The interest in the relation between the heart and the emotions comes from ancient times. Aristotle mistakenly thought that the brain was an organ that cooled down the passions from the heart; however, he also noted that negative emotions adversely impacted upon the health/disease processes [1
]. In 1628, William Harvey signaled the relation between the mind and the heart [2
] and in 1910, William Osler was the first researcher to publish a paper on the repercussion that emotions have upon the heart, mentioning the influence of anxiety on Angina Pectoris [3
]. One of the first scientific studies on the subject was the one published by Malzberg in 1937, in which he found a six-fold increase in the mortality rate adjusted per age in patients having coronary artery disease (CAD) and involutive melancholy when compared to the general population, and 40% of deaths were attributed to heart diseases [4
Cardiovascular (CV) diseases are the main cause of premature death and chronic disability in the world [5
] and mental and psychotropic substance abuse diseases are the main causes of years lived with disability worldwide. Stress-related disorders (SRDs) cause 1.1% of the disability-adjusted life years out of those caused by all other diseases worldwide [6
]. Furthermore, SRDs correspond to 10.4% of all mental and substance abuse diseases [6
]. The association between neuropsychiatric and CV diseases is bidirectional; neuropsychiatric symptoms are commonly present in patients with chronic systemic diseases [7
] and different types of psychiatric disorders including SRD, depression, emotional incontinence, delusions, and hallucinations, which are frequently observed after the occurrence of CAD [7
]. On the other hand, SRDs are considered as independent incidental risk factors to develop CAD, probably triggering the disease [9
]. SRD entities which have been related to CAD include generalized anxiety [10
], panic disorder [12
], and post-traumatic stress disorder [14
], among others. The association seems to be more prevalent in men than in women [15
] and approximately 36% of patients with CAD have at least one SRD. In addition, more than 45% of patients with CAD have previously had one or more SRDs in their lifetime [16
]. Due to this association, it has recently been proposed that there could be a common origin to these pathological entities.
The common origin of risk/resilience to CAD and SRD could involve: (a) common anatomical brain structures participating in CV and behavioral responses; (b) common mechanisms at subcellular structures (mitochondria, endoplasmic reticulum stress, telomere length) which are regulated by reactive oxygen species (ROS), inflammation, and intracellular calcium in myocytes and neural cells; (c) microbiome effects on the brain and the CV systems; and (d) common chemical mediators. Most of these mechanisms shall be dealt with in future reviews, while the participation of common neuro-immune-hormonal mediators constitutes the aim of the present review.
Epigenetic programming of the synthesis, release, and receptor expression of common mediators participating in the alternative risk of or resilience to comorbidity to CAD and SRD since early life stages, might contribute to the long-term modulation and restructuring of CV regulation networks and, at the same time, have relevance in situations of comorbid abnormal responses to stress. The term epigenetic refers to heritable traits of the expression of genes and to the subsequent phenotypic changes without there being alterations in the DNA sequence [17
]. The term was proposed in 1942 by C.R. Waddington [19
] and the concept has been modified accompanying molecular biology advances. The structure of DNA was still a mystery at that time, but the idea that genes produced a determined phenotype based on interactions with their environment held a great deal of truth.
Epigenetic programming refers to the influence produced by the exposure to specific conditions during critical periods of early life that modify the developmental pathways of the organism, leading to stable and long-lasting alterations that have effects when the individual reaches adulthood [20
]. The language of the epigenetic program is nowadays based on specific covalent modifications of the DNA and chromatin [21
]. Epigenetic “readers, writers, and erasers” may be targeted by nongenomic signaling, causing re programming [22
]. It is now known that epigenetic changes imply post-translational modifications of histones, the methylation of DNA, and the regulation by microRNAs. Several enzymes play a role in these modifications, among which histone-modifying enzymes such as histone acetyltransferases (HAT), which acetylate histone tails and histone deacetylases (HDAC) that deacetylate histone tails [23
], can be mentioned. Another group of important enzymes comprises the histone methyltransferases (HMT) and the histone demethylases. These post translational modifications of common mediators of CAD and SRD might participate in the programming or reprogramming of their neuro hormonal release and action determining risk or resilience.
