Hypertension, Origin Insistence, and Impulse Variance

Hypertension, Extraction Force, and Pulsation Variability

Dysregulation of the ans has been implicated in the ontogenesis of hypertension. Pulsation variability is a noninvasive cock to quantitatively idea cardiac autonomic action and has been victimised to document rock-bottom cardiac autonomic action in hypertension. The mightiness of decreased beat variability to calculate concomitant hypertension has not been fountainhead studied, and there are no studies of whether hypertension leads to changes in throb variance. We investigated the profane sequence linking hypertension, lineage pressure, and impulse variation in a population-based cohort of 11 061 individuals older 45 to 54 years at baseline. Individuals with hypertension had decreased beat variability at baseline, and this stand was precede across the total line power range. Among 7099 individuals without hypertension at baseline, low pulsation divergence predicted greater risk of sequent hypertension ended 9 eld of brushup. The chance symmetry (95% assurance interval [CI]) for the finish compared with the highest quartile of the mensuration bending of normal-to-normal R-R intervals was 1.24 (95% CI, 1.10–1.40), for the radical misbegot consecutive of sequential differences in normal-to-normal R-R intervals was 1.36 (95% CI, 1.21–1.54), and for R-R interval was 1.44 (95% CI, 1.27–1.63). Concluded 9 eld, there was no mensural expiration in the club of spay in pulsing disagreement among those with and without hypertension, although the differences in beat variability at reassessment were smaller than those at baseline. These findings olibanum reenforcement the thesis that the ans is convolute in the phylogenesis of hypertension, yet point that differences in the autonomic visibleness of hypertensives and normotensives do not increase with time.

Although the pathogenesis of virtually hypertension is unreadable, dysregulation of the ans has been interested in its phylogeny. Heartbeat variation (HRV) has emerged as a practical, noninvasive peckerwood to quantitatively ask cardiac autonomic dysregulation in hypertension. Studies get reported rock-bottom HRV among hypertensives 1–12 and that the coition between derivation from forcefulness and HRV is birth across a encompassing ambit of extraction pressures. 12,13 Entropy from the Framingham cohort and a subset of the Atherosclerosis Endanger in Communities (ARIC) cohort conjure that individuals with decreased HRV gestate an increased gamble of developing hypertension, although results are dissonant crosswise measures of HRV 1,2 and sex. 2 It is too unknown to what mark hypertensives and normotensives experience convertible declines in HRV. Thence, although the ans is snarly in the regularization of blood pressure, the temporal sequence linking hypertension and HRV is unclear. This discipline was designed to wonder this secular succession over 9 years in the integral ARIC cohort.

Discipline Cosmos

The ARIC battleground is a prospective study of the raw history and etiology of atherosclerotic disease and of cardiovascular disease issuance rates, with the workplace existence selected as a hazard try of 15 792 men and women old 45 to 64 years from 4 US communities. The study objectives, innovation, sampling organization, and cohort examination procedures get been described. 14 Eligible participants were interviewed at domicile so invited to a baseline clinical examination ‘between 1987 and 1989. Participants returned for 3 triennial follow-up clinical examinations. Forward each quiz, participants were asked to warm for 12 hours, to refrain from development tobacco, and not to record in vigorous activities. HRV was deliberate at the baseline and 3rd reexamination exams, whereas hypertension situation was assessed at each examination.

The tasting size for the baseline cross-sectional analysis was 11 061. Afterwards upgrade exclusion of individuals with dominant hypertension or without review entropy, the try size for the analysis of consequent hypertension was 7009. The sample size for the analysis of the effect of baseline hypertension on the subsequent convert in HRV was 6931. Enlarge riddance criteria can be embed at http://hyper.ahajournals.org.

Heartbeat Variability

HRV was assessed by 2-minute and 6-minute beat-to-beat pulsing recordings about 9 age obliterate. We focused on 3 HRV measures: the mean normal-to-normal R-R interval continuance, the touchstone diversion of normal-to-normal R-R intervals (SDNN), and the extremist recall squarely of serial differences in normal-to-normal R-R intervals (rMSSD) (beat milliseconds). SDNN reflects sum variance, and rMSSD estimates high-frequency variations in beat and primarily reflects the actions of the parasympathetic. 15 Whereas SDNN and rMSSD mensuration fluctuations in ans action, the mean R-R detachment measures the sum of the levels of parasympathetic and sympathetic influences.

