Lower Central Nervous System Serotonergic Function and Risk of Cardiovascular Disease
Where Are We, What’s Next?
See related article, pages 2228–2233.
In 1994 I hypothesized that “deficient central nervous system serotonergic function” is a neurobiological substrate that could account for the clustering of psychosocial, biological and behavioral characteristics that increase risk of developing cardiovascular disease.1 It is gratifying, therefore, to see in this issue of Stroke the report by Muldoon et al2 that an established index of reduced central nervous system (CNS) serotonergic function—a smaller prolactin response to intravenous administration of the selective serotonin reuptake inhibitor (SSRI) citalopram—is associated with more severe preclinical atherosclerosis as indexed by carotid artery intima-medial thickness. This finding provides encouraging evidence that dysregulated CNS serotonergic function plays a role in the pathogenesis of cardiovascular disease (CVD). There are 2 questions that must be addressed, however, before this role can be considered as established, the precise mechanisms understood, and the knowledge used to guide the development of improved approaches to the prevention, treatment and rehabilitation of CVD.
First, what determines the individual differences in prolactin response to 5HT reuptake inhibition? One important source of this variability across individuals is variation in genes that regulate 5HT synthesis (tryptophan hydroxylase), release and reuptake (5HT transporter) and metabolism (monoamine oxidase-A), and encode for 5HT receptors that mediate effects of synaptic 5HT on CVD endophenotypes. In their prior work this same group has demonstrated the importance of variation in some of these genes by showing that functional polymorphisms in the 5HT transporter (5HTTLPR) and monoamine oxidase-A (MAOA-uVNTR) genes moderate the prolactin response to agents that increase synaptic 5HT in the CNS.3,4 5HTTLPR genotype also influences levels of another index of CNS 5HT function—levels of the major 5HT metabolite 5HIAA in cerebrospinal fluid—but in ways that vary as a function of both race and gender.5 Such moderating effects indicate that the task of characterizing the role of 5HT-related genes in regulating CNS 5HT function and its effects on endophenotypes involved in the pathogenesis of CVD will be complex.
The second question whose answer will enhance our ability to apply knowledge of the role of CNS 5HT function in CVD pathogenesis to guide development of more effective approaches to prevention, treatment and rehabilitation is this: via what mechanisms do variations in CNS 5HT function influence CVD pathogenesis? As Muldoon et al have shown in their prior work, and convincingly confirm in the current report, reduced CNS 5HT function is associated with increased expression of most components of the metabolic syndrome. They also document that this increased expression of the metabolic syndrome mediates significantly, but not completely, the association they observe between reduced CNS 5HT function and greater maximum intima-medial thickness, indicating that effects of reduced CNS 5HT function on other predisease endophenotypes are also involved in pathogenesis.
One endophenotype that is a good candidate to account for additional variance in the effects of reduced CNS 5HT function on CVD pathogenesis is sympathetic nervous system–mediated blood pressure reactivity to psychological stress. Increased brain serotonergic neurotransmission achieved by loading with 5-hydroxytryptophan has been shown to decrease sympathetic nerve traffic in the cardiovascular system,6 and stimulation of 5HT1A receptors in medullary raphe nuclei produces concomitant decreases in sympathetic nerve discharge and mean arterial pressure.7 These findings combine with the demonstration that increased blood pressure reactivity to psychological stress is an independent predictor of increased coronary artery calcification8 to suggest that dysregulated CNS 5HT function may contribute to CVD pathogenesis via effects on sympathetically mediated cardiovascular reactivity to psychological stress. Other endophenotypes influenced by CNS 5HT function that deserve attention include decreased parasympathetic outflow, increased smoking, increased eating behavior and increased alcohol consumption.1
These answers to the questions posed above suggest that to understand the role of CNS 5HT function in the pathogenesis of CVD and then use this knowledge to improve approaches to CVD prevention, treatment and rehabilitation, it will be necessary to mount a prospective longitudinal study in which a large and diverse sample of young and middle-aged adults is genotyped for all the genes that are known to regulate 5HT synthesis, release and reuptake and metabolism as well as those that encode for 5HT receptors. This study will also need to assess all the candidate endophenotypes—health risk behaviors, metabolic syndrome components, cardiovascular reactivity to stress, hemostatic and immune system functions—that may be influenced by CNS 5HT and are known to contribute to CVD pathogenesis. And finally, it will be important to assess the sample for stressful life circumstances—low socioeconomic status, stressful life events, jobs that impose high demands with little control over how those demands are met, etc—that contribute to pathogenesis, both directly and via interaction with candidate genes. As this sample ages and CVD events accumulate, it will be possible to use sophisticated statistical approaches —eg, structural equation modeling—to document which 5HT-related genes are acting, either directly or via interaction with environmental stressors, to influence those endophenotypes that are the final common pathway to CVD events. The causal model that would be tested by such a study is shown in the Figure.
