The searches yielded the following number of articles for search term combinations, respectively: ACEs, chronic illness or disease, and adult — C = 67, M = 233, P = 261; ACEs and wounds — C = 28, M = 97, P = 57; epigenetics and wounds — C = 41, M = 337, P = 170. Sixty-eight (68) articles were selected for use and included population-based studies; literature reviews; epidemiologic data; meta-analyses; and systematic, cross-sectional, observational, and prospective studies as singular or mixed methods designs.
ACEs, epigenetics, and wound care: critical connections. A substantive overlap was noted between the risk factors generated by ACEs exposure, both for chronic diseases and health-risk behaviors, and the risk factors for wound development and disrupted healing. Because a higher number of ACEs via epigenetic influences affect gene expression, the development of adult chronic illnesses and factors such as chronic inflammation associated with wound development were shown to be accelerated.16,20,21 However, epigenetics and life experiences also affect wound healing via influences of comorbidities on cell activities and physiologic regulators.23
Wound development. Childhood adversity has a clear association with wound development given the research surrounding epigenetic science and subsequent adult chronic diseases and risky health behaviors that are associated with chronic wounds. Multiple population-based research studies and literature reviews support that persons with higher ACE scores are at greater risk for eating disorders (anorexia nervosa [AN], bulimia),24,25 cardiovascular disease,26,27 diabetes mellitus (DM),28-30 immune disorders,18,31 obesity,32 poor cardiometabolic outcomes,33 high-risk behaviors (heavy drinking, risky sexual behaviors, substance abuse), myocardial infarction, and depression and mood disorders.34-36 These risk behaviors and chronic diseases associated with higher ACEs scores are the risk factors consistently identified as predecessors to the morbidities associated with chronic wound healing 22,35 (see Figure 2).
Afifi et al24 used epidemiological data that were nationally representative of adults in the US (N = 36 309) to examine lifetime eating disorders. AN, bulimia, and binge-eating disorders were positively associated with childhood adversity and maltreatment.
The Huffhines et al29 review (N = 38) on diabetes and ACE was particularly compelling; the studies reviewed demonstrated a dose-response relationship wherein a threshold response (4 or more ACEs) was linked to diabetes development. The authors suggested that diabetologists and other care providers routinely screen for ACEs.
In a population-based, cross-sectional study of nationally representative US adults (N = 34 653), Raposo et al36 examined ACE association with mood and personality disorders. A higher number of ACEs was significantly correlated (P <.05) with higher rates of these mental health conditions, even after adjusting for covariates.
Notably, relationships between ACE scores above 4 and adult chronic illness and risky behaviors persist whether studies were performed retrospectively or prospectively.37 Population-based studies6,38 have shown higher ACEs scores also were associated with obesity and morbid obesity, especially in the presence of childhood sexual and physical abuse.
Higher ACEs scores are evident in more subtle ways as well. In reviewing adult disability in a cross-sectional, state-based, population-based survey (14 states and the District of Columbia), Schüsser-Fiorenza Rose et al39 used population data from the CDC BRFSS ACEs module for self-reported disability (N = 81 184); adult disability was positively associated with higher ACEs scores. Because >4 ACEs were reported, the odds ratios for adult disability was as high as 5.8 compared to persons with low ACEs scores. In a prospective, longitudinal study conducted among 233 adult patients, Lodhia et al40 examined surgical weight loss after bariatric surgery. Higher ACEs scores were associated with less weight loss postsurgery and also with higher total and LDL cholesterol levels postsurgery (P <.05).
In a state population health surveillance system (BRFSS) survey conducted annually by the CDC, Chanlongbutra et al41 examined the relationship between ACEs exposure and chronic disease risks and perceived health-related quality of life in residents of 9 states for the years 2011–2012. The researchers compared the responses of rural and urban dwellers >18 years of age to the CDC’s BRFSS (N = 79 810). Approximately 55% of rural respondents reported at least 1 ACE and nearly 15% reported 4 or more ACEs. Controlling for sociodemographic factors, rural respondents with higher ACEs scores reported poorer health, activity limitations, and heart disease. The odds of experiencing a heart attack, DM, asthma, and poorer mental health were significantly higher for persons with 3 or more ACEs (P <.05).
In their retrospective observational study, Crouch et al42 examined the association between ACEs and smoking-exacerbated illnesses (asthma, diabetes, chronic obstructive pulmonary disease) using 2014–2015 BRFSS data from South Carolina for persons who reported a smoking-exacerbated illness (N = 6321). More than 20% of the respondents had 4 or more ACEs, and persons with this higher score were significantly more likely to smoke even in the presence of smoking-exacerbated illnesses. Researchers suggest that ACEs exposure increases risky behavior, with smoking serving as a coping mechanism and pursued despite awareness of negative health consequences.
Epigenetics science consistently and persistently supports that higher ACEs scores are associated with chronic illness development and increased risk factors for wounds. Epigenetic influences manifest in interesting ways. Using a large, genealogical population database of >2 million of Utah’s founders and their descendants, Lee et al43 conducted a study where family genealogical information was readily available and analyzed susceptibility to surgical site infections (SSIs). When SSIs among 651 persons and their relatives were examined, an excessive relative risk (RR) for third-degree relatives was noted (RR = 1.62; P = .029). The researchers also noted a possible epigenetic influence (in addition to genetic connections) via environmental factors.
Wound healing. Multiple literature sources support that epigenetic processes influence wound/skin repair. In a literature review, Lewis et al44 described how epigenetic regulators dynamically influence keratinocyte proliferation, differentiation, and migration, thereby affecting dermal regeneration. These regulators also alter neoangiogenesis and the development of healing catalytic blood supply. In describing the development of liver fibrosis as a pathological disease process, Mann and Mann45 used data in the literature to note the impact of 3 epigenetic processes (DNA methylation, histone protein modification, and regulatory noncoding RNAs [micro RNAs]), on fibroblasts and myofibroblasts, subsequently affecting wound contraction, wound healing, and fibrotic disorders (eg, cirrhosis). A fascinating footnote to their discussion was their description of the influence of epigenetic traits on downstream fibrosis processes; these traits may be inherited from generation to generation to support adaptive responses in offspring in danger of similar insults.45 The literature supports the role of epigenetics in “overhealing” fibrotic wounds.46 Multiple literature reviews47,48 support the transgenerational influence of environment on wound healing; this linkage of exposure to childhood trauma49,50 to subsequent adult pathology in following generations is mediated through altered inflammatory processes.21,51
Using theoretical and clinical evidence reviews, the literature consistently supports that epigenetic processes via comorbidities influence “torpid” wound healing in the presence of chronic disease such as DM type 2 (DM2).52-54 Epigenetic changes in bone marrow progenitor cells influence subsequent inflammatory phenotypes and affect wound healing. A classic example is the influence of DM2 on macrophages, where DM2 affects macrophage activity with altered inflammatory “clean-up” of wounds55 and a persistent proinflammatory phenotype, creating a pattern of unrestrained inflammation characteristic of nonhealing wounds.