Heterogeneity in human cardiovascular function contributes to a deeper understanding of integrative mechanisms

INVITED EDITORIALSHeterogeneity in human cardiovascular function contributes to a deeper understanding of integrative mechanismsNisha CharkoudianNisha CharkoudianDepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MinnesotaPublished Online:01 Mar 2010https://doi.org/10.1152/japplphysiol.01385.2009This is the final version - click for previous versionMoreSectionsPDF (45 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations interindividual differences in physiological variables are often seen as an impediment to our ability to detect important differences between groups of subjects or to understand the influences of an intervention on a physiological response. Indeed, traditional statistical comparisons of differences between groups result in “nonsignificant” findings if variability in either or both groups is too great. However, when viewed from another perspective, the variability among individuals can be used as a key portal to potentially important insights into the integrative function of the organism.Cardiovascular physiology provides several examples of the importance of attention to interindividual differences. Several decades ago, Julius and colleagues (6, 7) reported that the interindividual variability in resting cardiac output, and its relationship to individual values for total peripheral resistance, gave important insight into the development of hypertension. They found a wide range of values for resting cardiac output, measured using direct Fick technique (range of ∼4–12 l/min) in healthy individuals and in individuals with borderline and overt hypertension. Furthermore, the relationship between cardiac output and total peripheral resistance was shifted to higher peripheral resistance values with the development of hypertension (6, 7).Dramatic increases in cardiac output and skeletal muscle blood flow during dynamic exercise are key contributors to the attainment of maximal oxygen consumption (V̇o2max). Interindividual variability in these responses can provide insight into the physiology behind the exercise responses. For example, there is a documented positive relationship between V̇o2max and peak skeletal muscle vasodilation that becomes stronger with aerobic exercise training (3, 9, 12). Although it is well recognized that both aging and reproductive hormones have pronounced influences on cardiovascular function, the influences of age and sex on the relationships between peak muscle blood flow and peak cardiac output have not received specific attention until now. In this issue of the Journal of Applied Physiology, Ridout and colleagues (11) present a careful analysis of the relationships between maximal cardiac output and peak blood flow in skeletal muscle evaluated during incremental knee extensor exercise. They report that, in young men, there was a significant positive relationship between peak cardiac output and peak femoral blood flow (or peak femoral vascular conductance). In older men, this relationship also existed, but was shifted to lower cardiac output values (consistent with lower peak cardiac output values previously reported in older men). In women, however, regardless of age group, the authors found no relationship between peak cardiac output and peak femoral blood flow or vascular conductance. The authors hypothesized that sex-specific influences on sympathetic neural-peripheral vascular interactions might contribute to these differences between the sexes. Additionally, it may be that there are two separate sets of influences contributing to the sex differences, one (sex hormone dependent) in younger women and another in postmenopausal women who would have less of an influence of circulating sex hormones.The sex differences reported by Ridout and colleagues (11) add important insight to a growing body of literature regarding differences in cardiovascular regulation between the sexes. We (1, 2, 4, 5) and others (10, 13) have evaluated interindividual contributions of variables affecting blood pressure, including sympathetic nerve activity, cardiac output, stroke volume and age. In healthy young men, there are important balances between cardiac output, sympathetic nerve activity, and peripheral vascular resistance that contribute to the normal regulation of arterial pressure (1). In women, however, these relationships are absent, suggesting that women rely on different cardiovascular mechanisms to maintain normal arterial pressure compared with men (4). For example, compared with men, women exhibited greater β2-mediated vasodilation for a given amount of adrenergic stimulation (8). This phenomenon could explain altered relationships between sympathetic neural activity, total peripheral resistance, and cardiac output in women. Greater β-adrenergic vasodilation in young women could also have contributed to the sex differences reported by Ridout and colleagues in their present report (11).In addition to the important insights provided by the novel findings of Ridout et al., their report also emphasizes the utility and importance of evaluating relationships among individual responses. While it is certainly important to evaluate group differences, interindividual analyses such as theirs provide important insights that would be missed if only mean and SE for each group were presented. For example, in Table 2 of the study by Ridout and colleagues (11), it is important to note the average effects of age and sex on variables such as cardiac output, V̇o2max, and peak leg blood flow. However, those data do not give us a similar level of understanding (or, perhaps, raise as many intriguing questions) as do the data in their Fig. 1 (11).The growing use of the term “individualized medicine” encourages all biomedical scientists and physicians to avoid inappropriate assumptions of homogeneity, even among normal healthy individuals. In this context, and as integrative physiology experiences a resurgence of appreciation in the biomedical literature, studies such as those by Ridout et al. 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