In 2002, Barker et al. [24
] suggested that environmental events happening during pregnancy could have consequences in the adult life of the product, leading to diseases such as cardiometabolic diseases (CMD) or type II diabetes. When nutrients are scarce, the fetus shows developmental plasticity and is capable of preserving the brain and heart blood perfusion in detriment of the growth of other organs [20
]. Therefore, the functioning of the brain and CV system is subject to epigenetic regulation. Post in 1999 [26
] published one of the first studies that proposed that CV diseases were mediated by epigenetic marks such as DNA methylation in cytosine-phosphate-guanine (CpG) islands in the estrogen receptor gene-α in patients undergoing coronary atherectomy or carotid endarterectomy. Low birthweight, an indication of an adverse gestational environment, has been associated with high cortisol levels, activation of the hypothalamus-hypophysis adrenal (HHA) axis, increased cortisol responses to stimulation with adrenocorticotrophic hormone (ACTH), lack of habituation to stress, and increased cortisol response to psychosocial stress in adult humans [27
Epigenetic regulation plays an important role in the determination of the adaptive or mal adaptive neural functioning and the behavioral responses to environmental stressors and maternal mental disorders may alter fetal development [28
]. The mechanisms involved include maternal hormonal influences such as high levels of glucocorticoids, alterations in placental functioning and perfusion, and epigenetic mechanisms in the product [20
]. There are reports of the epigenetic programming of metabolic diseases such as obesity, metabolic syndrome, diabetes mellitus, and their CV consequences [29
]. There are also recent reports of the programming of psychiatric disorders [31
]. However, there are no reports on the epigenetics of comorbidity between these entities. In contrast to the genome, which is only modified by the environment through irreversible mutations, the epigenome can be modified throughout life by active changes adopted by the individuals at different developmental stages. If changes are not induced by the individual, epigenetic programming persists and can even be inherited by the next generation. Epigenetic modifications are thus both stable and flexible [32
]. Therefore, comorbidity to SRD and CAD might also be simultaneously programmed or reprogrammed if mediated by epigenetic marks.
Briefly, summarizing the common brain anatomical structures that participate in CV and behavioral responses, there are at least three instances playing a regulatory role in the functioning of the brain-heart axis. They are the central nervous system (CNS), which is the main instrument to explore and evaluate environmental situations and in which the prefrontal cortex (PFC) plays a central role; the amygdala with its extension in the bed nucleus of the stria terminalis (BNST); the insula and the autonomous nervous system (ANS) with its sympathetic (SNS), parasympathetic, and enteric divisions [34
]; and the recently considered intrinsic cardiac nervous system (ICNS) [35
]. The PFC forms a binomium with the amygdala in the control of physiological and behavioral responses [34
]. The human PFC is unique since it allows for symbolic expression that renders it possible for the individual to evaluate the environmental stimulus and interpret it as it really is, or as a scary or insignificant stimulus that goes beyond the real environmental situation. The response generated to the environmental stimulus may thus correspond to the real situation or to a fantasized one. Furthermore, the PFC is the neuro-anatomo-physiologic substrate that determines decision making with the possibility of contributing to the development of risk of or resilience to diseases or to the reprogramming of the effects of early programming [21
]. The interpretation and the responses given by the PFC to these conditions also determine the epigenetic marks [32
In addition to the above mentioned neuronal structures and as mentioned previously, neuroinmunoendocrine mediators have been proposed to jointly participate in the common origin of SRD and CMD, including CAD. The systems responding to stress include a complex network of mediators with complex interactions whose knowledge is continually expanding. The variations in the production of these mediators could be programmed since the early stages of development, leading to the appearance of complex diseases in adulthood or to resilience to them, and could also be reprogrammed. In this paper, we analyze some of the common mediators of SRD and CAD involved in the comorbidity of these diseases and their mechanisms of action, the evidence of their programming in early development, and the possibility to act upon this predisposition and modify the outcome. Although studies on epigenetics of the comorbidity are absent, there are enough data on the epigenetics of each of the molecules participating in these diseases. Therefore, we are putting forward the theoretical hypothesis that epigenetics might contribute to their simultaneous appearance.
2. Similar Underlying Neuroendocrine Function in Psychiatric and Cardiometabolic Diseases
Cells from the whole body and those pertaining to neural structures synthesize and release different amounts of chemical molecules, depending on the tissue to which they belong. These molecules mediate communication between cells from the same tissue and with those of other tissues. Communication also depends on the expression of specific receptors that receive the signals. Cells from the heart and brain require similar chemical mediators.
Many neuroactive substances modulate the CV system through their action on the CNS or act directly on the heart and vessels. Some neurotransmitters, including some of the classical ones (acetylcholine, noradrenaline, adrenaline, dopamine, serotonin, and histamine), are among them. Neuropeptides are also included, such as vasopressin, oxytocin, natriuretic peptides (NPs), corticotrophin, angiotensin, thyroxin, Y neuropeptide, leptin, endothelin, orexins, apelins, interleukin 1b, and tumor necrosis factor-α (TNF-α) as well as steroids such as mineralo- and glucocorticoids, estrogens, and testosterone [36
]. Other substances involved are purines and gastric system transmitters (nitric oxide, hydrogen sulphide) [36
The effect of neurotransmitters is usually of a short duration and can be stimulatory or inhibitory. In contrast, the effects of neuropeptides are long lasting and may contribute to the long-term modulation and restructuring of regulatory CV networks, whilst also having relevance in stress situations [36
]. Since these neuroactive substances have direct effects upon the CV system and modulate this system through their actions on the CNS, they could have co-joint effects on CAD and SRD. In the following sections, we describe the effects of some of the most important peptides that may have this dual regulation and the evidence of their early programming. The reports on the epigenetic regulation of neuro- and cardio-endocrine mediators possibly having co-joint effects on the risk of developing SRD and CAD are summarized in Table 1
4. Possible Re-Programming of Expression of Cardio and Neuroactive Substances Participating in the Comorbidity of Neuropsychiatric and Cardiometabolic Diseases
At present, epigenetics is considered as a novel area for new therapies [180
] that may act by returning to chromatin to its previous state before being remodeled by environmental factors and reverse histone modifications that may be contributing to the development of abnormal phenotypes associated with diseases including SRD and CAD [21
]. These therapies include lifestyle changes that involve decision making and therefore participation of the PFC, currently used medications, and newly developed ones.