I recognize that funding for such an ambitious study may be hard to secure and that even if funding is secured it will be decades before the results enable us to identify with sufficient accuracy those who are at high risk and use the knowledge gained about the mechanisms responsible for that high risk to develop and implement effective preventive treatment and rehabilitative measures. It may be possible, however, to use studies that are already in progress, in which much of the needed data are already being collected, to accomplish the ambitious goals of the ideal study described above. The Atherosclerosis in Communities (ARIC) study includes 15 792 individuals who were aged 45 to 64 years at recruitment in 1986 to 1989.9 The Coronary Artery Risk Development in Young Adults (CARDIA) study included 5115 black and white men and women aged 18 to 30 years in 1985 to 1986.10 The National Longitudinal Study of Adolescent Health (Add Health Study) recruited a nationally representative sample of >20 000 adolescents in grades 7 to 12 in the United States in 1994 to 1995.11 All 3 of these ongoing longitudinal studies have obtained DNA on all participants, and data are being obtained relevant to most of the CVD endophenotypes, shown in the Figure.
As these 3 large cohorts—with mean ages ranging from 28 to 75 at the present time—continue to be followed and CVD events mount in number, it should be possible to achieve many of the aims described above for the ideal study and thereby confirm the validity of the causal sequence proposed in the Figure. Such confirmation could then lead to the design of interventions that target multiple points in the causal chain. A key criterion in the early evaluation of these interventions will be that they have a positive impact on the intermediate CVD endophenotypes. As Muldoon et al note, treatment with SSRIs has been reported to reduce expression of many of the endophenotypes that have been associated with reduced CNS 5HT function, and there is even evidence that treatment with SSRIs also may reduce the incidence of CVD events. There is also evidence that behavioral interventions that teach stress coping skills reduce not only psychosocial risk factors but also blood pressure both at rest and in response to psychological stress.12
Supported by National Heart, Lung, and Blood Institute grant P01HL36587, National Institute of Mental Health grant K05MH79482, Clinical Research Unit grant M01RR30, and the Duke University Behavioral Medicine Research Center.
R.W. is a founder and major stockholder of Williams LifeSkills, Inc and has a patent pending on the use of the 5HTTLPR L allele as a marker of stress-related CVD.
The opinions in this editorial are not necessarily those of the editors or of the American Heart Association.
Williams RB. Neurobiology, cellular and molecular biology, and psychosomatic medicine. Psychosom Med. 1994; 56: 308–315.
Muldoon MF, Mackey RH, Sutton-Tyrrell K, Flory JD, Pollock BG, Manuck SB. Lower central serotonergic responsivity is associated with preclinical carotid artery atherosclerosis. Stroke. 2007; 38: 2228–2233.
Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC. Serotonin-Related gene polymorphisms and central nervous system serotonin function. Neuropsychopharmacology. 2003; 28: 533–541.
Orer HS, Clement ME, Barman SM, Zhong S, Gegger GL, McCall RB. Role of serotonergic neurons in the maintenance of the 10-Hz rhythm in sympathetic nerve discharge. Am J Physiol 270 (Regulatory Integrative Comparative Physiology). 1996; 39: R174–R181.
Matthews KA, Shu S, Tucker DC, Whooley MA. Blood pressure reactivity to psychological stress and coronary calcification in the Coronary Artery Risk Development in Young Adults study. Hypertension. 2006; 47: 391–395.
The ARIC Investigators. The Atherosclerosis in Communities (ARIC) Study: design and objectives. Am J Epidemiol. 1989; 129: 687–702.
Harris, KM, Florey F, Tabor J, Udry JR. 2003. The National Longitudinal Study of Adolescent Health: Research Design [WWW document]. Available at: http://www.cpc.unc.edu/projects/addhealth/design.html.