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Sex is a potent modifier of the cardiovascular system
Leslie A. Leinwand
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, USA
Address correspondence to: Leslie A. Leinwand, Department of Molecular, Cellular, and Developmental Biology, 347 UCB, University of Colorado, Boulder, Colorado 80309, USA. Phone: (303) 492-7606; Fax: (303) 492-8907; E-mail: Leslie.Leinwand@colorado.edu.
Find articles by Leinwand, L. in: JCI | PubMed | Google Scholar
Published August 1, 2003 - More info
J Clin Invest. 2003;112(3):302–307. https://doi.org/10.1172/JCI19429.
© 2003 The American Society for Clinical Investigation
Despite the growing number of reports in the literature identifying sex-related differences in cardiac function in both rodents and humans, the underlying mechanisms have yet to be determined. Here, variables of experimental studies such as diet, animal model utilized, and age, in addition to sex hormones and other factors that may play a role in sex-related variations in cardiac responses to various pathophysiological conditions are discussed, suggesting that current approaches used in the study of cardiac disease require reevaluation.
There are numerous health problems that are affected by gender. Women are more susceptible than men to depression, osteoporosis, asthma, lung cancer due to smoking, and autoimmune disease (1). Gender effects in disease are complex, however, as exemplified by the observation that while the incidence of melanoma is slightly higher among women than men, mortality from melanoma is higher in men. Not all medical problems show gender dimorphism. For example, males do not differ from females in terms of their responses to infection (1). When it comes to heart disease, generally, of those individuals diagnosed with heart disease, women fare much better than men. Little is known about the basis for this difference in cardiovascular disease. Much focus has been placed on the potential cardioprotective role of estrogen. However, the recent finding that estrogen replacement in postmenopausal women actually increased heart disease has challenged this view (2).
Deriving a coherent view of potential players in sex-dependent differences in the heart requires analysis of both the clinical literature and the literature on sex-dependent differences in the cardiovascular system of laboratory animals. There is a major limiting factor in comparing rodent laboratory studies: the vast majority have been carried out on males only. However, this limitation appears to be changing. In the past year, a number of studies have appeared in which both males and females have been analyzed. An article in a recent issue of the JCI by O’Connell et al. (3) provided a glimpse into what promises to be a new way of thinking about genetic sex. In this report, the authors found that the α1-adrenergic receptors are critical in determining heart size and the ability of the heart to respond to both pathologic and physiologic stimuli, but only in male animals. Intriguingly, this sex-related difference did not disappear following ovariectomy of females. This article will discuss the fact that sex is an extremely potent modifier of the myocardium and will identify which pathways have been implicated in some of these differences. I hope it will become clear that future research should focus on the mechanisms by which both sex and diet can modify cardiovascular phenotypes.
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Rodent studies on sex-related differences in the cardiovascular system
What can we learn from animal studies about sex-related differences in heart disease? The literature regarding studies in animals falls into two general categories: (i) studies that deliberately address sex-related differences in the cardiovascular system; and (ii) studies in which the inactivation or manipulation of genes has resulted in the discovery of a sexually dimorphic phenotype. Most of the studies in the first category have involved subjecting wild-type rodents of both sexes to some pathologic or physiologic stimulus and observing how the heart responds (Table 1). These studies have generally been consistent with observations in clinical populations. Studies in the second category are beginning to provide the groundwork for understanding the basis for sex-related differences noted in the first category (Table 2). However, when we examine the animal model literature, there are two important things to note: Firstly, the majority of the literature is devoted to the study of male animals. Most of the basis for this (although not explicitly stated) is that female animals would need to be studied only at a fixed point in the estrous cycle and this would be impractical. A systematic analysis is warranted in order to analyze the cardiac responsiveness of male and female mice to a variety of stimuli and investigate how diet might modify cardiovascular phenotypes (see Phytoestrogens and heart disease).
On the surface however, rodent studies do not always appear to be consistent. It is important to ask whether the inconsistencies are telling us something meaningful. If the experimental rodent literature is examined closely, some of the inconsistencies can be explained because the studies themselves are not comparable. For example, different results have been obtained in comparing contractile performance in male and female rats. One study in papillary muscles from 6-month old rats found that males had significantly slower rates of contraction and relaxation than females (19). A similar study using the isolated working heart preparation revealed increased cardiac output in males (20). A third study using younger papillary muscles found no difference between the sexes until animals were 6 months of age (21). These alleged inconsistencies suggest that it is not possible to compare apples and oranges. It seems clear that the following parameters need to be assessed when trying to compare one study to another: (i) what are the ages of the animals; (ii) what species and what strain were used in the studies; and (iii) how, in the case of function, were the measurements made? For example, is it possible to freely compare cardiac function as assessed by echocardiography with that assessed in an isolated working heart preparation?
In the case of genetically manipulated rodents, most studies have been done in mice, narrowing one of these variables — species. Strain is still an issue, but most investigators now backcross their strains onto the C57B1/6 background. The age of the animals is still a major issue for several reasons. Phenotypes of genetically manipulated mice have been shown to vary over time (as mentioned above with wild-type rats). One striking example describes mice overexpressing the β2-adrenergic receptor (β2AR). At 2–4 months of age, male β2AR mice exhibited enhanced cardiac contractility. Between 8 and 12 months of age the mice developed severe fibrosis and contractile dysfunction (22). A second, and perhaps more important, issue in correlating rodent and human studies, has to do with extrapolating the time frame of rodent studies to humans. Many of the sex-related differences seen in humans do not emerge until well into adulthood, which in a mouse is roughly equivalent to at least 10–12 months of age. When reviewing the literature, it becomes apparent that many studies have been conducted on rats and mice of 4–6 months of age, so conclusions of a lack of sex-related differences in cardiac phenotypes may be premature. That said, now that more studies are including animals of both sexes, it is clear that sex plays a major role in cardiovascular function in rodents. Figure 1 shows a number of pathways implicated in these sex-related differences. As is obvious from the summary of recent studies that have documented sex-related differences in cardiovascular function of genetically manipulated animals (Table 2), in general, females have blunted cardiac responses compared to their male counterparts (or no response in some cases) following manipulation of a number of genes. They also have blunted responses to the inactivation of certain genes. The cardiovascular phenotype observed in females is also blunted or normal in cases of overexpression/activation or expression of a mutation. An augmented response in females has been reported in the case of constitutive activation of Akt, and a worse outcome for females was noted in mice overexpressing alcohol dehydrogenase (ADH).
Figure 1Pathways and factors affecting the cardiovascular system. The figure indicates how numerous variables, along with factors known to be important in the cardiovascular system, can converge.
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