In contrast to genetic mutations, the plasticity of epigenetic changes makes them attractive candidates for prevention or reversion by non-pharmacological intervention. The free will of the individuals to undertake healthy eating habits, perform exercise, and increase mental activity might help induce epigenetic modifications. Dietary lifestyles may alter epigenetic cues in neuropsychiatric and CMD risk in utero, after birth, or during life, since they contribute to the risk of developing these diseases by metabolic re programming of the epigenome [185
Several studies have reported that intestinal microbial steady-state imbalances can cause a range of metabolic diseases [186
]. Also, the influence of gut microbioma on microbe-related diseases in neuropsychiatric subjects has been explored in a number of studies. In 2004, Sudo et al. [189
] were the first to show that bacteria in the gut can influence stress responses. The precise mechanisms for gut-brain interaction remain unknown. Recently, in a study with maternally separated mice, it was suggested that disruptions to the normal development of the gut microbiome may influence future physical and mental health of the offspring [190
]. Elsewhere, Hoban et al. 2017 [191
] reported that the germ-free mice had blunted fear responses. In 2013, Tillisch et al. [192
] administered probiotic yogurt to a group of healthy humans and found that they had a reduced brain response to negative images.
This gut-brain connection could have clinical implications, as influencing the gut microbiome through diet may serve to ameliorate some psychiatric disorders. Dinan et al. coined the term “psychobiotics” in 2013 [193
] to describe live organisms that, when ingested, produce health benefits in patients with psychiatric illness. These include foods containing probiotics, live strains of gut-friendly bacteria.
Dietary interventions using natural compounds have been proposed to modify epigenetic cues. A growing number of epidemiologic studies point to a link between the ingestion of nutritional polyphenols and health benefits [194
]. A mixture of resveratrol and quercetin has proven to be effective to revert many of the altered variables caused by metabolic syndrome by regulating the histone deacetylase activity of sirtuins [195
Other interventions proposed include the reduction of glutamatergic receptor activation. This intervention has been found to be enough to counteract the negative effects of increased maternal care on increased CRF signaling [196
]. This effect requires enhanced nuclear levels and recruitment of the transcriptional repressor neuron restrictive silencing factor (NRSF), also known as repressor element-1 silencing transcription factor, to the Crh
]. NRSF chromatin binding was accompanied by methylation in CpG binding protein 2 (MeCP2) sites and was followed by accumulation of repressive epigenetic marks in the hypothalamus of immature and adult rats that had experienced increased maternal care [196
]. These mechanisms provide a new mechanistic pathway from early-life experience to phenotypic effects that result in human health and disease.
Another pharmacological manipulation in the adult that was able to reverse some of the effects of environmental influences such as maternal behavior and diet that caused epigenetic changes in neurons by altering histone acetylation, DNA methylation, and nerve growth factor-inducible protein A transcription factor binding, thus inducing long-term changes in GR
gene expression, was Trichostatin A and L-methionine administration. They influenced the epigenetic status of critical loci in the brain [199
Perinatal exposure to endocrine disrupting compounds such as xenoestrogens increases the risk of diseases by (re)programming the epigenome via alterations in DNA and histone methylation. Xenoestrogens induce nongenomic signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase, thus providing a direct link to disruption of the epigenome [22
]. Thus, inhibition of this pathway in a selective manner could also lead to re programming in diseases.
Several drugs with a potential capacity to modulate the epigenetic machinery and that could be suggested as new drugs for the treatment of several diseases have been proposed [200
]. These drugs have the capacity to modulate the activity of histone modifying enzymes that are related to DNA methylation and could therefore rescue the normal conformational structure of the chromatin and revert the changes induced by alterations in the environment. They could slow, stop, or even revert the long-term effects that increase the risk for these diseases [208
The area of study of epigenetic therapies is still in its beginnings and new and effective treatments will follow in the near future as experimental data accumulates and is tested for human use. Furthermore, the response of the epigenome to environmental insults throughout life seems not to be an accidental aberration happening only in early life and always leading to pathology, but a biological mechanism that helps adaptability of the genome to altered environments during life. It would be important to delineate if only chemical exposures such as diet or drugs or toxins can affect the epigenome or if the social environment can also act on it. This would imply that there might be signaling pathways which link extracellular environmental exposures and epigenetic machineries in mature somatic cells and that correct environmental exposures, including changes in the social environment, which might reverse damaging signals. The prospect that the social environment or individual behavior might alter our genome by modifying the epigenome might provide an explanation for the relationship between socioeconomic status and physical health. Hence new therapies that modify the social environment might be possible and are an intriguing possibility [211