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Cardiovascular as a Result of the Interactions Between , , and Inflammation: The COCCI Syndemic

Michael Clearfield, DO; Glenn Davis, MS; Jennifer Weis, DO; Gregory Gayer, PhD; Jay H. Shubrook, DO

From the Touro University Obesity and climate change conspire to create an environment in which sub- College of Osteopathic clinical vascular inflammation leads to progressive , which -CA in Vallejo. Drs Clearfield and Shubrook are contributes to the number 1 cause of global mortality: cardiovascular investigators in the National disease. The syndemic model requires 2 or more or contributors to Institutes of fi Cardiovascular Inflammation disease (such as obesity and climate change) clustering within a speci c Trial. population in addition to the associated societal and social factors, ultimately

Disclaimer: Jay H. Shubrook, creating an environment supportive of a greater adverse interaction. This an associate editor of The article explores the syndemic of obesity and climate change as a driver for Journal of the American cardiovascular disease. Osteopathic Association,was not involved in the editorial J Am Osteopath Assoc. 2018;118(11):719-729 review or decision to publish doi:10.7556/jaoa.2018.157 this article. Keywords: cardiovascular disease, climate change, inflammation, obesity Financial Disclosures: None reported.

Support: None reported.

Address correspondence to umerous breakthroughs in medicine and technology over the past half century Jay H. Shubrook, DO, Touro have addressed risk factors for and management of cardiovascular disease University College of (CVD); yet, despite these successes, CVD remains the number 1 cause of mor- Osteopathic Medicine-CA, N 1 1310 Club Dr, Mare Island, tality in both men and women. The evidence base for treating patients with major CVD Vallejo, CA 94592-1187. risk factors, such as hyperlipidemia, hypertension, and cigarette smoking, have resulted 2-5 Email: [email protected] in both robust improvements and national guidelines. Therapeutic and preventive inter- ventions have continued to improve cardiovascular (CV) outcomes, such that the most Submitted fi December 19, 2017; recent lipid-lowering trials have demonstrated continued bene ts from lowering low- accepted density lipoprotein cholesterol (LDL-C) to levels far below the targets elicited from January 17, 2018. current guidelines.6-10 However, even with the significant benefits associated with aggressive LDL-C lowering, there remains a considerable residual risk in both primary and secondary CV risk populations (Figure 1).

Historical Perspective on CVD Cardiovascular disease steadily increased through the first half of the 20th century, peaking around 1968, when the annual growth flattened.11,12 Since that time, CVD mortality rates have decreased from 507/100,000 to 254/100,000—a 50% decrease; yet, given the growth of the population and especially people aged 65 years or older, CVD remains the number 1 cause of mortality.11 Had the trend from 1900 to 1968 continued, it is estimated that an additional 1 million CVD deaths likely would have occurred in 2014.12

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35

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CV Event Rate, % 10 Placebo Treatment 5

0 IMPROVE IT FOURIER REVEAL JUPITER HOPE-3 Secondary Primary

Achieved LDL: 53 mg/dL 30 mg/dL 38 mg/dL 55 mg/dL 88 mg/dL

Figure 1. Residual cardiovascular (CV) risks in lipid-lowering trials persist despite low-density lipoprotein (LDL) lowering to levels below those generally recommended. Although beneficial, significant residual CV risk remains after . Patients at primary risk have never had a CV event; patients at secondary risk have a CV event in their history. Abbreviations: FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; HOPE-3, Heart Outcomes Prevention Evaluation–3; IMPROVE IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; REVEAL, Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification.

