Coronary atherosclerosis, adiponectin and a vegetarian diet : A SYSTEMATIC LITERATURE STUDY

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2015

Coronary atherosclerosis, adiponectin and a

vegetarian diet

A SYSTEMATIC LITERATURE STUDY

VERSION 2

KRISTIAN WESTERLING ANDERSSON SUPERVISOR: STELLA CIZINSKY

SCHOOL OF MEDICINE ÖREBRO UNIVERSITY Bachelor thesis, 15 ECTS JUNE 2015

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1 Abstract:

Background: On a global scale, cardiovascular disease (CVD) is the leading cause of

morbidity and mortality. Several lines of evidence now pinpoint inflammation as a key

regulatory process linking multiple risk factors for atherosclerosis and atherosclerotic

complications with altered arterial biology.

Aims: The aims of this essay are 1) to give an update on some of the possible factors in a

vegetarian diet that may counteract the development of coronary atherosclerosis, and 2) to

discuss if adiponectin could be a link between vegetarian diet and reduction of vascular

inflammation and prevention of coronary atherosclerosis development, and if adiponectin can

be a therapeutic target.

Method: To address my research questions, Primary problem, Intervention, Comparative

intervention and the Outcomes (PICO) were identified to frame this review. Utilizing the

PICO components, the inclusion and exclusion criteria for the literature search decided the

article type of relevance.

Results: 8 studies were included and analyzed.

Conclusion: Increased information about the pathophysiology of atherosclerosis provides a

basis for new approaches of patient management and prevention of atherosclerosis

development via different dietary regimens. Whether this can be done with vegetarian/plant

based diets has not been established. Further studies on the effect of diet on endogenous

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2

Abbreviations:

CABG - coronary artery by-pass graft CAD - coronary artery disease CVD – Cardiovascular disease CRP – C-reactive protein DM – Diabetes mellitus

HMW-ad – high molecular-weight adiponectin IGT – Impaired glucose tolerance

IL-6 – Interleukin-6

LDL - low-density lipoprotein

LMW-ad – low molecular-weight adiponectin MMW-ad – medium molecular-weight adiponectin PCAT - perivascular coronary adipose tissue

PICO - Primary problem, Intervention, Comparative intervention and the Outcomes PM – Purple Majesty

ROS - reactive oxygen species T2DM – type 2 diabetes mellitus TNFα – tumor necrosis factor alpha Total-ad – Total adiponectin VAT – Visceral Adipose Tissue

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3

On a global scale, cardiovascular disease (CVD) is the leading cause of morbidity and mortality. Atherosclerosis is part of this spectrum and characterized by thickening of the arterial wall in large and medium sized arteries due to inflammation, scarring, and cholesterol deposits [1]. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. This hypothesis on the pathophysiology of atherosclerosis provides clinical insight and is a practical tool that may aid patient management. It has also resulted in increased interest in various ways to prevent atherosclerosis development via different dietary regimens, including vegetarian/plant-based diets [2, 3, 4].

1.1 Background

In the 19th century, Rudolf Virchow suggested that atherosclerosis arises as a reaction to injury to the arterial intima. Although accepted as a theory for many years, the pathogenesis of atherosclerosis has evolved over the past 40 years [1]. Ross suggested in 1976 that atherosclerosis formed via a mechanism involving platelet aggregation on endothelial denuding injury [5]. Through gene targeting technology, the action of specific molecules in the pathogenesis of atherosclerosis has been tested in animal experiments. Data from such experiments support hypercholesterolemia and the immune system activation as main factors [1].

