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Psychosomatic Medicine 65:46-62 (2003)
© 2003 American Psychosomatic Society

REACTIVITY SPECIAL SECTION

Cardiovascular Reactivity and Development of Preclinical and Clinical Disease States

Frank A. Treiber, PhD, Thomas Kamarck, PhD, Neil Schneiderman, PhD, David Sheffield, PhD, Gaston Kapuku, MD, PhD and Teletia Taylor, PhD

From the Departments of Pediatrics and Psychiatry, Georgia Prevention Institute, Medical College of Georgia (F.A.T., G.K.), Augusta, Georgia; Department of Psychology, University of Pittsburgh (T.K., T.T.), Pittsburgh, Pennsylvania; Department of Psychology, University of Miami (N.S.), Miami, Florida; and Research Services, Veterans Administration Medical Center (D.S.), Gainesville, Florida.

Address reprint requests to: Frank Treiber, Medical College of Georgia, Georgia Prevention Institute, Bldg. HS1640, Augusta, GA 30912. Email: ftreiber{at}mail.mcg.edu

ABSTRACT

OBJECTIVE: The objective of this review is to evaluate the evidence for the hypothesis that cardiovascular reactivity can predict the development of preclinical (elevated blood pressure, ventricular remodeling, carotid atherosclerosis) and/or clinical cardiovascular disease states.

METHODS: A review of the literature was conducted examining prospective studies.

RESULTS: Three large epidemiological studies with long-term follow-up periods (20 years or more) have found blood pressure responses to the cold pressor task to be predictive of subsequent essential hypertension in initially normotensive samples. Studies showing less consistent results have tended to use shorter-term follow-up periods. A larger body of literature demonstrates consistent associations between stress-related cardiovascular reactivity and blood pressure elevations in youth over the course of 1 to 6 years; such relationships have not been consistently shown among adult samples. Moderately consistent evidence points to a positive relationship between reactivity and other measures of subclinical disease (increased left ventricular mass and carotid atherosclerosis) among the few prospective studies that have examined these issues to date. A number of additional factors, however, such as baseline levels of disease risk and exposure to psychosocial stress, seem to moderate these relationships. Health status at baseline also seems to moderate the association between reactivity and clinical coronary heart disease in recent reports: two of three existing studies in initially healthy samples show no evidence of a relationship between reactivity and clinical outcomes, whereas three of four studies in samples with preexisting coronary heart disease or essential hypertension show a positive relationship between reactivity and subsequent disease states.

CONCLUSIONS: There is reasonable evidence to suggest that cardiovascular reactivity can predict the development of some preclinical states (eg, increased left ventricular mass and blood pressure) states and perhaps even new clinical events in some patients with essential hypertension or coronary heart disease. However, much more information is needed concerning moderating and potentially confounding variables before the robustness of the positive relationships can become clinically useful.

Key Words: cardiovascular reactivity • prediction • essential hypertension • cardiovascular disease • preclinical disease • left ventricular mass.

Abbreviations: BMI = body mass index; BP = blood pressure; CHD = coronary heart disease; CPT = cold pressor task; CV = cardiovascular; CVD = cardiovascular disease; CVR = cardiovascular reactivity; DBP = diastolic blood pressure; EH = essential hypertension; HR = heart rate; LVM = left ventricular mass; MI = myocardial infarction; SBP = systolic blood pressure.

Despite recent declines over the past several decades, CVD continues to be the leading cause of death in adults in the United States, accounting for almost 950,000 deaths annually, more than 40% of all deaths (1). Necropsy studies have established that the pathogenesis of CVD has its origins in childhood (eg, Refs. 2–5). Although clinical manifestations of CVD are not generally apparent until late middle age, recent advances in noninvasive medical technology allow us to evaluate preclinical manifestations of CVD, permitting researchers to examine correlates of CVD before the development of frank disease.

Because only about 50% of the variance of new CVD cases can be predicted by classic risk factors, including family history, obesity, smoking, diabetes mellitus, and hypercholesteremia (6), much effort has been devoted to the identification of other potential risk factors. CVR, defined as the magnitude or pattern of an individual’s hemodynamic responses to behavioral stressors, has been identified as potentially playing a role in the development of CVD. In the earlier articles in this series, we have discussed some of the evidence bearing on the reliability of CVR, as well as its association with a variety of demographic and psychosocial factors (7). In brief, recent studies have indicated that behaviorally evoked CVR is a relatively stable individual difference characteristic, relatively consistent across time and moderately stable across stressors varying in the type of underlying response system elicited (eg, cardiac vs. vascular; active vs. passive) (8).

