European Journal of Cardiovascular Medicine

Hypertension is one of the most important risk factors for cardiovascular disease, and its global burden is expected to rise substantially in the coming decades [1]. In India, the prevalence of hypertension has increased steadily in both urban and rural populations [2,3], and blood pressure in the prehypertensive range is common even among young adults [4]. Because hypertension remains silent for many years, identification of young people at risk before blood pressure rises offers an opportunity for prevention.

A family history of hypertension is one of the strongest predictors of future hypertension. A positive family history, particularly when both parents are affected, is associated with a higher risk of disease in the offspring [5], and in the Johns Hopkins Precursors Study, parental hypertension was associated with a faster rise in blood pressure and a higher incidence of hypertension from young adulthood onwards [6]. The mechanisms by which this inherited risk is expressed are not fully understood.

Increased sympathetic activity is thought to play an important role in the development of essential hypertension [7,8]. A higher resting heart rate, a marker of sympathetic overactivity, is associated with higher blood pressure and cardiovascular risk [9]. Normotensive members of hypertensive families have been shown to have higher noradrenaline spillover [10] and exaggerated sympathetic responses to mental stress [11], suggesting that autonomic changes may precede the rise in blood pressure.

Heart rate variability is a simple, non-invasive measure of cardiac autonomic modulation [12]. Reduced heart rate variability predicts cardiac events [13] and the development of new-onset hypertension in population cohorts [14,15], and it is reduced in subjects with hypertension and high blood pressure [16]. Studies in normotensive offspring of hypertensive parents have reported reduced vagal and increased sympathetic modulation [17-20], and Indian studies have described altered cardiovascular autonomic responses [21] and sympathovagal imbalance in young prehypertensives and in offspring of hypertensive parents [22-24]. However, few studies from India have combined short-term heart rate variability with the standard battery of autonomic function tests in this group.

The objective of this study was to compare cardiovascular autonomic function, assessed by short-term heart rate variability and conventional autonomic function tests, between normotensive young adults with and without a parental history of hypertension, and to examine whether the changes are greater when both parents are hypertensive.

Study design and participants

This comparative cross-sectional study was conducted at Dr. D. Y. Patil Medical College, Pune, with recordings performed in the autonomic function laboratory. Participants were healthy normotensive undergraduate medical students aged 18 to 25 years. Written informed consent was obtained from each participant after the procedure was explained.

Participants with one or both biological parents diagnosed with essential hypertension and on antihypertensive treatment formed the study group, and those with both parents normotensive formed the control group. Parental history was obtained from the participant and confirmed with the parents, and parental treatment records were checked wherever available. Students with blood pressure of 140/90 mmHg or above, diabetes mellitus, cardiovascular, respiratory, renal, endocrine or neurological disease, those on any regular medication, smokers, alcohol users, trained athletes and those practising yoga or breathing exercises regularly were excluded. Female participants were studied in the follicular phase of the menstrual cycle.

The sample size was calculated to detect a difference in the LF/HF ratio between the groups, assuming an effect size of 0.75 (difference in means divided by the common standard deviation), a two-sided significance level of 5% and a power of 80%. This gave a minimum of 28 participants in each group, which was increased to 30 per group. Participants were selected by simple random sampling from lists of eligible students with and without a parental history of hypertension.

Anthropometry and resting measurements

Height and weight were measured with the participant in light clothing and without shoes, and body mass index was calculated as weight in kilograms divided by the square of height in metres. Waist circumference was measured midway between the lower costal margin and the iliac crest. After 15 minutes of supine rest, blood pressure was measured in the right arm with a mercury sphygmomanometer; the mean of three readings taken 2 minutes apart was used. Mean arterial pressure was calculated as diastolic pressure plus one third of the pulse pressure.

Recording of heart rate variability

Recordings were made between 9 and 11 a.m., at least 2 hours after a light breakfast, in a quiet room at a comfortable temperature. Participants were asked to avoid tea, coffee and strenuous exercise for 12 hours before the test. After 15 minutes of supine rest, a lead II electrocardiogram was recorded for 5 minutes during quiet spontaneous breathing using a computerised data acquisition system, and RR intervals were analysed with heart rate variability software according to the recommendations of the Task Force [12]. Ectopic beats and artefacts were edited manually. Time domain measures were the mean RR interval, the standard deviation of normal-to-normal intervals (SDNN), the root mean square of successive differences (RMSSD) and the percentage of successive intervals differing by more than 50 ms (pNN50). Frequency domain measures were obtained by fast Fourier transformation: total power, low-frequency power (LF, 0.04 to 0.15 Hz), high-frequency power (HF, 0.15 to 0.40 Hz), LF and HF in normalised units (nu) and the LF/HF ratio [25-27]. HF power and RMSSD were taken as indices of vagal modulation, and LF nu and the LF/HF ratio as indices of sympathovagal balance.