Both the innate and adaptive immune systems are involved in atherosclerosis. In addition to warding off infection, inflammatory processes are engaged in the repair mechanisms of damaged tissue, but inflammatory tissue remodeling may give rise to other pathologies. In hyperlipidemic patients, circulating low-density lipoproteins (LDLs) are deposited in the intima of the arterial wall. Here the lipoproteins react with reactive oxygen species (ROS) produced by macrophages or endothelial cells. Macrophages accumulate the oxidized lipids, but because these cells are unable to process the substrate sufficiently, they become bloated with lipids. Surrounded by un-engulfed lipids, the bloated macrophages are known as ”foam cells” and considered a principal element in the histopathology of atherosclerosis [1]. Other tissues, such as adipose tissue cells, also produce inflammatory cytokines. Adipose tissue is found throughout the body, and patients suffering from metabolic syndrome, with a buildup of abdominal adipose tissue (visceral adipose tissue, VAT) are at a higher risk of

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5 developing type II diabetes and atherosclerotic disease. Increased VAT means an increased expression of pro-inflammatory cytokines as well as conversion of androgens into estrogen.

Although adipose tissue produces pro-inflammatory cytokines, it also produces an

anti-inflammatory cytokine, adiponectin [6]. When secreted into the blood stream, adiponectin can be found in three forms of oligomeric complexes, divided into low, medium and high

molecular-weight adiponectin (LMW-, MMW- and HMW-Ad). Studies have shown that patients with coronary artery disease (CAD) have elevated total adiponectin (Total-Ad) concentrations [7]. Patients suffering from type II diabetes and/or obesity are prone to chronic low-grade inflammation and oxidative stress. This environment is adverse for adiponectin secretion [8].

1.2 Perivascular coronary adipose tissue

Far from affecting only larger arteries, atherosclerosis affects arteries of all sizes, including the coronary arteries. Coronary arteries are surrounded by perivascular coronary adipose tissue (PCAT), which is part of epicardial adipose tissue found primarily in the

atrioventricular and interventricular grooves. There are no obvious anatomical boundaries between epicardial adipose tissue and PCAT, but there may be differences in physiology. Epicardial adipose tissue receives blood supply directly from the coronary arteries and their branches, whereas mediastinal adipose tissue receives blood from a branch of a. thoracica

interna, namely a. pericardiacophrenica. The presence of dysfunctional or excessive PCAT is

suspected to be involved in induction of inflammation and later also atherosclerosis, plaque rupture and atherothrombosis [9].

A study by Baker et al. examining excised epicardial adipose tissue from patients who

underwent coronary artery by-pass grafting (CABG) found that epicardial adipose tissue have pathogenic amounts of mRNA comparable to omental adipose tissue. This support the notion that local chronic inflammation as well as systemic contributes to advance the pathogenesis of CAD [10].

1.3 Vegetarian/plant based diet and ischemic heart disease

The list of dietary complements that have effect on CAD is long and growing. The amount of supportive evidence for reducing risk factors of CAD varies, as it can be difficult to control the amount of variables in a varied diet [2]. However, a greater intake of fruits and vegetables has been associated with lower a risk of CVD, all-cause death, and cancer death [11]. This has

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6 led to the general health recommendation of consuming multiple daily servings of fruits and vegetables (5–9/day).

Research indicates an inverse relationship between CAD and based diets [4]. A plant-based diet is not the same as a vegetarian diet, as a plant plant-based diet does include meat, fish, poultry and dairy products. Compared to the average omnivore consumer, plant-based diets derive a greater proportion of food selection from vegetables, grains, legumes, fruits, nuts and seeds. A vegetarian diet excludes meat, poultry and fish (although variations exist, such as pescatarians and lacto-ovotarians, which are vegetarians supplementing their diet with fish or dairy, respectively).

De Lorgeril et al. showed that compared with a control group, a plant-based diet group had a 73% decrease in coronary events and a 70% decrease in all-cause mortality [12]. A

collaborative analysis using original data from 5 prospective studies (Oxford vegetarians, Britain, n = 11047, Health Food Shoppers, Britain, n = 9878, Adventist moral, California, n = 24538, Adventist Health, California, n = 28592 and Heidelberg, Germany, n = 1757) over a mean of 10.6 years showed that, compared with non-vegetarians, vegetarians had 24% reduction in ischemic heart disease death rates [13].