The "reactivity hypothesis" posits that CVR may play a role as a marker or mechanism in the pathogenesis of CVD (9). The objective of this review is to describe prospective work that has examined the role of CVR to behavioral or psychological stressors in the prediction of 1) sustained increases in BP and/or development of EH; (b) development of preclinical disease states, including ventricular remodeling and carotid atherosclerosis; and (c) clinical CVD or its progression.

Our emphasis on prospective rather than cross-sectional correlational studies in this review reflects our recognition that the association between CVR and CVD is potentially bidirectional. Prospective designs, especially those that examine changes in disease status or covary for initial levels of disease, are more easily interpreted insofar as they allow us to minimize the influence of preexisting disease on stress-related reactivity as an explanation for any associations observed. Of course, even prospective correlational studies cannot demonstrate causality and must be interpreted in light of their ability to rule out potential confounds. It is important to keep this point in mind when considering the implications of this work.

Several prospective studies have demonstrated that excessive BP responses to dynamic exercise may be a risk marker for future EH and CVD-related mortality (10). The present review, however, restricts its focus to those studies examining CVR to psychological demands (7).

PREDICTION OF PRECLINICAL CVD STATES IN HEALTHY INDIVIDUALS

The pathogenesis of CVD follows a relatively consistent progression (11–13). Devereux and colleagues (14–16) have coined the term "preclinical disease states" to describe pathogenic changes in CV structure or function that, if continued, will often progress to overt manifestations of CVD, including MI and stroke. During the past 10 years, an increasing number of reports have examined the association between acute CVR to laboratory stimuli on one hand and longitudinal changes in noninvasive measures of preclinical CVD on the other.

There are several advantages to the use of noninvasive preclinical measures in studies of CVD risk. First, in contrast with the use of invasive measures such as angiography, the use of noninvasive preclinical measures of CVD involves little risk; thus these assessments can be obtained in general population samples. Second, in contrast to investigations of disease end points, which may require large samples followed over decades, preclinical measures, examining the gradual progression of underlying disease processes over time, may allow us to observe significant effects in relatively small samples using a shorter duration of follow-up. Third, because the study of preclinical measures facilitates the use of healthy rather than diseased samples, some of the potential confounds associated with the study of disease (eg, the effects of knowledge of disease diagnosis on behavior, the effects of the disease or risk factor treatment on stress or stress responding) are reduced.

In this review we examine studies that included one of three types of preclinical measures. First, we cover those reports that have examined the relationship between reactivity and resting BP. When BP is at issue, EH, typically defined as a SBP exceeding 140 mm Hg and/or a DBP exceeding 90 mm Hg (17), is the typical target of treatment. Therefore, hypertensive status is the outcome measure of greatest interest in epidemiological reports. Measures of resting BP assessed on a continuous scale can also be informative, however, because even within the normotensive range, increased resting BP is a major independent risk factor for future EH and CHD (18–20). The processes by which exaggerated CVR has been posited to contribute to EH (eg, vascular remodeling and autoregulatory processes) (21, 22) should also be expected to affect resting BP in the normotensive range. Increases in resting BP over time, then, may constitute an important preclinical measure of CVD risk for the purpose of this review.

A second preclinical measure that is covered in this report involves the assessment of increased LVM. Left ventricular hypertrophy has been identified as a significant independent risk factor for CV morbidity, including MI, arrhythmia, congestive heart failure, and mortality (23–29). The risk conferred by enlarged LVM is independent of traditional CV risk factors (30) and of other measures of CVD, such as number of diseased vessels or ventricular function (31). Although this condition is important prognostically, its determinants are only beginning to be understood. In addition to the effects of resting BP and anthropometric factors (eg, height and body mass), a variety of hemodynamic and neuroendocrine factors that may be influenced by psychosocial stress have been shown to alter the development of LVM. These types of influences might be expected to be more prevalent among those who show a typical pattern of exaggerated hemodynamic responding during psychological stress.