CV Risk Factors factors: total blood cholesterol greater than or equal to Starting in the 1950s and then escalating into the 1960s 240 mg/dL, hypertension, BMI greater than or equal to

was a concern over the steep rise in CV events and mor- 30, hemoglobin A1c greater than or equal to 6.5%, and tality in the United States. To that end, several public current smoker. These risk factors accounted for health initiatives contributed to the plateauing of CV approximately half of the deaths due to CV events in mortality, such as the Surgeon General’s 1964 report 2009-2010.16 Smoking and Health,13 the 1977 Report of the Joint After adjusting for the Behavioral Risk Factor National Committee on Detection, Evaluation, and Surveillance System CV risk factor cut-points, there Treatment of High Blood Pressure,14 and the 1988 remains considerable residual risk. Recent trials17-19 National Cholesterol Education Program Adult suggest that if more robust cut-points were implemen- Treatment Panel report,15 all of which recommended ted for these 5 CV risk factors, the residual risk would more aggressive approaches to CV risk factors. As a still persist, albeit further reduced. component of these guidelines, the traditional risk Other CV and metabolic risk factors include high factors of age, gender, total cholesterol and high- serum glucose, high triglyceride, and low HDL-C density lipoprotein cholesterol (HDL-C) levels, systolic levels. Individually, these risk factors have not demon- blood pressure, smoking history, and were strated similar significant CVD risk reductions as incorporated into the Framingham Risk Score and later found with LDL-C reduction, blood pressure lowering, in the Global Risk Assessment for Primary Prevention and cigarette smoking cessation and, therefore, have not to predict CV risk.2,15 Starting in 1984, the self- promulgated similar guidelines indicating therapeutic reported risk factor status from the Behavioral Risk targets for the management and/or prevention of Factor Surveillance System incorporated 5 CV risk CVD.20-22

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Residual CV Risk and Table. Metabolic Syndrome Waist Circumference Criteria for Metabolic Syndrome27 In the Third Report of National Cholesterol Education Program Adult Treatment Panel III,23 the diagnostic cri- Waist fi teria for metabolic syndrome were de ned as the presence Criteria Circumference of at least 3 of the following 5 risk factors: abdominal ATP III, AHA, ACC obesity, elevated triglyceride level, decreased HDL-C Men ≥102 cm (40 in) level, elevated blood pressure, and elevated fasting Women ≥88 cm (35 in) glucose level. When the metabolic panel of glucose, tri- IDF (European, US, Canada, glycerides, and HDL-C are evaluated collectively for Middle Eastern, Sub-Saharan metabolic syndrome, the residual risk for CVD is African) 24 increased independent of body mass index (BMI). This Men ≥94 cm (37 in) increase in CVD risk with metabolic syndrome may Women ≥80 cm (31 in) fi explain, in part, the signi cant residual risk that remains, IDF (South Asian, Japanese, as shown in Figure 1, when traditional risk factors for Chinese, Ethnic South and Central Americans) CVD are improved.25,26 Additionally, when more than 3 ≥ of the metabolic syndrome risk factors are combined, Men 90 cm (35 in) there is a continuous trend of increasing CVD risk.25 Women ≥80 cm (31 in) Other risk factors, including insulin resistance, proin- Abbreviations: ACC, American College of ; AHA, flammatory state, and pro-thrombotic state, were also American Heart Association; ATP III, Adult Treatment Panel III; IDF, International Diabetes Federation. noted in the definition of metabolic syndrome but were not included in the diagnostic criteria because these risk factors could not be easily identified by routine clin- insulin sensitivity, absent of diabetes, dyslipidemia, or ical evaluation.23 However, these additional metabolic hypertension, and designated as metabolically healthy risk factors are most notably associated with obesity.23 obese (MHO).29-31 The definition of MHO varies somewhat, with the most common being overweight or obese without the presence of metabolic syndrome.31 Residual CV Risk and Obesity Using that definition, the of MHO generally The Canadian guidelines for the diagnosis and manage- ranges from 20% to 30% of the obese/overweight ment of dyslipidemia and the prevention of CVD, as population.24,29,31 well as those from the American College of Clinical Compared with metabolically healthy normal-weight Endocrinologists for management of dyslipidemia and people, metabolically healthy overweight and MHO prevention of CVD, have used the International people tend to progressively increase CV risk as their Diabetes Foundation (IDF) definition for metabolic weight increases when followed up for more than syndrome.27,28 In the IDF model, central obesity (waist 10 years.24,29 This finding suggests that an increase in circumference, 31 inches in women and 35-37 inches in residual CV risk may occur as weight increases in men, depending on ethnicity) is an essential criterion people who are MHO such that about half will transition and requires the addition of 2 of the other metabolic from metabolically healthy to unhealthy over the next risk factors to complete the criteria defining the meta- decade.32 However, the trials investigating MHO did bolic syndrome (Table).28 not control for other metabolic risk factors, such as People with a BMI of 30 or greater without meta- insulin resistance and proinflammatory state; thus, bolic risk factors represent a subgroup with normal people who transition from metabolically healthy to