Conventional autonomic function tests

The standard battery of cardiovascular autonomic function tests was performed after the heart rate variability recording, with rest between tests [28]. Parasympathetic function was assessed by the heart rate response to deep breathing at six breaths per minute (expiration-inspiration ratio and the difference between maximum and minimum heart rate), the Valsalva ratio (longest RR interval after release divided by the shortest RR interval during a 15-second strain at 40 mmHg), and the 30:15 ratio on standing from the supine position [29,30]. Sympathetic function was assessed by the fall in systolic blood pressure on standing and the rise in diastolic blood pressure during sustained handgrip at 30% of maximum voluntary contraction for up to 4 minutes, measured with a handgrip dynamometer.

Statistical analysis

Data were entered in Microsoft Excel and analysed with Python version 3.13 using the SciPy and statsmodels libraries. Normality was checked with the Shapiro-Wilk test. Continuous variables were expressed as mean ± standard deviation and compared between the two groups with the unpaired t test; because a few variables deviated from normality, the comparisons were confirmed with the Mann-Whitney U test, which gave the same conclusions. Sex distribution was compared with the chi-square test. Controls, subjects with one hypertensive parent and subjects with both parents hypertensive were compared with one-way analysis of variance followed by Tukey's post hoc test. The correlation of the LF/HF ratio with blood pressure and body mass index was assessed with Pearson's correlation coefficient. A p-value below 0.05 was considered significant.

A total of 60 participants were studied, 30 in each group. In the study group, 17 participants had one hypertensive parent (mother in 13, father in 4) and 13 had both parents hypertensive. The two groups were similar in age, sex distribution, height, weight, body mass index and waist circumference. Resting heart rate (70.5 versus 69.7 beats/min, p = 0.588) and systolic blood pressure (p = 0.412) did not differ between the groups. Diastolic blood pressure (74.3 versus 72.0 mmHg, p = 0.074) and mean arterial pressure (88.0 versus 86.1 mmHg, p = 0.051) were slightly higher in the study group, but the differences were not statistically significant (Table 1).

Table 1. Baseline characteristics of the study and control groups

Values are mean ± SD. Study group: one or both parents hypertensive; control group: both parents normotensive. Unpaired t test; chi-square test for sex.

The mean RR interval was similar in the two groups (p = 0.649). In the time domain, SDNN, RMSSD and pNN50 were significantly lower in the study group (p < 0.001 for each). In the frequency domain, total power (p = 0.022) and HF power (p < 0.001) were lower, and LF power was higher (p < 0.001), in the study group. In normalised units, LF nu was higher and HF nu lower in the study group, and the LF/HF ratio was 1.39 ± 0.38 compared with 0.78 ± 0.22 in controls (p < 0.001) (Table 2).

Table 2. Short-term heart rate variability in the study and control groups

Values are mean ± SD. Unpaired t test. SDNN: standard deviation of normal-to-normal intervals; RMSSD: root mean square of successive differences; pNN50: percentage of successive intervals differing by more than 50 ms; VLF: very low frequency; LF: low frequency; HF: high frequency; nu: normalised units.

Among the conventional tests, the expiration-inspiration ratio during deep breathing was significantly lower in the study group (1.27 ± 0.08 versus 1.40 ± 0.07, p < 0.001), although the difference between maximum and minimum heart rate did not differ significantly (p = 0.186). The Valsalva ratio (p = 0.613), the 30:15 ratio (p = 0.302) and the fall in systolic blood pressure on standing (p = 0.486) were similar in the two groups. The rise in diastolic blood pressure during sustained handgrip was significantly greater in the study group (21.5 ± 3.2 versus 17.2 ± 3.1 mmHg, p < 0.001) (Table 3).

Table 3. Conventional cardiovascular autonomic function tests in the study and control groups

Values are mean ± SD. Unpaired t test.

When the participants were grouped by the number of hypertensive parents, there was a graded change in heart rate variability. The LF/HF ratio was 0.78 in controls, 1.23 in those with one hypertensive parent and 1.60 in those with both parents hypertensive (p < 0.001), and on post hoc analysis each group differed significantly from the others (one parent versus both parents, p = 0.003). HF nu, LF nu and the expiration-inspiration ratio showed the same gradient, with significant differences between one and both hypertensive parents. SDNN, RMSSD and the handgrip response differed from controls in both subgroups, but the difference between one and both parents was not significant. Resting heart rate and diastolic blood pressure did not differ significantly across the three groups (Table 4). In all 60 participants, the LF/HF ratio showed a weak positive correlation with mean arterial pressure (r = 0.29, p = 0.025) and with the diastolic response to handgrip (r = 0.48, p < 0.001), but not with diastolic blood pressure (r = 0.21, p = 0.102) or body mass index (r = 0.06, p = 0.649).