A third measure of preclinical disease to be examined involves ultrasound assessments of plaque or wall thickness in the carotid arteries. Such measures have been shown to be moderately associated with atherosclerosis in other vessel beds (32, 33); these measures have been prospectively associated with the risk for CV events (eg, MI, sudden cardiac death) as well, even in community samples (34–38). Nonhuman primate models suggest that exaggerated CVR may be associated with increased risk for atherosclerosis in the coronary as well as the carotid arteries (39). To the extent that carotid ultrasonography can be used to assess early stages of atherosclerosis, we should expect that these measures might be associated with exaggerated reactivity in humans as well.

STUDY SELECTION CRITERIA

Studies selected for this review had to meet several criteria: 1) they had to have been published in an English-language journal, 2) they had to use a behavioral or psychological stressor and measure HR or BP responses to that stressor, 3) they had to have an average of at least 1 year between baseline and final assessments, and 4) they had to report the results of an inferential statistical analysis. As noted above, we gave greater weight to studies that controlled for the baseline level of the outcome variable in the analysis.

PREDICTION OF FUTURE BP LEVELS

There have been three studies using CVR to the CPT that examined the prediction of EH over periods of 20 years or longer. In the first study, Wood et al. (40) administered the CPT to 300 normotensive 7- to 17-year-olds in 1934 and again to a subset of the sample (N = 151) in 1961. EH diagnoses were available in 1979 for 94% of the sample that had been tested on both occasions. Those who showed SBP responses >=25 mm Hg or DBP responses >=20 mm Hg on one or both occasions (10% of the sample) were much more likely to have developed EH than those whose BP responses were below the cutoffs on both occasions (71% vs. 19%). In the second study (41), the CPT was given to 910 European American male medical students (mean age, 23 years) whose subsequent EH status was ascertained by annual questionnaires 20 to 36 years later. Menkes et al. (41) found that SBP reactivity predicted EH after adjustment for age at study entry, obesity, resting SBP, cigarette smoking, and parental history of EH before 65 years of age. The excess risk associated with SBP reactivity was not apparent until the study sample aged some 20 years and was most apparent among those in whom EH developed before 45 years of age.

In a third study (42), Kasagi et al. administered the hand CPT to 824 normotensive Japanese men. Over a 28-year follow-up, those whose BP had increased 20 mm Hg or more were more likely to have developed EH. This was particularly the case among subjects older than 40 at baseline. Similar findings were observed after controlling for attained age, BMI, and resting BP at baseline.

Several studies have examined adults over a shorter period of time and have also found that CVR in the laboratory successfully predicted subsequent BP levels. These studies are noteworthy because they used psychological challenges other than CPT or in addition to CPT, suggesting that the relationships observed may not be limited to a specific eliciting stimulus.

For example, Markovitz et al. (43) reported on the 3364 men and women enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study (ages 19–31 years; mean age, 27), who underwent a three-task reactivity protocol (CPT, video game, and mirror star-tracing challenges) and were followed for 5 years. The major positive finding of the study was that SBP reactivity to the video game was associated with SBP increases over the 5-year period. Subsequent analyses showed that the relationship held for men but not for women. Reactivity to CPT and the mirror tracing task, on the other hand, did not predict significant BP change.

Everson et al. (44) conducted a 4-year follow-up on a Finnish cohort of 508 initially normotensive men. They found that exaggerated BP reactivity in anticipation of a bicycle exercise challenge predicted hypertension status (ie, >=165/95 mm Hg) at follow-up. These findings remained after controlling for a variety of risk factors (eg, age, adiposity, alcohol use, smoking, and physical activity level).

Borderline hypertensives have been the subjects for a few of the CVR studies predicting future BP levels or EH status. For example, in one study of borderline hypertensives, those who exhibited an exaggerated DBP response to mental arithmetic and increased BP recovery time after the task were significantly more likely to develop EH 5 years later (45). In a 10-year follow-up study of 70 borderline hypertensives, Borghi et al. (46) found that CVR to mental arithmetic was a significant predictor of those who later developed EH. In a study of 46 borderline hypertensive adolescents, Falkner et al. (47) also suggested that CVR to mental arithmetic was predictive of those who later developed EH during a follow-up period of up to 41 months.