A common misconception is that a vegetarian/plant-based diet is automatically low in fat and that this would be advantageous. Rather than placing emphasis on the quantity of fat, both clinical and epidemiologic studies have yielded results stressing that the type of fat is of greater importance for CAD [3].

Kahleova et al. presented a study of how a calorie-restricted vegetarian diet affects insulin resistance and inflammatory markers in type 2 diabetes mellitus (T2DM) [14]. Data showed an increase in adiponectin in the experimental group, while no change in the control group. This indicates a potential relationship between vegetarian diet and adiponectin levels.

2. Key questions

An association between inflammation and the development of atherosclerosis has been established [1]. Vegetarian/plant-based diets containing various factors seem to reduce the development of atherosclerosis. Do these factors act by reducing vascular inflammation? Do they act via a common link, and if so, can a common link be identified?

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7 2.1 Aims

My aims of this essay are 1) to give an update on some of the possible factors in a vegetarian diet that may counteract the development of coronary atherosclerosis, and 2) to discuss if adiponectin could be a common link between vegetarian diet and reduction of vascular inflammation and prevention of coronary atherosclerosis development. I will also discuss the possibility of adiponectin as a therapeutic target in patients with coronary atherosclerosis.

3. Method

3.1 Literature search

To address my research questions, Primary problem, Intervention, Comparative intervention and the Outcomes (PICO) were identified to frame this review. Utilizing the PICO

components, the inclusion and exclusion criteria for the literature search decided the article type of relevance [15]. The inclusion criteria included all patient-based studies involving coronary atherosclerosis, inflammation, CVD, PCAT and polyphenols with regard to adiponectin and/or vegetarian diet.

The literature search consisted of three phases: 1) selection of studies based on the inclusion and exclusion criteria, attempting to include as many relevant studies as possible. The search encompasses relevant scientific papers published between 1976 and 2015. Papers have to be written in English and include adult subjects only. A few experimental studies were included to support molecular mechanisms. Table 1 (see appendix I) summarizes the keywords, search results and selection criteria. 2) Quality assessment of the articles. Reading abstracts and then excluding articles based on relevance. 3) Displaying relevant data to answer the aims of this review.

3.2 Quality assessment

To ensure a manageable number of articles, all duplicates were removed reducing the total number of articles from 97 to 59. The next exclusion was of articles which investigate children, as this review will focus on adults (remaining n = 58). The next exclusion was of articles where the main polyphenol source investigated is not through a plant-based or vegetarian diet. Thus all studies investigating wine, tea, cocoa powder, and juice were excluded (remaining n = 34). All studies primarily focusing on exercise were also excluded (remaining n = 29). Studies which focus on diseases not primarily associated with coronary atherosclerosis, atherosclerosis and CVD were excluded (remaining n = 26). From these 26 papers, 18 articles were excluded as the research focus of the papers was not on adiponectin in

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8 relation to vegetarian diet (remaining n = 8). Thus, 8 papers remained for further analysis [8, 10, 16, 17, 18, 19, 20, 21].

3.3 Ethical considerations

Since all papers presented in this essay have been published in peer-reviewed journals, I have made the assumption that any ethical permits required already have been obtained prior to publication by the original authors.

With regards to the present essay, no patient journals have been used, and thus no identifying data has been accessed.

4. Results

4.1 The effect of a vegetarian diet.

The Lifestyle Heart Trial, a prospective, randomized, controlled trial, investigated whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year. The study consisted of 48 patients, 28 in the experimental group (low-fat vegetarian diet, stopping smoking, stress management training, and moderate exercise), and 20 in the usual-care control group. The Lifestyle Heart Trial found that 82% of patients diagnosed with heart disease who followed a plant-based diet program had some level of regression of atherosclerosis [16].