Table 4. Heart rate variability and autonomic tests by the number of hypertensive parents

Values are mean ± SD. One-way analysis of variance with Tukey's post hoc test: a, controls versus one parent; b, controls versus both parents; c, one parent versus both parents (p < 0.05).

This study found that normotensive young adults with a parental history of hypertension had markedly reduced heart rate variability, with lower vagal indices (SDNN, RMSSD, pNN50, HF power and HF nu) and a higher LF nu and LF/HF ratio, than age- and body mass index-matched young adults with normotensive parents. They also had a lower expiration-inspiration ratio and a greater diastolic pressor response to sustained handgrip. These changes were present even though resting heart rate and blood pressure did not differ significantly between the groups, and the shift in sympathovagal balance was greatest when both parents were hypertensive.

Our findings agree with earlier studies in offspring of hypertensive parents. Piccirillo and colleagues found reduced vagal modulation and a higher LF/HF ratio in normotensive offspring of hypertensive subjects [17], and similar autonomic abnormalities were reported in young Brazilian and Slovenian subjects with a family history of hypertension [18,19]. In a large Taiwanese population study, a family history of hypertension and prehypertension were each associated with reduced heart rate variability [20]. In Indian studies, offspring of hypertensive parents showed altered cardiovascular responses to exercise [21], and sympathovagal imbalance was greater in prehypertensive offspring of two hypertensive parents than of one [22], consistent with the gradient seen in our study. Sympathovagal imbalance has also been described in young prehypertensives and in hypertensive patients in the Indian population [23,24].

The greater pressor response to handgrip and the higher LF/HF ratio suggest increased sympathetic reactivity, which has been proposed as an early mechanism in the development of essential hypertension [7,8]. Normotensive members of hypertensive families show increased noradrenaline spillover [10] and exaggerated sympathetic activation during mental stress [11]. Unlike some earlier reports, resting heart rate was not raised in our study group [9], and resting blood pressure was only marginally higher. This suggests that altered autonomic modulation and reactivity can be detected before changes in resting heart rate or blood pressure appear. The reduction in RMSSD, HF power and the expiration-inspiration ratio indicates that withdrawal of vagal tone contributes to the imbalance. In contrast, the Valsalva ratio, the 30:15 ratio and the postural blood pressure response were normal, showing that conventional reflex tests are less sensitive than spectral analysis of heart rate variability for detecting these early changes. The weak correlation of the LF/HF ratio with mean arterial pressure further links autonomic imbalance with blood pressure regulation.

The clinical importance of these findings lies in the predictive value of heart rate variability. In the ARIC and Framingham cohorts, reduced heart rate variability preceded and predicted the development of hypertension [14,15], and it is associated with higher blood pressure and with cardiac events [13,16]. Because parental hypertension predicts a faster rise in blood pressure from early adulthood [5,6], short-term heart rate variability, which is simple, non-invasive and inexpensive [12], could help identify young people with a family history who are already showing autonomic imbalance. With the rising burden of hypertension in India [1,3], such individuals could be targeted for lifestyle measures such as regular physical activity, weight control, reduced salt intake and breathing exercises, which have been shown to improve autonomic function [30].

Strengths and limitations

The strengths of this study are the use of both short-term heart rate variability and the standard battery of autonomic function tests, the strict exclusion of factors known to affect autonomic function, and standardised recording conditions. It has limitations. The sample size was small and the participants were medical students, who may not represent the general population. Parental hypertension was based on history and treatment records, and some parents of control participants may have had undiagnosed hypertension. Short-term recordings do not capture circadian variation, and the cross-sectional design does not show whether the autonomic changes predict the later development of hypertension in these individuals.

Normotensive young adults with a parental history of hypertension had reduced vagal modulation, a shift of sympathovagal balance towards sympathetic dominance and an exaggerated pressor response to handgrip, even though their resting heart rate and blood pressure were similar to those of controls. These changes were greatest when both parents were hypertensive. Short-term heart rate variability is more sensitive than conventional reflex tests for detecting these early changes and may help identify young people at risk of hypertension, who can be advised on lifestyle modification and followed up with regular blood pressure monitoring.