The baseline resting, resistless, 2-minute beat-to-beat R-R detachment data were self-collected and analyzed according to exchangeable protocols and methods. 16–18 At the net brushup examination, 6-minute records were self-contained under similar conditions. 16 Details of the processing of these HRV records can be ground at http://hyper.ahajournals.org. Thirster records were obtained at the concluding follow-up gabfest than the baseline chin-wag to receive more exact HRV estimates. These different lengths resulted in estimates that were not mastermind wish. We hence applied adjustment equations to the 6-minute records by using equations derived from a set of 271 6-minute records from the reappraisal interrogation that were truncated at 2 transactions and reprocessed:

with correlation coefficients between observed 6-minute and 2-minute values of 0.99, 0.90, and 0.94, independently. We did not canvass frequency-domain measures because their functioning in the margin equations was considered unsufferable.

Other Measurements

Sitting blood pressure was mensural 3 times with a random-zero hydrargyrum sphygmomanometer subsequently a 5-minute rest; the average of the expiry 2 readings was victimised. Hypertension was defined as systolic derivation press ≥140 mm Hg, diastolic occupation closet ≥90 mm Hg, or self-reported use of medications for hypertension during the 2 weeks by the clinic examination.

Participants alike brought to the examination all medications they had taken in the preceding 2 weeks. Toughened hypertensives were self-reported users of medications for hypertension and/or those who were fetching medication from leastwise 1 of the pastime music classes: ace (ACE) inhibitors, β-blockers, ca channelise blockers, diuretics, or other antihypertensive medication. Individuals without high-minded bloodline strength who were not self-reported users of medications for hypertension but who brought in 1 of the specific medications mentioned were classified as antihypertensive music users but were besides considered normotensive.

Trained interviewers administered questionnaires that assessed heater report, physical activeness, educational skill, and remembrance. Hummer billet was characterized as menstruation, erstwhile, or ne’er. Instruction was classified as less than high, heights, or greater than eminent. Diabetes was defined as a quick glucose class ≥7.0 mmol/L, a nonfasting level ≥11.1 mmol/L, a self-reported fix diagnosis, or pharmacologic hypoglycemic discourse.

Statistical Analysis: Cross-sectional

Therein cosmos, SDNN and rMSSD were positively skewed. In sparkling of the validity of our statistical models to departures from n unloose sample sizes, we elected not to logarithmically transmute these measures for tranquility of interpretability of the transpose in HRV models. We first measured familiarised center for the HRV measures by hypertension precondition. We too analyzed the tie-up ‘between descent violence and HRV by pooling normotensives and hypertensives and using linear relapse to form the estimated scrap in HRV associated with a 10-mm Hg addition in ancestry closet. Because of a corpse centre fitting by antihypertensive medicine use, models included a consideration for medicine use and a medication-blood force interaction depot. To settle whether line pressure and HRV were associated throughout the line insistency orbit, we fit certified quadratic splines stratified by medicament use, with knots at the 5th, 25, 50th, 72, and Xcii percentiles of the blood force distribution. 19 To compare the relative strengths of the HRV-blood urgent associations, we computed warm correlation coefficients, stratified by antihypertensive medicament use, and familiarized for age, sex, wash, employment center, diabetes, gage, teaching, and bmi (BMI). When indicated, we investigated the issue of exceptional medicine classes by using indicator variables.

Statistical Analysis: Consequent Hypertension

Ensuant hypertension was defined as systolic blood insistence ≥140 mm Hg, diastolic demarcation pressure ≥90 mm Hg, or self-reported use of antihypertensive medications at any of the 3 review examinations among baseline normotensives. We exploited Weibull parametric models for detachment censored data to calibre the riskiness ratio of developing sequent hypertension. The Weibull moulding is an accelerated-failure magazine model and a proportional-hazards modelling. 20 To molding whether the coitus was flatcar, we specified the exposure by victimization forefinger variables for the HRV quartiles, with glare cutpoints of 26.3, 34.8, and 45.9 ms for SDNN; 17.3, 24.6, and 34.9 ms for rMSSD; and 824.5, 904.4, and 988.8 ms for R-R interval. We besides fit models with continuous HRV measures and newspaper these results as the danger ratio associated with a 1-interquartile scope growth in the HRV eyeshade. We examined potency picture revision by sex, diabetes, and BMI by victimization interaction terms.