A follow-up randomized clinical trial study consisting of 93 patients investigated whether patients could be motivated to make and sustain comprehensive lifestyle changes over 5 years, and if so, whether the progression of coronary atherosclerosis could be stopped or reversed without using lipid-lowering drugs as measured by computer-assisted quantitative coronary arteriography. The experimental group had a greater regression of coronary atherosclerosis after 5 years than after 1 year. In the experimental group, 91% experienced reduction in the frequency of angina pectoris episodes. 53% in the control group, nourished by the American Heart Association diet, had progression of atherosclerosis [17]. The reduction in low-density lipoprotein (LDL) in the experimental group was comparable to results achieved with lipid-lowering medications.

Of all the vegetables consumed daily per capita in the United States, potatoes rank as number 1 [18]. Especially pigmented potatoes contain high concentrations of antioxidants, including phenolic acids, anthocyanins, and carotenoids. Vinson et al. present data from two studies in their article, one smaller single dose study (8 participants; 7 males and 1 female) and one larger (18 participants; 7 males and 11 females). In the single dose study subjects were required to adhere to a low polyphenol diet 3 days prior to the study. The participants had to

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9 refrain from food items such as alcoholic beverages, coffee, tea, cola, chocolate, fruits,

vegetables, and fruit juices, however meat, milk products, and pasta were allowed. The participants then fasted 10h prior to obtain fasting blood samples. 24 hour urine was collected the day prior to the appointment. The participants consumed 6-8 small potatoes (Purple Majesty, PM) with skins or the equivalent amount of potato starch (in biscuit form) along with 240 ml of water. The procedure was repeated so that data was collected from each participant both with whole potatoes and with potato starch [18].

In the supplement study, participants were instructed to consume six to eight microwaved small PM potatoes with skins for lunch and dinner daily for a period of 4 weeks. The potatoes were provided to the participants, and reheated by microwave for a time period determined by the participant. No other potatoes were consumed during the study. Two 7-day food

consumption questionnaires were filled out during the study. Half the subjects (randomly chosen) were given potatoes at the beginning of the study and half the subjects were given no potatoes to consume. After 4 weeks, the groups were switched and after an additional 4 weeks the study concluded [18].

Vinson et al. found that in the single dose, with the potato diet the amount of antioxidants in plasma and urine increased, whereas with the refined potato starch both decreased. The researchers concluded that refined potato starch acted pro-oxidative. In the supplement study, the researchers observed that when the participants had been on the potato diet, both their diastolic and systolic blood pressure had decreased 4.3% and 3.5% respectively. PM potatoes were concluded to be an antihypertensive agent [18].

Covas et al. performed a large randomized cross-over controlled trial on the antioxidative effects of phenolic compounds found in olive oil [19]. Of the 344 men aged 20-60 screened, 200 were selected to participate in the study. Inclusion criteria were for the participant to be a strict non-smoker, have normal blood pressure, provided written informed consent and were in general good health. Exclusion criteria included besides smoking, taking antioxidant supplements, hyperlipidemia, obesity, diabetes, hypertension, intestinal disease or any other disease. Women were excluded to avoid potential interference from estrogens. The

participants were then randomly assigned to three groups receiving three different daily doses of olive oil (high in phenols 366 mg/kg, medium in phenols 164 mg/kg and low 2.7 mg/kg). The daily dose consisted of 25 mL (about 22 g) replacing other raw fats. The regimen was carried out for 3 weeks followed by a 2 week wash-out period. The study investigated

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10 of the antioxidant status of the participants. Parameters were measured at the beginning of the study, pre-intervention and post-intervention. Blood samples were collected at fasting state together with 24-hour urine, and anthropometric variables were recorded. The researchers found that oxidative stress markers decreased linearly with increasing phenolic content of the oils. The conclusions from the study was that the phenolic content of olive oil can provide benefits regarding plasma lipid levels and risk of oxidative damage [19].