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unhealthy may represent a modified version of meta- factors, such as remnant lipid, LDL-C, and HDL-C bolic syndrome. In addition, Ortega et al30 included the particle size and number, lipoprotein(a), lipoprotein- level of fitness into the MHO definition and demon- associated phospholipase-A2, homocysteine, uric acid, strated that those with high fitness who had MHO repre- sitosterols, and subclinical inflammation.33 The 2013 sented a subgroup with no apparent additional CV risk. American College of Cardiology and American Heart Association (ACC/AHA) guidelines, as well as the Reynold Risk Score, evaluated many potential risk Residual CV Risk and Normal Weight factors and determined, to date, that these guidelines The converse of MHO is normal-weight obesity, or have insufficient evidence to be included in the people who are of normal weight (BMI <25) but with primary analysis for CV risk.2,34,35 In the future, some metabolic syndrome or insulin insensitivity.28,31 if not many of these risk factors may eventually be People with normal-weight obesity have been shown shown to merit inclusion among the traditional risk to demonstrate an increased CV risk independent of factors. BMI.28,29 Another definition of normal-weight obesity Other modifiable risk factors, such as socioeconomic includes those with a normal BMI but increased waist status, health care access, discrimination and bias, sed- circumference or waist/hip ratio when defining CV entary lifestyle, and lack of fitness may likewise affect risk.33 CV outcomes.16,36 It is beyond the scope of this review In the IDF guidelines, the waist circumference cri- to detail all of these novel risk factors, and we therefore teria were modified by both gender and ethnicity, defin- focus on the unique interactions associated with air ing waist circumference differently depending on the pollution, dysmetabolic obesity, and their interface ethnic populations (Table). In the Multi-Ethnic with socioeconomic factors as they relate to CV risk. Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America trials, cardiometabolic risk factors for nonwhite popula- Residual CV Risk and Subclinical tions (specifically Chinese Americans, blacks, Inflammation Hispanics, and South Asian Americans) demonstrated In the 2013 ACC/AHA guideline on the treatment of greater CV risk and risk factors compared with white blood cholesterol, a group of biomarkers and non- populations at a BMI of 18 to 25.19 When the BMI invasive tests were recommended for consideration in fell into overweight and obese categories, the loss of people for whom the decision to treat remained the disproportionate increase in metabolic risk in non- unclear.2 Additional CVD risk factors include family white groups essentially disappeared, as it aligned with history of premature CVD, high-sensitivity CRP the CV risk in the white population.19 (hs-CRP) greater than or equal to 2 mg/L, ankle bra- chial index less than 0.9, coronary artery calcium score greater than or equal to 300 Agatston units or greater Residual CV Risk and Emerging than or equal to the 75th percentile for age, gender, Risk Factors and ethnicity. Defining CV risk usually involves the risk from the Pertinent to this discussion was the inclusion of the traditional risk factors of age, gender, total cholesterol, inflammatory biomarker hs-CRP.2 The added CV risk and HDL-C levels, systolic blood pressure, smoking from subclinical inflammation as measured by hs-CRP history, and diabetes. However, once these risk factors has been shown in both men and women to significantly are accounted for, a residual risk remains that may be improve global CV risk prediction.35,37 Results from associated with a of other proposed CV risk the Canakinumab Anti-Inflammatory Thrombosis