Statistical Analysis: Limiting in HRV

We defined the mean yearbook permute between baseline and follow-up as review HRV deduction baseline HRV, all divided by the bit of eld ‘between baseline and reexamination. We present the intend annually neuter in HRV, both with and without appointment for baseline HRV.

Analyses that familiarised for baseline HRV were corrected for amount misunderstanding in baseline HRV measures, blood instancy, and continuous endanger factors, aft assuming random intraindividual confident measure outgrowth variations in these variables. Dog a previously described procedure, 21,22 we victimised a relapse standardisation method to chasten for multivariate measuring error. 23 Measurement errors for all baseline independent variables were untrue to be statistically independent, too as those ‘between HRV measurements taken at baseline and followup.

Dependableness coefficients are available from perennial measurements 1 to 2 weeks apart on 63 individuals victimization the ARIC protocol for R-R detachment (0.92), SDNN (0.86), and rMSSD (0.91). On the arse of dependableness coefficients of 0.99 for weight and aggrandizement, we used an hypothesis of 0.95 for BMI. Unpublished results from 190 ARIC participants with repeated measurements 1 to 2 weeks apart during the imprimatur follow-up exam current gave reliability coefficients of 0.75 for systolic pedigree instancy and 0.62 for diastolic ancestry pressure. Statistical analyses were performed with SAS version 8 (SAS Engraft, Inc).

Cross-sectional Findings

Of the 3577 hypertensives at baseline, 72% were hardened with antihypertensive medicament. Further details of the workplace cosmos can be primer in the online-only entropy append (unattached at http://www.hypertensionaha.org).

Oil SDNN, rMSSD, and R-R interval were lour among hypertensives compared with normotensives, and this fight persisted afterward registration for age, sex, race, study essence, diabetes, gage, instruction, and BMI (Tabularise 1 ). Set hypertensives had a higher rMSSD and longer R-R interval than did untreated hypertensives, with no going for SDNN. Treated hypertensives and normotensives had a like rMSSD and R-R interval. Because of the gang of music combinations and voltage self-contradictory by reference, it was laborious to resolve the effects of unlike medications on HRV. Loosely, those victimization β-blockers had HRV subject or greater than that in untreated hypertensives, whereas those victimization diuretics or ACE inhibitors had a scowl HRV (data not shown).

Table 1. Adjusted * Way (95% CIs) for Baseline HRV Measures by Predominant Hypertension Precondition: ARIC Battleground

Higher contrast press was associated with markedly lour HRV in the total cohort (data not shown). There was considerable printing modification by antihypertensive medication use, with stronger associations among individuals not using antihypertensive medications (Table 2 ). The associations accompanied be stronger for diastolic than for systolic lineage hale, as deliberate by warm correlation coefficients (entropy not shown). Splines supported the use of a i analogue terminal in the models and revealed that, if anything, the slope of the HRV-blood urgent tie was steeper at lower ancestry pressures. Too, the associations were charge greater when the analysis was restricted to normotensives (data not shown).

Add-in 2. Estimated Differences * (95% CIs) in HRV Measures for Each 10-mm Hg Step-up in Origin Insistence by Antihypertensive Medicine Use: ARIC Study

Sequent Hypertension

Astern fitting for age, sex, backwash, correction place, hummer, education, and BMI, we observed an turnabout flat congress ‘between HRV at baseline and growing of hypertension (Table 3 ). In models with continuous HRV measures, we name a luck symmetry (95% self-assurance interval [CI]) for a 1-interquartile clasp diminution (20 ms for SDNN, 18 for rMSSD, and 174 ms for R-R detachment) of 1.11 (95% CI, 1.05–1.18) for SDNN, 1.12 (95% CI, 1.06–1.17) for rMSSD, and 1.18 (95% CI, 1.12–1.26) for R-R breakup. We did not support any appreciable interaction with age, sex, or fleshiness, although middling stronger associations were discovered among diabetics than nondiabetics (data not shown).

Tabulate 3. Adjusted * Luck Ratios (95% CIs) of Ensuant Hypertension From Weibull Models Complete 9 Age of Reassessment, by Quartiles of Baseline HRV: ARIC Study

Multifariousness in HRV

Compared with the baseline cross-sectional discernment, individuals who had HRV data at the third reassessment interrogation accompanied be sparingly jr. and were less potency to be black or virile, more likely to be never-smokers, or more super educated, less probably to be diabetic, and to get fairly higher baseline SDNN and R-R detachment (joy see http://hyper.ahajournals.org).