4.2 The role of adiponectin.

Increasing adiponectin by using the lipid-lowering drug niacin failed to generate improvement of endothelial function, insulin sensitivity and anti-inflammation according to a clinical trial study by Westphal et al. [20]. Short-term (6 weeks) niacin treatment was administered in a randomized, placebo-controlled, double-blind study of 30 men with the metabolic syndrome. Despite an increase of adiponectin by 56% compared to the study participants receiving placebo, inflammatory parameters such as resistin, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6) and C-reactive protein (CRP) remained constant [20].

However, when attempting to raise adiponectin levels using fenofibrate (a cholesterol

reducing drug) in another study [21], the results were quite different compared to Westphal et al. The study encompassed 46 patients with primary hypertriglycemia (24 with metabolic syndrome) in a randomized, double blinded placebo controlled, cross-over design. With a daily dosage of 200 mg fenofibrate for 8 weeks, the experimental group showed decreased inflammatory markers, increased adiponectin and increased insulin sensitivity in both hypertriglycemic and metabolic syndrome patients [21]

Baker et al. obtained excised epicardial adipose tissue in 46 CABG patients and compared it with samples of adipose tissue collected from three other areas (abdominal subcutaneous adipose tissue n = 30, omental adipose tissue, n = 14 and thigh adipose tissue, n = 13) from non-CABG, non-T2DM patients undergoing elective surgery. Blood samples were collected prior to surgery and serum levels of insulin, adiponectin, leptin, CRP and resistin were measured and compared to 38 non-diabetic patients with no prior history of CAD. The patients in the CABG-group showed a fivefold decrease in adiponectin expression compared to thigh controls. Adiponectin expression was significantly lower in both abdominal

subcutaneous and omental adipose tissue [10].

Sun et al. determined serum adiponectin, CRP, TNF-α and IL-6 in 50 impaired glucose tolerance (IGT) patients and 106 T2DM patients all suffering from periodontitis [8]. The

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11 participants were divided into three groups, the IGT group (50 patients), T2DM without macrovascular disease group (DM1 group, 58 patients) and T2DM with macrovascular disease group (DM2 group, 48 patients). The DM2 group included 20 patients with heart disease, 12 with carotid artery atherosclerosis, 14 with lower extremity atherosclerosis, 2 with carotid atherosclerosis and coronary heart disease. All three groups were then divided into two subgroups, one group that received periodontal treatment and one group that did not receive periodontal treatment. The experimental group was compared to a control group of 30 healthy participants (17 men, 13 women). The results showed that the treated subgroup had increased serum adiponectin which supports that inflammation suppresses adiponectin release [8].

5. Discussion

As outlined by Gardner in 2001 [2], there’s no “silver bullet fix” for CAD through a simple ”eat this - do not eat that.” The reality is that the dietary factors influencing CAD are complex and could very well present a challenge for nutrition professionals to present the findings to the public. Increased information about the pathophysiology of atherosclerosis provide a basis for new approaches to patient management, and in different ways to prevent atherosclerosis development via various dietary regimens [2, 3, 4].

5.1 Effects of factors in vegetarian/plant-based diets.

Polyphenols derived from dietary plant intake have protective effects on vascular endothelial cells, possibly as antioxidants that prevent the oxidation of low-density lipoprotein. A review by Vita [22] suggested that the reduced risk of CAD events may be related to beneficial effect of polyphenols on endothelial cell function. On the basis of cell culture studies, it was

suggested that polyphenols may positively affect critical steps in atherogenesis, including LDL oxidation, nitric oxide release, inflammation, oxidative stress, cell adhesion, foam cell formation, smooth muscle cell proliferation, and platelet aggregation. Positive support for a beneficial clinical effect of polyphenols was provided by Zamora-Ros et al. [23] who evaluated the relationship between total urinary polyphenols (TUP) and all-cause mortality during a 12-year period among older adult participants. The authors concluded that TUP is an agent which independently reduces mortality among community-dwelling older adults and that a high dietary intake of polyphenols may be associated with longevity. One of the strengths of Zamora-Ros’ study is the number of participants (807) of both sexes. This

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12 Zamora-Ros’ study is that they only measured TUP at enrollment, not continuous throughout the study. This does not take into account that the TUP most likely would have fluctuated during the course of the study, depending on the polyphenol content of individual meals.

