase BRS which in turn bring the sympathovagal balance back towards nonnal.The benefit of blocking the type-I receptor (ffi,) of Angiotensin II by losartan is also derived from its ability to increase No production from vascular endothelium and neuron which in turn facilitate the regulation of BRS and HRV in losartan treated hyper- tensive group 25.Furtherrnore, NO has been demonstrated to augment cardiac vagal control in human suggesting beneficial effect on BRS and HRV26.