Variability—The Drama of the Circulation

Abstract

J Clin Hypertens (Greenwich).

The two most common vital signs, ie, pulse and blood pressure (BP), are obtained to seek guidance in clinical management of patients in virtually all primary care practices. Even a cursory glance at their values, whether it is within a person over time or between patients on a particular day, reflects an amazing degree of variability. In this brief editorial we provide a focused review of the assessment and the importance of variability in within‐patient heart rate and BP and conclude with a few thoughts about the discordance in significance attached to these ubiquitous clinical measures.

Heart Rate Variability

Heart rate variability (HRV) is a measure of variation in heart rate and it assesses modulation of the autonomic control of heart rate rather than the average level of autonomic inputs. ¹ It has become the conventionally accepted term to describe variations of both heart rate and RR intervals. Other terms used in the literature include “cycle length variability,”“RR variability” (where R is a point corresponding to the peak of the QRS complex of the electrocardiographic wave and RR is the interval between successive Rs), “heart period variability,” and “RR interval tachogram.”

Variations in heart rate are normally observed in association with diurnal rhythms, exercise, stress, respiration (increases with inspiration and decreases with expiration), BP changes, changes in body temperature, and hormonal changes (renin‐angiotensin system). ² The attenuation or lack of HRV is an unhealthy and ominous sign that develops as a result of autonomic dysfunction (ie, increased sympathetic tone and/or decreased vagal tone). It has been reported in association with fetal distress, coronary artery disease, congestive heart failure, sudden death, and diabetes mellitus. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹²

The availability of 24‐hour ambulatory electrocardiographic monitoring (ie, Holter recordings) has provided a unique clinical tool to measure HRV. Calculation of the variations in RR intervals (ie, time domain methods) and/or detailed analysis of the underlying rhythm (ie, frequency domain methods) permit a fairly precise analysis of the ongoing events. ² Time domain methods are easier to perform, free of placebo effect, and are frequently used to evaluate intervention therapies. On the other hand, frequency domain methods are preferable when short‐term recordings are investigated. Both methods are highly correlated. ¹

There are two classes of time domain variables: one is based on the intervals between successive normal QRS complexes (the so‐called normal‐to‐normal [NN] intervals) and the other is based on comparisons of the lengths of adjacent cycles. Measures based on an analysis of the NN intervals include the following: the standard deviation of the NN intervals, HRV triangular index (which is calculated by dividing the number of all NN intervals by the maximum of the density distribution), and the standard deviation of the average NN intervals. ¹ , ² These inter‐beat interval‐based measures are influenced by both short‐term (eg, respiration) and long‐term (eg, circadian) factors and are measured in milliseconds. The root mean square successive difference is a time domain variable based on comparisons of the lengths of adjacent cycles. It is a marker for short‐term components of HRV and primarily reflects vagal tone.

Frequency domain methods are more complex and are primarily used when short‐term recordings are investigated (2–5 minutes). The variables that have been studied include high‐frequency power, low‐frequency power, very low‐frequency power, ultra low‐frequency power, and total power, and they are usually expressed as milliseconds squared or normalized units. For a thorough and in‐depth discussion of these methods as well as their clinical implications, the reader is invited to consult the European Society of Cardiology and the North American Society of Pacing Electrophysiology task force report. ²

HRV analysis is easily applicable in adult medicine, but physiologic influences such as age must be considered. The most important application is the surveillance of postinfarction and diabetic patients to prevent sudden cardiac death (SCD).

Reports from the original Framingham Heart Study cohort and the Framingham Offspring Study indicate that reduced HRV predicts not only increased risk for all‐cause mortality ⁴ but also deaths from coronary heart disease and congestive heart failure. ⁵

HRV is a predictor of long‐term survival after an acute myocardial infarction and has a direct correlation with ejection fraction and exercise capacity and an inverse relationship with left ventricular failure. ³ Patients with decreased HRV have decreased vagal tone or increased sympathetic tone and may have higher risk of ventricular fibrillation. Depressed HRV is a predictor of mortality and arrhythmic complications and is independent of other recognized risk factors. A diminished standard deviation of the NN interval correlates with the degree of left ventricular dysfunction and peak creatine phosphokinase values. ²

While coronary artery disease is the predominant cause of SCD in dialysis patients, reduced HRV may also play a role in the higher risk of SCD in this patient population. ⁷

Autonomic diabetic neuropathy (characterized by degeneration of small sympathetic and parasympathetic small nerve fibers) is a clinical entity associated with a 50% mortality rate at 5 years. ¹¹ Bedside testing (Valsalva maneuver, tilt test) is useful but not sensitive ¹⁰ ; therefore, its early detection (using HRV short‐ and long‐term variability methods) is important for risk stratification and ultimate management.

BP Variability

In considering BP variability, care must be taken to distinguish between diurnal BP phenomena (eg, nighttime dipping) and shorter‐term BP variability (BPVar). Although the focus of this review is on the latter, some discussion of the diurnal BP phenomena is necessary to clarify the metrics used to describe BPVar.