Other studies have shown that polyphenols may have an effect on LDL oxidation. In one study, dietary polyphenols reduced plasma LDL oxidation by 20% [24]. Resveratrol and alcohol-free wine polyphenols protected LDL from oxidation [25]. These data suggest that polyphenols found in fresh fruits and vegetables may help prevent atherogenic lesions by down-regulating oxidation of LDL. There is also evidence that dietary intakes of flavanones, anthocyanidins, and certain foods rich in flavonoids may be associated with lower CHD and total CVD mortality in postmenopausal women [26].

The Lifestyle Heart Trial presented data suggesting that diet can be effective against the progression of atherosclerotic lesions [16, 17], yet this was in combination with cessation of smoking, exercise and encouragement. It is difficult to claim that diet alone caused the positive effects.

How vegetables are prepared does matter. Vinson et al. described how frying potatoes in hot oil incorporates the fat into the potato, thus raising the fat content while significantly reducing the mineral and ascorbic acid content per weight[18]. An alternative cooking method such as boiling or steaming vegetables would thus help maintain the mineral and ascorbic acid content.

Animal studies have demonstrated a mechanistic link between intestinal microbial

metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and CAD through the production of a pro-atherosclerotic metabolite, trimethylamine-N-oxide (TMAO). Since omnivorous human subjects were found to produce more TMAO than did individuals who consumed primarily a plant-based diet (vegans or vegetarians) [27], an appropriately designed probiotic intervention may serve as a therapeutic strategy for CVD.

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13 Figure 1: From diet to disease. High fat foods are rich in the phospholipid phosphatidylcholine (PC) and its metabolite choline (C). Intestinal biota converts C to TMA. The enzyme FMO3 metabolizes TMA to TMAO. The metabolite is then dispersed via blood and may lead to plaque formation. After a figure by Rak and Rader [28]

Thus, manipulation of commensal microbial composition may be a novel therapeutic approach for the prevention and treatment of atherosclerotic heart disease and its complications.

5.2 The role of adiponectin

Can adiponectin be the common link between the factors in vegetarian/plant-based diets that reduce vascular inflammation and prevent coronary atherosclerosis development, and thus be a therapeutic target in patients with coronary atherosclerosis? Circulating adiponectin levels are inversely related to the inflammatory process [8], oxidative stress, and metabolic

dysregulation. Intensive lifestyle modifications and pharmacologic agents, including PPARγ agonists, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders [29, 6]. Understanding of the dietary interventions that can modulate adiponectin may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, obesity and coronary atherosclerosis.

5.3 Systematic literature study as a method

The challenge of a systematic literature study is on formulating the right question, and selecting appropriate key words when performing the search [15]. It also requires diligence and careful selection also when excluding papers to avoid bias. Not selecting key words specific enough yields a large number of papers, making the selection process time consuming. PICO can work beautifully when well formulated. Experience in reading reference materials will speed up and facilitate the process, yet the only way to acquire experience is by trying.

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14 6. Conclusions

Many factors in vegetarian/plant based diets seem to be able to reduce the inflammatory reaction that leads to development of coronary atherosclerosis. Modulating adiponectin may be a possibility to improve vascular health. Whether this can be done with vegetarian/plant based diets has not been established, and further studies on the effect of diet on endogenous adiponectin are needed in order to better understand the role of the cytokine in atherosclerosis.

7. Acknowledgements

I would like to thank Dr. Ole Fröbert for his help hunting down references and willingness to offer constructive criticism. I would also like to thank Dr. Johan Brandt for his help and willingness to discuss the paper right up to the deadline.