Matthews et al. (48) subjected 182 middle-aged adults as well as their 154 school-aged children to two psychological stressors (serial subtraction and mirror-image tracing). Their findings indicated that CVR in men, women, and boys reliably predicted subsequent BP levels 6.5 years later even after statistically controlling for age, obesity, and resting BP at study entry.

In addition to these positive findings, there are a number of prospective studies in adults that have not found strong evidence of the unique predictive value of CVR (eg, Refs. 49 and 50). For example, as part of a 4.9-year prospective study, Carroll et al. (50) evaluated responses to a problem-solving task (Raven’s matrices) at baseline in 1003 men who were aged 35 to 55 years (mean = 44) at entry into the study; men who had already developed EH (ie, 6%) were excluded. Although pressor reactions to the behavioral task correlated significantly with follow-up BP (r = 0.22), the independent predictive value was minimal (R2 increase = 0.01) after controlling for baseline BP and other variables. The results were similar for the subset (N = 796) followed up at 10.8 years (51). In a different cohort followed up 5 years later, similar results for the CPT were observed (52).

With regard to youth, 10 additional studies, besides those of Wood et al. (40) and Matthews et al. (48) mentioned above, have assessed associations between stressor-related BP reactivity and subsequent BP elevations in normotensive children and adolescents (see Table 1) using CPT (53–55) and a variety of purely psychological challenges (eg, video games, serial subtraction, mirror-tracing, reaction time) to predict subsequent BP levels (54, 56–63). In brief, all 10 studies reported positive results. For example, Murphy et al. (63) measured BP reactivity to a video game challenge in 292 European American and 46 African American third graders to predict resting BP levels 4 years later. Regression analyses indicated that among African American children, DBP and SBP responsivity to the video game were stronger predictors of BP levels 4 years later than was resting BP at study entry. In contrast, among European American children, resting BP at study entry was the best predictor of BP level 4 years later. Video game BP responsivity enhanced the prediction of subsequent SBP but not DBP. In summary, when resting BP, resting HR, obesity, and age were entered as the first four variables in regression models, the video game BP responses continued to be significant predictors of subsequent BP in both European American and African American children.


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  		TABLE 1. Summary of Univariate and Multivariate Findings of Longitudinal CVR Studies
 

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More recently, Treiber et al. (54, 55, 60, 61, 64) reported a series of findings on a longitudinal study of African American and European American children (6–16 years old at study onset) having family histories of EH. After controlling for ethnicity, gender, anthropometrics (eg, height, weight, adiposity), and initial resting BP levels, the investigators found that SBP and DBP responses to a video game challenge and forehead CPT each predicted resting SBP and DBP at both 1 and 5 years of follow-up. The most comprehensive study in this series examined 385 normotensive youths (mean age, 12.7 years at baseline) who had been evaluated annually on four occasions after the initial baseline visit. Aggregated measures of SBP and DBP reactivity to a battery of stressors (ie, video game, social competence interview, parent-child conflict discussion, postural change) were assessed at baseline. Separate prediction models for each year were derived from stepwise hierarchical block regressions and applied to all other years. The most generalizable model revealed that SBP and DBP reactivity accounted for 2% to 6% and 1% to 4% additional variance, respectively, after accounting for significant contributions of traditional risk factors, including ethnicity (African Americans > European Americans), gender (males > females), family history of CVD, anthropometrics (increased waist-to-hip ratio, height, weight, BMI), and initial baseline BP levels. It should be noted that a higher proportion of the BP variance (4% to 56%) was accounted for by CVR within the various prediction models. In summary, it seems that CVR is a consistent independent predictor of future hypertensive status when long-term (ie, >=20 years) follow-ups are conducted. CVR is also predictive of future BP levels 1 to 6 years later, but its predictive value is sometimes limited when adjustments are made for baseline BP and other variables known to be related to BP (eg, weight, adiposity, gender, ethnicity).

