Keywords

Introduction

Cardiovascular disease (CVD) and subsequent heart failure claims at least half a billion lives every year, around the globe. According to estimates available through the World Health Organization, around 17.9 million people died of CVD in 2016 [1]. There are a number of risk factors for the development of CVD such as hypertension, diabetes, hyperlipidemia, coronary disease, valvular disease and certain genetic mutations [2,3,4]. In combination with neurohormonal and cellular changes, the heart is capable of acutely compensating for many of the stresses arising from these pathophysiological conditions through a combination of structural and functional remodeling [5]. However, prolonged stress leads to maladaptive remodeling and the permanent loss of function of the heart and culminates in heart failure [6]. There are a number of therapeutic strategies currently being used to prevent, abate or reverse the development of heart failure [7]. For mild cases of CVD, life style modifications is the first step of therapy and pharmaceutical agents are prescribed when the disease has already progressed beyond what is manageable with life style changes [8, 9]. In certain cases such as valvular disease, electrical abnormalities and structural disabilities of the heart at birth, surgeries or devices such as pacemakers are used as the first step in treatment of the disease [7]. However, despite all of the modern biomedical inventions and advanced therapeutic methodologies, heart failure still claims millions of lives every year around the globe. This scenario leads us to think of alternative strategies that may more effectively prevent the development or arrest the progression of CVD into overt heart failure and mortality.

The obesity epidemic is directly and indirectly associated with millions of deaths every year [10]. Obesity is a condition wherein excess fat gets deposited under the skin and in other major organs of the body. This increased adiposity further increases risk of development of diabetes, hypertension, vascular diseases and other independent risk factors of cardiovascular disease [11]. Heart failure is a major cause of death in obese patients and the millions of individuals becoming obese every year are at risk of developing some form of heart disease [12].

Family genetics, gene abnormalities, diet, level of physical activity and other environmental factors are considered to be the major risk factors of obesity [13,14,15,16]. Genetic predisposition, together with diet plays a significant role in the development of obesity [17]. The development and increased availability of energy dense foods has certainly boosted the incidence of obesity around the globe (Fig. 15.1) [18]. High caloric intake accompanied by low physical activity results in increasing lipids stored as fat. After a certain point, cells that store fat (adipocytes) cannot keep up with the demand and become dysfunctional [19]. Healthy, smaller adipocytes secrete cardioprotective beneficial adipokines such as adiponectin. In contrast, dysfunction, enlarged adipocytes secrete pro-inflammatory adipokines such as leptin [20]. This adipocyte dysfunction leads to high levels of circulating lipids which subsequently results in increased uptake of lipids by other organs. Increased lipid deposition contributes to cellular stresses resulting in dysfunction of the organ [21]. The heart is one of the target organs in hyperlipdemic situations and the resulting stress causes cardiac dysfunction that culminates in heart failure [22].

Fig. 15.1
figure 1

Evolution of obesity. From: https://www.flickr.com/photos/christopherdombres/7350782488

Full size image

Earlier forms of therapies were all derived from natural products. Different types of plants were used to treat all human ailments [23, 24]. Many of these medications were either eaten as the food by itself or mixed in combination with other foods [25, 26]. Nutraceuticals is the modern term for compounds that are naturally derived that, together with nutrition, delivers medicinal effects [27]. By this definition, resveratrol (RES) can be considered a nutraceutical as it is a polyphenol that is mainly found in grapes and other berries. Over the years, research has shown that RES has strong medicinal properties against a variety of human ailments including cancer, cardiovascular diseases, diabetes and some types of infections [28]. Cardioprotective properties of RES have been well documented and has recently also been shown to be beneficial in human clinical trials [29, 30].

Obesity

Obesity is a condition wherein excess fat accumulates in the body. A way to assess obesity is to classify individuals using the body mass index (BMI) which is calculated by dividing body weight by the square of that individual’s height. For adults the classification of obesity states is as follows (Table 15.1).

Table 15.1 Classification based on BMI
Full size table

However, BMI is not a direct measure of fat stores and hence additional measurements are required to calculate the levels of body fat [31]. Waist circumference, skin fold test, waist to hip ratio calculation and modern techniques such as whole-body air displacement plethysmography (ADP), underwater weighing, dual energy X-ray absorptiometry (DXA) and even ultrasound techniques can be used to accurately determine body fat composition [32,33,34,35,36]. A small percentage of the obese population are completely healthy despite being obese and are often termed as being “healthy-obese” [37]. However, in most cases obesity is accompanied by several comorbidities and obese individuals experience poor quality of life and suffer psychologically from social stigma [38, 39]. Obesity is a manageable condition and in some cases completely reversible with life style changes including increasing physical activity, adopting a caloric restricted diet, taking medications and in some cases surgery [40,41,42]. Irrespective of the status of national development (underdeveloped, developing or developed), the growing incidence of obesity and increased dependence on health care systems has become a major worldwide concern [43,44,45,46,47].

World Statistics

At least 2.8 million deaths that occur every year are associated with being obese or overweight. The prevalence of obesity worldwide has almost tripled since 1975 and as of 2016, a total of more than 1.9 billion adults were considered obese or overweight. Shockingly, more people reside in countries where obesity causes more deaths than being underweight [48]. The prevalence of obesity was highest in the Americas (approximately 62% overweight and 26% obese) and lowest in South East Asia (approximately 14% overweight and 3% obese). Women are reported to be more prone to obesity when compared to men around the world [48, 49]. In some African and Mediterranean countries, the prevalence of obesity in women is almost double that of men. Income is also correlated with the increased prevalence of obesity [18].