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15 8. References

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4. Tuso P, Stoll SR, Li WW. A plant-based diet, atherogenesis, and coronary artery disease prevention. Perm J. 2015 Winter;19(1):62-7.

5. Ross R, Glomset JA. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med. 1976 Aug 12;295(7):369-77.

6. Lim S, Quon MJ, Koh KK. Modulation of adiponectin as a potential therapeutic strategy. Atherosclerosis.2014 Apr;233(2):721-8.

7. Rizza S, Gigli F, Galli A, Micchelini B, Lauro D, Lauro R, Federici M. Adiponectin isoforms in elderly patients with or without coronary artery disease. J Am Geriatr Soc. 2010

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8. Sun WL, Chen LL, Zhang SZ, Ren YZ, Qin GM. Changes of adiponectin and inflammatory cytokines after periodontal intervention in type 2 diabetes patients with periodontitis. Arch Oral Biol. 2010 Dec;55(12):970-4. doi: 10.1016/j.archoralbio.2010.08.001.

9. Maurovich-Horvat P, Kallianos K, Engel LC, Szymonifka J, Fox CS, Hoffmann U, Truong QA. Influence of pericoronary adipose tissue on local coronary atherosclerosis as assessed by a novel MDCT volumetric method. Atherosclerosis. 2011 Nov;219(1):151-7.

10. Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D, Bonser RS, Kumar S, McTernan PG. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol. 2006 Jan 13;5:1.

11. Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ. Fruit, Vegetable, and Antioxidant Intake and All-Cause, Cancer, and Cardiovascular Disease Mortality in a Community-dwelling Population in Washington County, Maryland. Am J Epidemiol. 2004 Dec 15;160(12):1223-33.

12. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial

infarction: final report of the Lyon Diet Heart Study. Circulation. 1999 Feb 16;99(6):779-85. 13. Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, Burr ML, Chang-Claude

J, Frentzel-Beyme R, Kuzma JW, Mann J, McPherson K. Mortality in vegetarians and non-vegetarians: a collaborative analysis of 8300 deaths among 76,000 men and women in five prospective studies. Public Health Nutr. 1998 Mar;1(1):33-41.

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16 14. Kahleova H, Matoulek M, Malinska H, Oliyarnik O, Kazdova L, Neskudla T, Skoch A, Hajek

M, Hill M, Kahle M, Pelikanova T. Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with Type 2 diabetes. Diabet Med. 2011 May;28(5):549-59. doi: 10.1111/j.1464-5491.2010.03209.x.

15. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP J Club 1995;123(3):12-3.

16. Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990 Jul 21;336(8708):129-33.

17. Ornish D, Scherwitz LW, Billings JH, Brown SE, Gould KL, Merritt TA, Sparler S, Armstrong WT, Ports TA, Kirkeeide RL, Hogeboom C, Brand RJ.

Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998 Dec 16;280(23):2001-7.

18. Vinson JA, Demkosky CA, Navarre DA, Smyda MA. High-antioxidant potatoes: acute in vivo antioxidant source and hypotensive agent in humans after supplementation to hypertensive subjects. J Agric Food Chem. 2012 Jul 11;60(27):6749-54. doi: 10.1021/jf2045262. Epub 2012 Feb 6.

19. Covas MI, Nyyssönen K, Poulsen HE, Kaikkonen J, Zunft HJ, Kiesewetter H, Gaddi A, de la Torre R, Mursu J, Bäumler H, Nascetti S, Salonen JT, Fitó M, Virtanen J, Marrugat J; EUROLIVE Study Group. The effect of polyphenols in olive oil on heart disease risk factors: a randomized trial. Ann Intern Med. 2006 Sep 5;145(5):333-41.