PREDICTION OF LVM

As noted earlier, although increased LVM is the strongest predictor of CVD morbidity and mortality other than advancing age, only a few longitudinal studies have examined the possible predictive role of CVR on LVM. Georgiades et al. (65) investigated CVR as a predictor of 3-year changes in LVM in a sample of 66 middle-aged, borderline hypertensive men. BP and HR reactivity scores were aggregated on the basis of responses to mental arithmetic and isometric muscle contraction tasks. After adjusting for initial LVM, mean arterial pressure reactivity accounted for 15% of the variance in LVM change. This is the only study, to date, that has examined measures of CVR as predictors of LVM change in an adult sample.

A few studies have been conducted using CVR to predict cardiac structure among children and adolescents. One by Murdison et al. (66) examined a comprehensive set of demographic, anthropometric, and CV predictors of LVM with data collected an average of 2.6 years earlier in a sample of 30 European American and 56 African American normotensive youths with family histories of EH (mean age, 12.6 ± 2.3 years at initial visit). An aggregate index of mean arterial pressure responsivity to a battery of laboratory stressors (ie, parent-child conflict discussion, social stressor interview, video game challenge, and postural change) was a significant predictor of LVM/height2.7 and left ventricular hypertrophy at follow-up. These findings held after adjusting for a variety of significant covariates, including initial LVM/height2.7, weight, and ethnicity (African Americans > European Americans).

Recently Kapuku et al. (67) examined predictors of future LVM in a cohort of 71 European Americans and 75 African American normotensive adolescents. Subjects were initially an average of 14.2 ± 1.8 years of age and evaluated on two occasions separated by an average of 2.3 years. SBP reactivity to a virtual reality car-driving simulation was a significant independent predictor of LVM/body surface area at follow-up even after adjustment for the significant contributions of initial LVM/body surface area, weight, gender (males > females), and baseline resting total peripheral resistance. However, responses to a video game and cold pressor stimulus were not significant independent predictors. These associations were not consistent when a measure of height-adjusted LVM was used.

Papavassiliou et al. (68) included the CPT in a battery of stressors (ie, postural change, treadmill exercise, CPT) in the prediction of LVM 3.6 years later in a sample of 46 European American and 22 African American children (7.9 ± 0.7 years at baseline). Controlling for significant covariates (eg, baseline weight), CVR to the CPT did not contribute to the prediction of LVM. Measures of LVM were not collected at baseline, so investigators were unable to assess the contribution of reactivity to changes in LVM over time.

In sum, three of four recent prospective studies have demonstrated some significant associations between measures of BP and changes in LVM. The one study in this group that did not show a significant association was distinguished by the absence of baseline measures of LVM, hindering its ability to assess longitudinal change. Although this literature shows reasonably consistent results, it should be noted that a number of the comparisons examined were not significant across tasks or measures. The types of task characteristics and response measures that might be expected to be most strongly associated with LVM progression are currently unknown.

PREDICTION OF CAROTID ATHEROSCLEROSIS

Four longitudinal studies have examined the relationship between reactivity and carotid atherosclerosis in three independent samples (69–72); all have reported some positive results, although the patterns of the findings have been quite varied (see Table 1).

In the first published prospective study in this area, Barnett et al. (69) assessed the relationship between CVR and 2-year progression of carotid plaque in a heterogeneous sample (194 men with an average age of 48 years and 157 women with an average age of 53 years at follow-up). A portion of this sample (N = 170) had been referred to an atherosclerosis prevention clinic for treatment of symptoms or risk factors associated with CVD, and another portion (N = 181) were apparently healthy volunteers. Both medicated and unmedicated individuals were studied; those on medication affecting CV function were asked to refrain from medication use for 24 hours before participating in the study. CVR was assessed using the Stroop Color Word Interference Task, with task-related responses residualized on baseline measures. Measures of plaque area were assessed from B-mode images in the right and left common, external, and internal carotid arteries. Among the unmedicated subgroup (N = 136), SBP reactivity accounted for an additional 7% variance of the change in plaque area after adjustment for age, baseline BP, and other risk factors. DBP and HR reactivity were not significantly associated with disease progression in the multivariate analyses.

