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EDITORIAL COMMENT |
Departments of Psychiatry and Psychology, Stress and Health Research Program, University of North Carolina, Chapel Hill, NC 27599
In the previous article, Carroll and colleagues (1) have presented the results of the second phase of the prospective Whitehall II study, examining blood pressure (BP) reactivity to a mental stressor in middle-aged men as a predictor of subsequent BP level and hypertension development. In phase one (2), reactivity was a significant predictor of BP 5 years later, but accounted for less than 1% of additional variance after inclusion of three overlapping predictors: age, initial screening BP, and resting baseline BP. In phase two, essentially the same result was obtained after 10 years of follow up, when many more individuals had become hypertensive (N = 114). Their conclusion is the same for both phases of this major investigation: BP reactivity measures are related to subsequent BP, but are not strong enough predictors for clinicians to find them useful in assessing risk of later hypertension (1, 2).
The classic "Reactivity Hypothesis" that provided the framework for the Whitehall study and many other investigations in the previous millennium was somewhat youthfully naïve and could be paraphased: "People need to take notice of behavioral stress responses. Since persons who at high risk for hypertension are more often high stress reactors, then let’s hypothesize a simple linear relationship between higher BP responses to stress at initial testing and greater BP increases or higher BP levels at retest." But prospective studies of hypertension take decades from conception to completion. During those decades, many other interesting psychosocial studies have been completed examining stress and stress buffers because they influence short-term stress responses and longer-term cardiovascular health outcomes. Among many other important findings, these studies have shown associations between BP increases and indices of long-term stress exposure such as negative affect and job strain (3, 4) and also have documented the importance of the presence of stress buffers including social support from family and friends in reducing both short-term stress reactivity and long-term cardiovascular health risks (5, 6).
Equally relevant to our framework of understanding about stress exposure and stress reactivity are findings from the animal literature on hypertension development in animals exposed to chronic stress. Three notable examples are Henry’s rodent model of psychosocial hypertension achieved through designing social environments to increase confrontations regarding dominance (7–9), Lawler et al. (10) and Sanders and Lawler (11) borderline hypertensive rat (BHR) that develops sustained hypertension after weeks of daily exposure to shock avoidance conflict tasks, and Anderson et al.’s (12) dog model that similarly involves daily shock avoidance. These models establish that stress exposure inducing regular periods of high BP reactivity can be a critical causal factor leading to later hypertension. However, these models also demonstrate something that the early Reactivity Hypothesis seems to have overlooked. In all three animal models of stress-related hypertension, the stress exposure itself only leads to hypertension if there is either a genetic susceptibility to hypertension or if there is an additional environmental factor potentiating adverse physiological consequences of stress. Having one parent that is a spontaneously hypertensive rat (SHR), the BHR animals are genetically susceptible to hypertension from either increased stress or high salt intake (11). Use of Henry’s confrontational social environment with various genetic strains of rats has shown that many strains do not develop hypertension in this environment, including certain strains that acutely demonstrate large BP increases during acute dominance confrontations (8, 9). Anderson et al.’s (12) mongrel dogs do not develop hypertension despite daily stress exposure unless the animals concurrently have both high salt intake and deficient potassium intake as well. Altogether, these observations suggest that models of hypertension dealing with a single stress factor and ignoring potential interactions with other genetic and environmental factors are too simplistic.
It is time for the Reactivity Hypothesis to reflect its advancing maturity and yield its place to the next generation. Newer, more complex corollaries of this hypothesis are already in early development. Carroll et al. (1) agree that for future papers, they may use the valuable prospective data from the Whitehall II cohort to explore possible interactions between stress reactivity and stress exposure as well interactions with genetic susceptibility, defined by family history of hypertension. Our own research with a much smaller sample (N = 103 young men) who completed a 10-year follow-up study provided an initial encouraging findings about the fruitfulness of examining these factors in interaction (13). Our study suggested that compared with persons having a negative family history, the combination of having a family history of hypertension and also being a high stress responder was linked to seven-fold increase in risk of developing borderline to mild hypertension, while having a family history and being a low or moderate stress responder was associated with less than a two-fold increase in risk. High stress responders reporting high daily stress exposure also had greater SBP and DBP increases at follow-up than those with low daily stress, after controlling for effects of family history. It is worth noting that our results were not consistent with the assumption of a linear relationship between cardiovascular stress responses and change in BP or BP status. Similar to prior work on cold pressor reactivity by Menkes and colleagues (14), only at the highest quartile of reactivity did our results suggest an increase in risk. Thus, there seemed to be a threshold effect rather than a continuous increment of risk associated with increasing stress reactivity. Finally, our relationships would have been weaker if we had not defined high cardiovascular responsivity based on both SBP and DBP and on responses to two stressors, using z-scores to combine cardiovascular response information from different measures and tasks.
Based on these observations, we concluded that the Reactivity Hypothesis already had produced one next generation hypothesis, that we labeled the Gene and Environment Modulated Reactivity Hypothesis. This hypothesis assumes that there is substantial plasticity in the relationship between genetic factors and hypertension development. The outcome (hypertension development or not) in those with high genetic susceptibility (family history) is environmentally modifiable, influenced by both level of exposure to environmental stress and by the individual’s characteristic responsivity to stress, which may itself have both genetic and past experiential determinants. Under this newer hypothesis, very high cardiovascular stress responses will be related to greater risk of later BP elevation if they occur in individuals with high genetic susceptibility and/or those with frequent high stress exposure. After the lead of recent work on risk of coronary and carotid artery disease (15), this hypothesis could be applied in a different context to examine stress reactivity and family history in interaction with indices of stress exposure at work, or alternatively, with low family support or other measures of stress exposure at home (3–6, 16). Other related hypotheses seem ready for preliminary testing. For example, one could focus on the interaction of personality factors like hostility or extremes of anger expression with family history of hypertension and cardiovascular stress responsivity (17, 18). Alternatively, one might examine not peak stress responses but slowness of cardiovascular recovery after stress exposure in interaction with genetic susceptibility to hypertension (19, 20). Still another direction might focus on interactions of salt and potassium intake or other aspects of diet (21, 22) and physical activity (23) with stress reactivity and family history. Based on results from the CARDIA study (24), testing of these hypotheses would have an improved chance for success if analyses were performed assuming that effects might well differ for women vs. men; effects might also differ by age group and menopausal status.
Even when these next generation hypotheses involving stress reactivity have been tested, it is uncertain whether the findings, however strong, will achieve wide clinical applicability unless the techniques for determining levels of key stress exposure variables, stress susceptibility factors (including cardiovascular responsivity to stress), and stress buffers are brief. It will be a challenge to develop assessment batteries that function with maximum efficiency in the clinic and with limited patient burden at home as well.
REFERENCES
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