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Outcomes Study (CANTOS) demonstrated a significant type of adipose. A mechanistic pathway has been pro- decrease in CV events in participants with a history of posedbywhichPM2.5 induces oxidative and who also had an hs-CRP greater inflammation, resulting in acute, subacute, and chronic than 2 mg/L by reducing inflammation using the select- responses promoting atherosclerosis and CV ive interleukin 1β (IL-1β) inhibitor, canakinumab.38 The events44,45 (Figure 2). CANTOS is the first such trial to focus on decreasing In an analysis of 36 epidemiologic studies evaluating subclinical inflammation as an independent risk factor population-attributable acute triggers for myocardial for reducing CV events. The CANTOS used baseline infarction, traffic exhaust was found to be the single hs-CRP as a downstream surrogate marker for upstream most serious preventable cause to the general public.46 39 inflammation as a result of IL-1β activation. Both short-term and long-term exposure to PM2.5 have Given the significance of inflammation demonstrated been associated with progressive atherosclerosis, CV by the CANTOS, those risk factors most significantly events, and mortality.47,48 In 2015, the impact of air attributed to increasing inflammation via activation of pollution as designated by ambient PM2.5 was the the 1L-1β pathway may be viewed as potential thera- fifth-ranking mortality risk factor globally, resulting in peutic targets to reduce the residual CV risk. Weighted an estimated 4.2 million deaths and 103 million multiple logistic regression analysis of CV risk factors disability-adjusted life years.48,49 adjusted for age and race identified obesity as the risk The Harvard Six Cities Study reported that the PM2.5 factor most strongly associated with elevated hs-CRP averaged between 11 and 29.6 mg/m3 and demonstrated levels.40 a 28% increase in CV events for each 10 mg/m3

increase in PM2.5. In an extended 30-year follow-up, these pollutants were reduced in all 6 cities to less than Residual CV Risk Associated With 18 mg/m3, with an estimated reduction in CV mortality Air Pollution and Climate Change by 30% to 40%.50 Air pollution, especially smaller particulate matter Today, more carbon dioxide is being released into the

(PM) less than 2.5 mm(PM2.5), has been shown to atmosphere and, as a consequence, the oceans are produce an inflammatory response that induces macro- warming and acidifying. The combination of increasing phage release of IL-1α,IL-1β, and IL-33 signaling ocean temperature and acidity diminishes the ocean’s pathways, activating the adaptive immune system via capacity to absorb carbon dioxide emissions at its the nucleotide-binding oligomerization domain–like current level, thus resulting in more PM remaining in the receptor family, pyrin domain-containing 3 (NLRP3) atmosphere and further exacerbating this problem.51 In inflammasome.41,42 Activation of NLRP3 results in the United States, exposure to atmospheric nitric oxide further production of IL-1β, with consequent down- and PM2.5 is 38% higher in communities predominately stream effects driving the inflammatory process by sig- inhabited by Hispanics, blacks, and people in the naling the production of IL-6 and hs-CRP.39 The lowest socioeconomic strata.52 This increased exposure inflammatory cascade provoked by PM2.5 is similar to to pollutants in the atmosphere is implicated in glucose the one instigated in metabolically unhealthy obese dysregulation and insulin resistance, and it may help patients, in whom metabolically unhealthy adipose explain the in both obesity and diabetes in tissue is characterized by increased NLRP3 inflamma- these communities.53,54 The far-reaching global health some activation.43 It appears that the type of adipose effects of pollution fall most heavily on the world’s (metabolically unhealthy vs metabolically healthy) poor communities, where more than 90% of pollution- may induce inflammation and dysmetabolic outcomes, related deaths occur in low-income and middle-income thus increasing the overall risk as a function of the countries.55 The world’s poorest countries remain

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Particulate matter induces pulmonary oxidative stress and in flammation Central

FAT Acute activation of lung autonomic Further activate nerveous system Subacute and chronic Subacute and chronic inflamed fat response with systemic adipokines spillover into circulation (PAI-1, resistin) Can trigger ACS via vasoconstriction and plaque instability

Systemic oxidative stress and Activates liver acute phase inflammation response clotting factors, fibrinogen, CRP

Cell inflammation Increase cytokine Oxidized lipids activated WBC, expression IL-6, dysfunctional HDL platelets TNF-a

Figure 2.