Recently Matthews et al. (70) followed a group of healthy middle-aged women (N = 238) who had been administered two behavioral stressors (ie, public speaking, mirror-image tracing) as part of a baseline evaluation approximately 2 years before collection of ultrasound measures of carotid disease (mean age at follow-up, 57.6 years). Although task-averaged SBP or DBP responsivity was not associated with later evidence of carotid disease, stress-related change in pulse pressure (increases in the magnitude between SBP and DBP during task responding) was significantly associated with future carotid plaque thickness after controlling for resting pulse pressure, age, smoking, and triglyceride levels. Pulse pressure at rest can be used to index the reduced arterial distensibility that occurs with aging and disease (71). It is possible that task-related pulse pressure change is also an index of arterial changes. This study is important because of its use of a healthy female sample. Because measures of carotid plaque were not available at baseline, however, reverse causality (differences in disease contributing to differences in reactivity) cannot be ruled out.

Two recent prospective studies from the Kuopio Ischemic Heart Disease Risk Factor study evaluated the contributions of a novel measure of CVR to predict progression of carotid artery disease (72, 73). SBP changes were assessed while participants were seated in anticipation of bicycle exercise (compared with resting clinic measures) as an index of CVR to mental stress. Each study included assessment of moderating factors, environmental influences that might be expected to enhance the hypothesized effects of reactivity on disease progression. Everson et al. (72) showed that there was a significant interaction between SBP reactivity and job demands across three different measures of carotid disease progression (changes in mean intima-media thickness, maximum intima-media thickness, and plaque height) in the sample (N = 591 employed men with complete data), with the high demands/high reactor group showing the greatest degree of 4-year disease progression in each case. The pattern of effects was observed even among those men without prevalent ischemic heart disease; however, the strongest effects were observed among the portion of the sample with some evidence of carotid thickening at baseline.

A similar interaction between reactivity and socioeconomic status was reported by Lynch et al. (73) in this sample, such that greater 4-year progression of carotid disease was observed among those who were both high reactors and low in socioeconomic status (N = 882 men with complete data on measures used). Although there is some debate about the interaction findings (see Ref. 74), a reanalysis of the data found CVR predictive of the development of carotid atherosclerosis (75).

In summary, published studies from three longitudinal samples are broadly consistent with the proposition that exaggerated BP reactivity may be predictive of the development of carotid atherosclerosis. Two of these samples include measures of longitudinal change in disease, and both have involved participants at high risk for CVD, raising the possibility that preexisting clinical or subclinical disease may moderate the observed relationship between reactivity and CVD progression.

PREDICTION OF CLINICAL CHD OR ITS PROGRESSION

The evidence to date linking exaggerated reactivity with subclinical disease is of greatest significance to the extent that such findings can inform us about risk for clinical events. Seven published studies have examined the relationship between reactivity and clinical end points; three of these have examined community samples, and four have examined patients with preexisting disease.

One of the earliest studies in this literature, by Keys et al. (76), examined BP responses to the cold pressor in 279 healthy middle-aged (45–55 years old) men as a predictor of the development of CHD over a 20-year follow-up. The investigators used a cutoff point of 20 mm Hg change in DBP as an index of exaggerated task-related reactivity. Those who met this criterion were 2.4 times more likely to experience a MI or die of CHD-related causes than those who were less physiologically reactive to the task. A second prospective study by Coresh et al. (77), using a larger (N = 905) sample of male European American medical students (19–35 years of age) failed to replicate this finding, showing that neither SBP nor DBP reactivity to the cold pressor was predictive of cardiovascular morbidity or mortality over a follow-up period of 2 to 42 years.

Recently Carroll et al. (78) also reported negative findings in a large (N = 1493) sample of older men (average age, 56.8 years). Their data showed that BP responses to the CPT were unrelated to 9-year incidence of CVD events or mortality. Failure to replicate the Keys et al. (76) findings in the context of these two larger cohorts raises questions about the generalizability of the results. Alternatively, it should be noted that all of these studies were conducted in healthy samples, groups of individuals for whom the power to detect clinical CHD events (eg, MI) may be generally quite low.

In contrast to some of the above findings, results from recent prospective investigations examining the prognostic relevance of reactivity in patients with preexisting EH or CHD were positive. Manuck et al. (79) examined the prognostic value of CVR to the Stroop Color Word task among a small (N = 13) group of post-MI patients (10 men, 3 women). During a mean follow-up of 57 months (range, 39–64 months), five patients developed a clinical event (subsequent stroke or recurrent MI). The patients who suffered subsequent events had shown significantly larger SBP and DBP responses to the Stroop task during initial testing than the eight event-free subjects.