1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217-23. PMID: 15652604.
2. Gupta R, al-Odat NA, Gupta VP. Hypertension epidemiology in India: meta-analysis of 50 year prevalence rates and blood pressure trends. J Hum Hypertens. 1996;10(7):465-72. PMID: 8880561.
3. Gupta R. Trends in hypertension epidemiology in India. J Hum Hypertens. 2004;18(2):73-8. PMID: 14730320.
4. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. PMID: 14656957.
5. Hunt SC, Williams RR, Barlow GK. A comparison of positive family history definitions for defining risk of future disease. J Chronic Dis. 1986;39(10):809-21. PMID: 3760109.
6. Wang NY, Young JH, Meoni LA, Ford DE, Erlinger TP, Klag MJ. Blood pressure change and risk of hypertension associated with parental hypertension: the Johns Hopkins Precursors Study. Arch Intern Med. 2008;168(6):643-8. PMID: 18362257.
7. Julius S, Nesbitt S. Sympathetic overactivity in hypertension. A moving target. Am J Hypertens. 1996;9(11):113S-120S. PMID: 8931844.
8. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690-7. PMID: 19720958.
9. Palatini P, Julius S. Heart rate and the cardiovascular risk. J Hypertens. 1997;15(1):3-17. PMID: 9050965.
10. Ferrier C, Cox H, Esler M. Elevated total body noradrenaline spillover in normotensive members of hypertensive families. Clin Sci (Lond). 1993;84(2):225-30. PMID: 8382587.
11. Noll G, Wenzel RR, Schneider M, Oesch V, Binggeli C, Shaw S, et al. Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation. 1996;93(5):866-9. PMID: 8598076.
12. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation. 1996;93(5):1043-65. PMID: 8598068.
13. Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation. 1996;94(11):2850-5. PMID: 8941112.
14. Liao D, Cai J, Barnes RW, Tyroler HA, Rautaharju P, Holme I, et al. Association of cardiac autonomic function and the development of hypertension: the ARIC study. Am J Hypertens. 1996;9(12 Pt 1):1147-56. PMID: 8972884.
15. Singh JP, Larson MG, Tsuji H, Evans JC, O'Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension. 1998;32(2):293-7. PMID: 9719057.
16. Schroeder EB, Liao D, Chambless LE, Prineas RJ, Evans GW, Heiss G. Hypertension, blood pressure, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study. Hypertension. 2003;42(6):1106-11. PMID: 14581296.
17. Piccirillo G, Viola E, Nocco M, Durante M, Tarantini S, Marigliano V. Autonomic modulation of heart rate and blood pressure in normotensive offspring of hypertensive subjects. J Lab Clin Med. 2000;135(2):145-52. PMID: 10695659.
18. Lopes HF, Silva HB, Consolim-Colombo FM, Barreto Filho JA, Riccio GM, Giorgi DM, et al. Autonomic abnormalities demonstrable in young normotensive subjects who are children of hypertensive parents. Braz J Med Biol Res. 2000;33(1):51-4. PMID: 10625874.
19. Maver J, Strucl M, Accetto R. Autonomic nervous system activity in normotensive subjects with a family history of hypertension. Clin Auton Res. 2004;14(6):369-75. PMID: 15666064.
20. Wu JS, Lu FH, Yang YC, Lin TS, Chen JJ, Wu CH, et al. Epidemiological study on the effect of pre-hypertension and family history of hypertension on cardiac autonomic function. J Am Coll Cardiol. 2008;51(19):1896-901. PMID: 18466806.
21. Sowmya R, Maruthy KN, Gupta R. Cardiovascular autonomic responses to whole body isotonic exercise in normotensive healthy young adult males with parental history of hypertension. Indian J Physiol Pharmacol. 2010;54(1):37-44. PMID: 21046918.
22. Pal GK, Pal P, Nanda N, Lalitha V, Dutta TK, Adithan C. Sympathovagal imbalance in prehypertensive offspring of two parents versus one parent hypertensive. Int J Hypertens. 2011;2011:263170. PMID: 22121472.
23. Pal GK, Amudharaj D, Pal P, Saranya K, Lalitha V, Gopinath M, et al. Study of sympathovagal imbalance by spectral analysis of heart rate variability in young prehypertensives. Indian J Physiol Pharmacol. 2011;55(4):357-63. PMID: 23362729.
24. Pal GK, Adithan C, Dutta TK, Amudharaj D, Pal P, Nandan PG, et al. Assessment of sympathovagal imbalance by spectral analysis of heart rate variability in prehypertensive and hypertensive patients in Indian population. Clin Exp Hypertens. 2011;33(7):478-83. PMID: 21978027.
25. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981;213(4504):220-2. PMID: 6166045.
26. Pagani M, Lombardi F, Guzzetti S, Rimoldi O, Furlan R, Pizzinelli P, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res. 1986;59(2):178-93. PMID: 2874900.
27. Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84(2):482-92. PMID: 1860193.
28. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985;8(5):491-8. PMID: 4053936.
29. Wieling W, van Brederode JF, de Rijk LG, Borst C, Dunning AJ. Reflex control of heart rate in normal subjects in relation to age: a data base for cardiac vagal neuropathy. Diabetologia. 1982;22(3):163-6. PMID: 7075917.
30. Pal GK, Velkumary S, Madanmohan. Effect of short-term practice of breathing exercises on autonomic functions in normal human volunteers. Indian J Med Res. 2004;120(2):115-21. PMID: 15347862.