20. Westphal S, Borucki K, Taneva E, Makarova R, Luley C. Extended-release niacin

raises adiponectin and leptin. Atherosclerosis. 2007 Aug;193(2):361-5. Epub 2006 Aug 2. 21. Koh KK, Han SH, Quon MJ, Yeal Ahn J, Shin EK. Beneficial effects of fenofibrate to

improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care. 2005 Jun;28(6):1419-24.

22. Vita JA. Polyphenols and cardiovascular disease: effects on endothelial and platelet function. Am J Clin Nutr. 2005 Jan;81(1 Suppl):292S-297S.

23. Zamora-Ros R, Rabassa M, Cherubini A, Urpí-Sardà M, Bandinelli S, Ferrucci L, Andres-Lacueva C. High concentrations of a urinary biomarker of polyphenol intake are associated with decreased mortality in older adults. J Nutr. 2013 Sep;143(9):1445-50.

24. Carmeli E, Fogelman Y. Antioxidant effect of polyphenolic glabridin on LDL oxidation. Toxicol Ind Health 2009 May-Jun;25(4-5):321-4.

25. Frémont L, Belguendouz L, Delpal S. Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sci

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17 26. Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA, Jacobs DR Jr.

Flavonoid intake and cardiovascular disease mortality: a prospective

study in postmenopausal women. Am J Clin Nutr. 2007 Mar;85(3):895-909

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18 9. Appendix I

Table 1 Results of literature search in pubmed

Subject matter Key words Hits Relevance to the heart

Clinical trials

Studies included (n)

Atherosclerosis atherosclerosis AND vegetarian diet 63 19 3 2 atherosclerosis AND inflammation 13891 2497 151 0 atherosclerosis AND adiponectin 1232 190 19 0 atherosclerosis AND inflammation

AND adiponectin

372 71 8 8

Coronary atherosclerosis

coronary atherosclerosis AND vegetarian diet

44 19 2 2

coronary atherosclerosis AND Inflammation

5928 2340 227 0

coronary atherosclerosis AND adiponectin

624 211 23 0

coronary atherosclerosis AND inflammation AND adiponectin

144 67 7 7

Inflammation inflammation AND vegetarian diet 34 3 0 0 inflammation AND adiponectin 2752 253 30 30 Cardiovascular

disease

cardiovascular disease AND vegetarian diet

404 133 11 0

cardiovascular disease AND inflammation

52467 13848 923 0

cardiovascular disease AND adiponectin

3386 811 73 0

cardiovascular disease AND atherosclerosis

68177 16140 1442 0

cardiovascular disease AND inflammation AND adiponectin

870 186 18 0

cardiovascular disease AND

inflammation AND adiponectin AND atherosclerosis

263 61 7 7

cardiovascular disease AND

inflammation AND adiponectin AND atherosclerosis AND vegetarian diet

0 0 0 0

perivascular coronary adipose tissue

perivascular coronary adipose tissue AND vegetarian diet

0 0 0 0

perivascular coronary adipose tissue AND inflammation

37 26 1 0

perivascular coronary adipose tissue AND atherosclerosis

36 21 1 0

perivascular coronary adipose tissue AND adiponectin

21 15 0 0

Polyphenols polyphenols AND vegetarian diet 10 4 0 0

polyphenols AND inflammation 780 28 4 4

polyphenols AND atherosclerosis 345 49 4 4

polyphenols AND adiponectin 29 1 0 0

polyphenols AND coronary atherosclerosis

80 37 6 6

polyphenols AND cardiovascular disease

1093 224 22 22

polyphenols AND perivascular coronary adipose tissue

0 0 0 0

polyphenols AND inflammation AND atherosclerosis

61 4 2 2

polyphenols AND inflammation AND coronary atherosclerosis

8 5 3 3

polyphenols AND inflammation AND atherosclerosis AND cardiovascular disease

37 4 2 2

Preliminary n =

Coronary atherosclerosis, adiponectin and a vegetarian diet : A SYSTEMATIC LITERATURE STUDY