Alderman et al. (80) examined the prognostic value of CVR among a large (N = 1737) group of previously untreated patients with elevated BP selected from a worksite-based EH control program. This study used an unusual method for measuring CVR: BP changes were examined across two different BP assessment sessions 1 week apart. The first was performed by an RN, the second by an MD. Over the 14-year follow-up (during which time BP treatment was initiated across the sample), those in the highest tertile of CVR (ie, MD-obtained DBP - RN-obtained DBP = CVR) were more than twice as likely to suffer a MI as compared with the remainder of the sample. The assumption of the study was that BP assessment by an MD was more stressful than by an RN and that the difference between the two readings is a measure of CVR.

In a study of 90 CHD patients, Krantz et al. (81) examined the prognostic significance of CV and ischemic changes during mental arithmetic and a public speaking task. Over a median duration of 3.5 years, 35% of the sample experienced new cardiac events. Subjects with a peak DBP response in the highest third of the distribution on either one of the two stressors showed a higher probability of demonstrating new events when compared with the remainder of the sample (50% vs. 28% of these groups showing new events, respectively). There were no significant associations with SBP or HR reactivity.

Although three recent studies in patient samples have shown significant associations between reactivity and clinical events, one such study has not replicated these results. Ahern et al. (82) examined the relationship between CVR to a video game task and 1-year cardiac mortality or cardiac arrest in a group of 340 post-MI patients enrolled in a randomized multicenter study for the treatment of arrhythmia. Interestingly, HR reactivity was inversely associated with mortality in this sample, with the survivors showing significantly larger heart rate responses to the video task compared with those who subsequently had a cardiac arrest or died during the follow-up period. Although the reasons for such discrepant results are not clear, it is possible that nonsurvivors either disengaged from the potential stressor or were less able to provide an optimal physiological response. This could be because of an already compromised heart or because of ß-receptor downregulation due to a high level of sympathetic nervous system stimulation. It should be noted that some of the previous studies that have shown positive associations between stress-related BP responding and subclinical measures (69, 83) have also found trends suggesting inverse relationships between HR reactivity and disease among high-risk samples.

In conclusion, the evidence linking reactivity with clinical events in healthy samples is scanty, although most of the recent studies examining the association between CVR and new clinical events in samples with preexisting EH or CHD do point to significant relationships between BP reactivity and increased risk.

DISCUSSION

Despite inconsistencies in the literature, there now exists a small and growing body of evidence linking CVR with measures of subclinical and clinical CVD. Increased emphasis is needed in this literature on statistical power requirements, measurement standardization, and investigation of mechanisms and moderating factors that may influence these associations.

The three large epidemiological studies that initially enrolled large cohorts of normotensive subjects and followed them for at least 20 or more years have provided reasonable evidence that the extent of BP response to CPT may portend an increased risk for development of EH (40, 41, 84). The studies by Borghi et al. (45) and Falkner et al. (47) suggest that reactivity in young borderline hypertensive subjects can be used to predict stable EH several years later. Findings from a number of large-scale studies that have documented relationships between reactivity to behavioral tasks and subsequent resting BP levels have shown generally positive results. Among the issues that need to be resolved is the extent to which demographic factors, methodological differences, and disease characteristics in the sample may influence the observed results. Thus far, tasks as diverse as CPT, serial subtraction, social competence interview, mirror-image tracing, and video games have been used as CVR challenges that predict subsequent increase in resting BP level (43, 45, 48, 61, 63). Furthermore, the results from a variety of studies indicate that the relationship between CVR and subsequent resting BP level can be documented based on responses to challenge in children (61, 63), adolescents (48), young adults (43), and middle-aged individuals (48). The studies of exaggerated reactivity as a predictor of BP elevations in youth are particularly interesting. All 10 reports (see Table 1) showed associations between stressor-related BP reactivity and BP elevations 1 to 6 years later, and some of the investigations showed an impressive degree of internal replication across tasks and time.