SDNN and rMSSD decreased finish the 9 years of followup enchantment R-R detachment increased (Postpone 4 ). The differences in HRV by baseline hypertensive consideration had decreased well by the review essay. The differences in the valuate of change of HRV between normotensives and all hypertensives were not statistically fraught, yet, with or without alteration for baseline HRV. Treated hypertensives and normotensives had alert interchangeable mean annual changes. Whereas untreated hypertensives had different rates of alter compared with normotensives, the focus was not consistent across HRV measures.

Defer 4. Familiarized * Gist (95% CIs) and Yearbook Designate Changes (95% CIs) of HRV by Baseline Hypertensive Circumstance: ARIC Oeuvre


Not only was rife hypertension associated with decreased HRV but too the association between HRV and ancestry insisting was present across the full lineage pressure range. Individuals with low HRV at baseline were at an increased endangerment of evolution hypertension complete 9 eld of review, thus indicating that decreased HRV oftentimes precedes the development of hypertension. Although there were no measurable differences in the rate of modification in HRV among those with and without hypertension complete 9 eld, the differences in HRV at followup were smaller than those at baseline.

Cross-sectional Findings

As the largest such study to employment, our findings concerning HRV and prevailing hypertension are agreed with old big, population-based 1–3,12 and case-control 4–9 studies. Although there is discrepancy approximately the connector ‘between normalized low-frequency power and hypertension, these studies agree that individuals with predominant hypertension get lower SDNN, lower high-frequency power and low-frequency power in outrank units, and rock-bottom R-R detachment. About of these studies focused on frequency-domain measures, with fewer reporting on rMSSD 2 or SDNN. 1–3,6 We implant compare or higher HRV among users of β-blockers and decreased HRV among users of ACE inhibitors and diuretics. This differs from the findings of the Hoorn and the Framingham studies, which background frown HRV among users of β-blockers (Framingham and Hoorn) and diuretics (Hoorn). 3,24

Recluse 2 studies get examined the tie of HRV with origin press throughout the bloodline press telescope on a continuous or interval denture. One examined systolic and diastolic forcefulness and too flora slenderly stronger associations for diastolic than systolic bloodline crush. 12 In the otc battleground, the association between systolic bloodline effect and SDNN was greatly weakened by leeway for age. 13 Another ferment, small and especial to hypertensives, found lonesome weak associations ‘between descent imperativeness and HRV. 11 Our entropy presentation that the HRV-blood press tie extends to low pipeline pressures and is stronger among lower lineage pressures than among bloodline pressures in the hypertensive range. This decision is signification, because it shows that the connector between line insistence and HRV is continuous, without a marked threshold and with important effects fastened at relatively low blood pressures.

Consequent Hypertension

To our noesis, good 2 studies let examined the congress ‘between HRV and ensuant hypertension. The Framingham battlefield reported the 4-year cumulative incidence of hypertension based on 2-hour HRV records and engraft an connectedness ‘between logarithmically transformed low-frequency power among men fair and no association for SDNN and high-frequency might in either sex. Odds ratios adjusted for baseline blood imperativeness were presented, which mightiness be an overadjustment, because lineage effect is on the causal pathway between HRV and hypertension. 2 In a subset of ARIC records with slenderly different ip, Liao et al 1 reported an increased 3-year cumulative incidence of hypertension by quartile of high-frequency power and SDNN, with no connector for low-frequency power. Our association for SDNN is smaller than that reported by Liao et al, which might be caused by random try error, repel differences in informatics, or unalike review periods.

To value the potency elf of retrogression to the destine, we perennial these analyses with a deject baseline hypertension cutpoint (blood urgent ≥130/85) or a higher sequent hypertension cutpoint (bloodline pressing ≥160/90); this did not appreciably change the results.

Our findings with regard to HRV and attendant hypertension insinuate that ans dysregulation precedes the development of clinical hypertension. This interpretation is supported by the drill of Reaven et al, 25 Palatini and Julius, 26 and Julius and Nesbitt, 27 which posits that dysregulation of the ans is elusive in the ontogeny of clinical hypertension. Reaven et al emphatic the increased benevolent activity, whereas Julius and coworkers described both benevolent overactivity and parasympathetic withdrawal. In fact, sympathetic overactivity could apology many components of the multiple metabolic syndrome, of which hypertension is bazaar one element.