Particulate matter (PM2.5) inducing at-risk adipose cells to acute, subacute, and chronic systemic oxidative stress and inflammation. Abbreviations: ACS, acute coronary syndrome; IL, interleukin; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAI-1, plasminogen activator inhibitor 1; TG, triglyceride; TNF-α, tumor necrosis factor α; WBC, white blood cell.

greatly affected by household air pollution and con- and atmospheric carbon dioxide surpassing 300 parti- taminated drinking water, while rapidly developing cles per million, both starting in the late 1960s and countries are affected by emerging environmental early 1970s.57 hazards, such as ambient air pollution, toxic chemicals, Another intervention occurring at that time was an and pesticides.55 attempt to address one of the perceived risk factors for coronary heart disease—saturated fat—by replacing dietary fat with carbohydrates.58,59 At the same time, The COCCI Syndemic high-fructose corn syrup was moving into the market- The syndemic model requires evidence that 2 or more place as a sweeter and cheaper food additive. In a his- diseases or contributors to disease (such as obesity and torical analysis by Kearns et al,59 it was noted that at climate change) clustering within a specific population, the time of these recommendations, the epidemiologic in addition to the associated societal and economic and mechanistic studies associating sucrose with coron- factors, ultimately creates an environment that supports ary heart disease were available, albeit somewhat less an adverse interaction in a given population. The classic robust than those for saturated fat, resulting in a recom- example of a syndemic is the concurrent of mendation to only recommend reducing cholesterol by HIV and Mycobacterium ,whichresultin substituting polyunsaturated fat for saturated fat.58,59 worsening symptoms, enhanced disease progression, As an unintended consequence of prioritizing the and increased pathogenic load.56 To that end, the emer- reduction of fat in the diet, carbohydrate intake, espe- gence of (1) the obesity coincided with cially fructose consumption, tripled, contributing (2) changes in climate and air quality as a result of PM greatly to the obesity epidemic.60,61

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The Global Burden of Disease Study analyzed 79 behavioral, environmental, and metabolic risks from Dysmetabolic obesity C CVD O Obesity 62,63 1990-2015 in 195 countries and territories. This C Climate study revealed that over the past 25 years, there were 4 C Change I Inflammation risk factors that both increased exposure to the given risk factor and resulted in more than 100 million disability- Adverse Syndemic interaction adjusted life years. The leading risk factor was obesity fol- 62,63 lowed by blood glucose and systolic blood pressure. Enhanced disease The fourth risk factor, which demonstrated both increased and progression associated exposure plus increased disability, was ambient PM.64 Air pollution and with negative CVD climate change Thus, the industrialization of our planet has resulted in health outcomes an increased risk for the development of CVD. Figure 3. The concept of the additive CV risk as a result of The synergisms between dysmetabolic obesity and climate change/air combining obesity, metabolic syndrome, inflammation, pollution to enhance atherosclerosis, subclinical inflammation, and subsequent cardiovascular events. Abbreviation: CVD, cardiovascular disease. and climate change has been reviewed previously.64-66 However, the proposed COCCI (CVD, Obesity, Climate Change, and Inflammation) syndemic highlights In a recent comprehensive review,68 the Lancet this interaction using a different model by also focusing Commission on Pollution and Health concluded that on the biosocial complex, further demonstrating the pollution of land, water, and air is the largest environ- intensification of CVD beyond that noted by any compo- mental cause of disease and premature death globally nent individually (Figure 3). and is responsible for approximately 16% of all deaths worldwide. In the Lancet Commission report,68 it is estimated that nearly 92% of pollution-related deaths Socioeconomic and Environmental disproportionally occur in low- and middle-income Impact on the COCCI Model countries. However, even in countries at a higher- In the syndemic model, certain segments of the popula- income strata, pollution-induced disease and death still tion seem to be more susceptible to adverse outcomes occurs and is noted predominately among minorities than otherwise anticipated for that specific population. and marginalized members of society.68 The concept of syndemics goes beyond , as The 25-year trends from the Global Burden of it encompasses social, environmental, and economic Disease Study mortality rankings place air pollution factors that contribute to further detrimental effects. In fifth and high BMI, seventh.48 What may be even the COCCI syndemic, the obesity epidemic is more more disconcerting relative to the COCCI syndemic is prevalent in the Hispanic and black populations than in that as much as one-third of overweight people may the non-Hispanic white and Asian populations.52,53,67 meet criteria for increased waist circumference33 and