Both diurnal and shorter‐term BP phenomena are measured via 24‐hour BP monitoring. Typically, nighttime dipping is defined as a reduction of mean nighttime BP to levels <90% of mean daytime levels and is associated with favorable cardiovascular prognosis. ¹³ BPVar is most often defined in terms of the standard deviation of BP readings and is associated with adverse cardiovascular outcomes (as discussed below). If one naively considers both BPs—day and night—in calculating the standard deviation, however, some of the “variability” measured will result from nighttime dipping, which will, in turn, bias BPVar outcome associations toward the null. So as to disentangle the effects of BPVar from nighttime dipping, many studies separately calculate daytime and nighttime BPVar and either measure the individual association of each to outcome or combine daytime and nighttime values via time‐weighted average.

Experimental data suggest that BPVar is causally associated with adverse cardiovascular sequelae. In rat models, sinoaortic denervation leads to marked increases in BPVar, with little effect on absolute BP levels. ¹⁴ , ¹⁵ , ¹⁶ Relative to sham‐operated controls, denervated rats demonstrate an increased propensity toward developing biventricular hypertrophy, ¹⁴ atherosclerosis, ¹⁵ , ¹⁶ structural damage of the heart and kidneys, ¹⁷ and adverse arterial remodeling. ¹⁸ Evidence suggests that BPVar may induce cardiovascular disease via promotion of endothelial cell damage, tissue renin‐angiotensin activation, inflammation, and/or cardiac myocyte apoptosis. ¹⁹

Human data suggest that increased BPVar is associated with cardiovascular disease. Observational studies demonstrate that patients with greater baseline BPVar experience greater rates of cardiovascular morbid events, ²⁰ stroke, ²¹ and progression of carotid intima to medial wall thickness, ²⁰ target organ damage scores, ²² and left ventricular hypertrophy. ²³ It is important to note that each of these studies was conducted in convenience samples of patients (typically from hypertension referral clinics), questioning the generalizability to the general population. In addition, each study considered surrogate end points. Therefore, the best evidence to date regarding the adverse sequelae of BPVar come from two longitudinal, population‐based studies. Among a random sample of 1542 people from Ohasama, Japan, incrementally greater standard deviation of systolic (and diastolic) BP was potently and independently associated with greater cardiovascular mortality over a mean follow‐up of 8.5 years. ²⁴ Similarly, among a random sample of 2012 people from Monza, Italy, greater diastolic BPVar (albeit defined by a more complex metric based on spectral analysis) was independently associated with greater cardiovascular and all‐cause mortality during a 148‐month follow‐up period. ²⁵ To date, no randomized controlled trials have been conducted, in part due to our limited ability to selectively manipulate BPVar independently of BP level. Thus, although these data are suggestive, no definitive proof exists that causally link BPVar to the development of cardiovascular disease.

Recently, studies have begun to examine the association between BPVar and cardiovascular disease among hemodialysis patients. Dialysis patients are of particular interest given the heightened amplitudes of their BP fluctuations and their excessive rates of cardiovascular morbidity and mortality. Preliminary data suggest that increased BPVar is associated with greater all‐cause and cardiovascular mortality. ²⁶ , ²⁷ More data are needed to better delineate the role of BPVar in promoting cardiovascular disease in this population. Future studies should be mindful that the degree of BPVar observed during and between dialysis may be different and may bear different prognostic significance. Moreover, further complexities imposed by the intermittent nature of hemodialysis (eg, that BP falls during the course of dialysis may be beneficial) ²⁸ , ²⁹ need be considered.

Beyond cardiovascular disease, preliminary data suggest that greater BPVar is associated with disease in other organ systems. For example, in a cross‐sectional study of 803 hypertensive patients, greater systolic BPVar was associated with the presence of chronic kidney disease (defined as an estimated glomerular filtration rate of <.60 mL/min/1.73 m²). ³⁰ The complex interplay between renal and cardiovascular pathophysiology and the cross‐sectional nature of this study, however, leaves in doubt the direction of causality. Further, longitudinal studies are needed to clarify the role of BPVar and noncardiovascular outcomes.

Summary

How do we reconcile these discordant observations? In an era that increasingly emphasizes biochemistry, imaging, and genetics, it is progressively challenging to think in a (patho)physiologic manner. A reduction in HRV is an ominous portent because of the physiologic need of frequent heart rate adjustments to deal with issues such as stress, volume challenges, position changes, and meals. Since there is a relatively narrow range in cardiac stroke volume, adjusting the heart rate turns up or down the cardiac output in response to physiologic demands. The loss of such an adaptation points to diseases that suppress or ablate autonomic balance, such as diabetes, and serves as one of several key indicators revealing the severity of underlying disease. In the case of BP, the goal of the circulation is to maintain steady blood flow by protecting the mean arterial pressure through adapting the systemic vascular resistance to the fluctuations in cardiac output. The loss of this adaptation, which increases BP variability, occurs as a result of stiffening of the vessels from age, diabetes, kidney disease, hypertension, environmental exposures, and also from similar kinds of autonomic imbalance as noted for reduced HRV. So, like the drama masks above, there is both good and bad in variability when it comes to the primary vital signs of the circulation. Vive le difference!