Alter in HRV

Julius and colleagues 27,28 hike clue that, as position of the “blood force-out request property” of the cns, sympathetic timbre will run to decrease later the underdeveloped of hypertension. Law-abiding that many individuals with balmy or moulding hypertension hurt increased cardiac output, normal vascular resistivity, and an increased pulsation, Julius and colleagues hypothesized that drawn-out ancestry personnel heave, increased openhearted activeness, and decreased parasympathetic fulfill lead to a calibration of cardiac product, an increase in vascular hole-and-corner and parasympathetic footprint, and a step-down in eleemosynary shade. This hypothesis thus suggests that the HRV of hypertensives and normotensives would list to encounter with time. Mostly, this is what we discovered in our cohort, although we did not discover any essential differences between hypertensives and normotensives in the scope of alter in HRV.

We familiarise our findings for the change in HRV both unadjusted and adjusted for baseline HRV values because there is argument concerning adjustment for baseline values. When adjusting a convert for the baseline amount, one must adjust for measuring misconduct, alternatively the resulting estimates will be coloured. 22 The unadjusted values compare the alter in HRV enchantment ignoring the picture of baseline HRV, whereas the familiarised values compare the multifariousness in HRV conditional on baseline HRV. Given the correlation between baseline HRV and the form in HRV, roughly estimates are affected by limiting for baseline HRV. Our overall conclusions, nevertheless, are not.

This study used a big, biracial, population-based cohort with 9 eld of review to analyse the coition between HRV and hypertension from many worldly viewpoints. To highlight about weaknesses in our results, we were limited by the different recording lengths at baseline and follow-up. Although our passage equations were pass rightful for time-domain measures, they were inadequate for frequency-domain measures. HRV measurements were operable at troglodyte 2 condemnation points, which extra the types of analyses that we could fulfill. Furthermore, whereas both HRV recordings were taken during the morning, the mean recording dress at the reassessment quiz was around 1 hr soonest than the mean arrangement time at baseline, so HRV circadian rhythms stirred our estimates. Although there was a tidy sum of deficient HRV information, the differences in cardiovascular luck factors ‘between those with HRV s and the totality cohort were nestling. In humanitarian, 2633 individuals did not looking the iii reassessment examination. Complex interference regimens and the possibility of extension solidus made exploring the differences between treated and untreated hypertensives backbreaking. Although we had excellent entropy on hypertension incidence, the continuation of predominant hypertension at baseline was unknown.


Our findings apprise that there is a decline in HRV relatively onetime in the underdeveloped of hypertension, although we did not remark any essential differences in the measure of qualifying in HRV ‘between hypertensives and normotensives o’er 9 age. Our prospective results also prove that decreases in autonomic nervous determination raven the growth of clinical hypertension. These findings are therefore consistent with the hypotheses of Julius and colleagues concerning the “blood instancy pursuance property” of the cns. 27,28 However, autonomic regulation of beat is the resolve of the complex interplay of several factors. By victimization short-term, time-domain HRV measures, we let solitary portion captured cardiac ans number. So, there are aspects of convention and affected autonomic regularization that are not reflected in our results. Furthermore, disposed that extraction force is a complex trait compulsive by the interaction of multiple inherited, environmental, and demographic factors and that involves host autoregulatory responses, it is uncorrectable to moulding to what degree decreases in autonomic unquiet aim are a movement or a backwash of hypertension. Advance studies are required to isolate the respective contributions of openhearted overactivity versus parasympathetic sezession, besides as the contribution of various antihypertensive treatments, on changes in HRV.


This study was supported by House Tinder, Lung, and Descent Launch ARIC grants N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022 and HRV agreement 5-R01-HL-55669. The example for this article was accomplished enchantment the lead-in beginning (E.B.S.) was a predoctoral beau in the Cardiovascular Disease Epidemiology Preparation Diffuse at the University of N Carolina and was supported by NIH cede 5-T32-HL-07055. The authors thank the rung and participants in the ARIC field for their all-important contributions and Drs Dana Loomis and Wayne Rosamond for their review of and comments on ms drafts.

  • Criterion 1000 8, 2003.
  • Retool criterion Haughty 29, 2003.
  • Accepted September 30, 2003.


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