From the COCCI perspective, PM2.5 exposure seems that the harmful impact on and the envir- to induce adverse risk to a greater degree in children, onment may persist in a linear fashion to PM2.5 levels elderly people, racial minorities, and persons in a lower well below our current national safety standard of 12 income strata.68-71 Globally, the attributable deaths and mg/m3.70,71 Using these expanded criteria, these 2 risk disability-adjusted life years from noncommunicable factors may indicate a CV risk greater than reported diseases are increasing to a great degree, owing to and present a plausible explanation as to why a signifi- rising levels of PM2.5 in the most populated low- and cant residual CV risk persists after accounting for the middle-income countries in east and south Asia.49 traditional CV risk factors.

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Discussion Health and Equity,76 to help address how the medical The COCCI syndemic has affected the entire planet and community can respond to this growing concern.74 appears to be growing despite all of our current efforts. This guide is a resource and reference that investigates This growth is promulgated in any region or population the complex and multifaceted connections between with concurrent environmental and/or socioeconomic climate change/air pollution and its disproportionate stresses. Wealthy energy-consuming nations are gener- burden on .76 ally responsible for many, if not most, of these stresses, Given the significant residual risk for CVD after while many of the poorer countries may be the recipient traditional risk factors have been addressed and the of much of the increased risk.49,72 So what can we, as resultant continuation of CVD as the number 1 cause health care professionals, do to help decrease CVD of mortality across the globe, it behooves the health caused by the interaction between dysmetabolic obesity care system to reevaluate and then readdress this crisis. and climate change/air pollution and inflammation? These concerns are exacerbated in low-income popula- On May 10, 2017, the World Obesity Federation pre- tions that are disproportionately affected by an sented a case that “early diagnosis and treatment of increased prevalence of obesity, increased consumption childhood obesity could be considered similar to of carbohydrates, especially those associated with high ,” using the rationale that preventing a fructose corn syrup, and issues with transportation disease can occur through proactive public policy.73 systems, zoning laws, and industrial policies that 49,77 The World Obesity Federation argued that as infectious further increase their PM2.5 exposure. diseases have been effectively controlled by changes to the environment, such as improved sanitation to reduce the levels of communicable diseases, the obesity epi- Conclusion demic could be controlled by changes to the environ- We put forward a hypothesis that a syndemic model ment to reduce the mediators causing obesity.6 Such including CVD, obesity associated with metabolic syn- changes would require collaboration between govern- drome, and climate change/air pollution may create an ments, health care professionals and their organizations, opportunity for novel approaches to improve the CVD environmental authorities, and the food industry, epidemic. However, there is wide belief among physi- among others. However, patients with obesity are also cians that much of the public health and societal issues confronted by implicit and explicit bias, which often germane to this syndemic are not under their purview results in stigmatization, adverse health outcomes, and and therefore “not my job.”78 The result of such an health care disparities, which together create an obs- approach skirts the complexity of this issue and, ultim- tacle for positive interventional efforts.74 ately, results in a disconnect between managing a A similar argument has been made by the American symptom rather than the root cause. The COCCI syn- College of who, in 2016, published75 an demic highlights the importance for the health care urgent call for action by the medical community to community to rise to the challenge to address this address climate change. This statement encourages complex issue as both a social justice issue and a prior- physicians to become educated about climate change ity for overall public health and well-being. and its effect on health and how best to respond. The Center for Climate Change and Health, in partnership References

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