With respect to left ventricular morphology, the literature on reactivity as a predictor of longitudinal changes in LVM is sparse at this time. Only four longitudinal studies have been conducted, and all but one (65) involved pediatric samples (66–68). Findings were promising across these studies, but there is clearly a need for further prospective research in this area, particularly with adult samples. Some evidence suggests that in adults the association between exaggerated reactivity and LVM may be particularly strong among individuals with higher resting BP (9, 85), suggesting potential moderating influences that deserve further exploration in the context of prospective research. Given the clinical relevance of left ventricular hypertrophy, this would seem to be an important research priority.

The recent prospective studies examining reactivity and ultrasound measures of carotid atherosclerosis are notable for the diversity of methods and sample characteristics; the results of these studies however, do point to the possible importance of preexisting subclinical disease and exposure to psychosocial stress as potential moderators of the influence of reactivity.

Although longitudinal studies linking CVR with clinical end points have been inconsistent, more positive results have been shown in relatively small samples of individuals with preexisting EH (80) or CHD (86). It is interesting to note here that the relationship between CVR and disease risk may reflect more than the effects of acute hemodynamic changes on CV risk. Thus, in the Krantz et al. (81) study in CHD patients, the CVR-outcome relationship was predicted by ischemic changes in addition to task-related hemodynamic response changes.

One of the striking characteristics of the CVR literature involves the wide range of operational definitions used for assessing individual differences in stress-related CVR, with some studies examining acute changes during traditional laboratory-based tasks, such as CPT and mental arithmetic tasks (eg, Refs. 42 and 49), and others using more nontraditional methods, such as examining CV changes during different types of medical visits or anticipation of bicycle exercise (72). Average readings within tasks or averaged readings across tasks are variously used as assessment methods. That a number of findings have been replicated despite this methodological diversity, in some sense, provides credence to the results. On the other hand, such measurement differences contribute to our difficulty in understanding inconsistent findings. Moreover, the availability of multiple scoring options and measures within each study introduces the potential for Type I error in this literature. For example, in a number of studies that show isolated positive results, there are multiple measures, tasks, or subgroups for which no significant findings are shown.

One suggestion for further work in this area involves the development of appropriate summary scores, reducing the number of comparisons conducted within each study, and the adoption of common standards of assessment. The use of multiple occasions of measurement is suggested (multiple readings, multiple tasks and/or assessment over multiple time points) as a means of enhancing the reliability of reactivity assessment. We would suggest that stronger or more consistent associations might be possible under such circumstances.

Another suggestion for future work in this area involves the need to specify statistical power requirements in light of the outcome measures and the population characteristics used in each investigation. It is possible that some of the negative results in this area result from inadequate statistical power, particularly those involving brief follow-up periods, relatively healthy samples, and/or clinical disease end points. As a related point, in this growing literature, the availability of obtained effect sizes for significant as well as for insignificant findings will be important for future quantitative reviews of the area.

Several of the recent studies reviewed suggest that a more challenging sociodemographic environment (eg, high job demand, low socioeconomic status, or high life stress) may exacerbate the impact of CVR on development of subclinical CVD (57, 72, 73). If CVR reactivity is seen to be a characteristic that emerges in the presence of psychological stress, it stands to reason that any hypothesized effects of exaggerated reactivity should be stronger among those who are exposed to a more demanding environment. This "diathesis-stress" hypothesis deserves further conceptual development and empirical evaluation within the context of CVR and the psychosocial environment. Related to this, Light (87) recently proposed that CVR research findings over the past several decades have led to the need for generation of the next iteration of the "reactivity" hypothesis, which she termed the "gene and environmental modulated reactivity hypothesis." That is, individuals who exhibit high CVR will be more likely to develop EH and/or CHD if they also have high genetic susceptibility (eg, family history of EH) and/or are exposed to chronic stress. Studies evaluating this hypothesis should prove helpful in understanding the link between CVR and development of CVD.

The literature is not entirely consistent. Methodological issues, including those of statistical power and reactivity assessment, call for increased attention. In addition to methodological differences, moderating factors may include the age, gender, and ethnicity of participants; the presence or absence of preexisting disease; genetic characteristics; and the presence or absence of chronic psychosocial stress. Despite the potential complexity of these issues, we are encouraged by the preponderance of positive results, including those obtained in studies using preclinical measures of disease. Given the pace of research in this area, we anticipate that the next few years should yield important developments in our understanding of the relationship between exaggerated CVR and the pathogenesis of CVD.

Received for publication June 5, 2001.

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