Canadian Statistics

According to the latest data published by Statistics Canada, roughly 1 in 4 Canadian adults (27%) are obese [50]. Statistics Canada data from 2018 shows that 69.4% of men and 56.7% of women 18 years and older are overweight or obese [51]. These estimates are higher than from the self-reported data in 2009 which showed 59.2% of Canadian men and 43.9% of women in the overweight or obese category [52]. The number of obese children and youth is also increasing with 30% between the ages of 5 and 17 being obese or overweight [53,54,55]. The geographic distribution of obesity varies within the country. The lowest reported prevalence being 22% in British Columbia, while the highest in New Brunswick along with Newfoundland and Labrador where prevalence is as high as 38% [50]. Obesity is also seen more commonly in certain ethnic populations [56, 57].

Obesity in Children

Childhood obesity is another major area of concern as it possesses several health risks including cardiovascular disease and early mortality in their adulthood [54, 58, 59]. Based on data from Statistics Canada in 2018, 23.7% of children between the ages 12–17 years are overweight or obese [51]. Obesity in children and youth is measured using a different set of BMI cut-offs. According to the International Obesity Task Force (IOTF), a BMI greater than 21.22 and 26.02 kg/m2 for 12 year old boys and girls respectively, is categorized as obese. There are other systems of BMI categories so the estimates of childhood obesity may vary accordingly. For example, in the 2004 Canadian Community Health Survey based on the IOTF system, obesity rates were reported to be 8.2% among children and youth (2–17 years). However, based on the Centers for Disease Control system, the estimate increased to 12.7%, while based on the WHO system it was estimated to be 12.5% [60].

Health Costs

Obesity is associated with a number of co-morbidities. The risk of type 2 diabetes, hypertension, cardiovascular diseases and cancers increases significantly with being obese. Due to social stigma around obese individuals, a number of psychological conditions are also prevalent among the obese [61, 62]. Premature mortality rates are also reported to increase alongside the severity of obesity [10]. All these factors contribute to an increased life time dependence on the health care system by these individuals when compared to the non-obese. This directly results in higher than normal health expenditure per obese individual and puts a burden on the health care system. Estimates based on 2008 data put health care costs related to obesity between $4.6 billion to $7.1 billion per year [63]. These cost figures show how important it is to ramp up the awareness and fight against obesity, especially among those who are in the higher risk categories [64].

Overall, the increasing prevalence of obesity is a major global health concern and needs immediate attention to protect future generations. Race, sex, income and other socioeconomic factors have been seen to be associated with increased risk for obesity [65]. Childhood obesity is also increasing which is particularly alarming given that the risk of obesity increases with age. Childhood obesity also results in early onset of comorbidities such as diabetes, hypertension and reduced life expectancy [66].

Pathology of Obesity

Adiposity/obesity and Adipose Dysfunction

Obesity is a condition that develops due to excess fat deposition in the body overtime. Generally, excess energy in the body is stored as fat. Accordingly, the amount of fat stored is the difference between food (energy) intake and energy expenditure (Fig. 15.2).

Fig. 15.2
figure 2

Energy balance

Full size image

Human body stores excess circulating lipids in adipocytes [67, 68]. These stored fats are kept as a reserve energy bank that is used during a state of fasting [69]. Adipocytes are normally an integral part of the human body and are required for normal physiology. However, when circulating lipids are chronically higher than normal, the amount of fat deposits also increases. Overtime, the increased adiposity results in pathological changes of obesity [70]. There are many factors such as energy dense diet, physical inactivity, gene mutations and/or other pathophysiological conditions that contribute to increased circulating lipids [71, 72].

Adiposity could be increased in two different ways, either by increasing the number (hyperplasia) or the size (hypertrophy) of adipocytes [73, 74]. The first is considered to be physiological; while the second, wherein the adipocyte enlarges, is considered pathological [75]. Earlier, adipose tissues were considered as just a store of fat. However, later it was discovered that adipose tissues are also an endocrine organ and adipocytes secrete hormones (adiponectin, leptin and resistin), cytokines (TNF-α, IL-6) and proteins (cholesteryl ester treansfer protein, angiotensin II, plasminogen activator inhibitor 1) involved in the metabolism and functions of the liver, muscles, vasculature, brain and other organs of the body [76]. Cytokine secretions from adipocytes are generally known as adipokines [77]. Some adipokines are beneficial while others cause unhealthy effects on biological functions [20]. In normal or healthy conditions, adipocytes secrete more adipokines which are beneficial, while in pathophysiological conditions where adipocyte dysfunction occurs, the balance will be shifted to an increased release of detrimental adipokines [75, 77]. The origin of adipocyte dysfunction is mainly associated to the physiological demands of storing very high levels of fat. Resident macrophages are also present among the adipocytes and are involved in fat storage and secretion of cytokines. The adipocytes and macrophages are highly involved in the genesis of chronic inflammation in the adipose tissue and release of pro-inflammatory factors into the blood [78]. Consequently, there is also increased lipolysis and release of free fatty acids into circulation. Accordingly, adipose tissue is considered to be the major source of the pathophysiological effects in obesity [19, 79]. This also makes adipocytes a potential drug target to ameliorate the metabolic disarray in obese conditions. To some extent, targeting adipocyte dysfunction has shown promise in preventing or improving metabolic imbalances in obesity [80].

Obesity and Cardiovascular Disease

According to seminal Framingham Heart Study, the risk of developing heart failure in obese individuals was 2 times that of normal weight subjects [81]. It has been found that 32−49% of heart failure patients are considered obese; furthermore, obese patients develop heart failure up to 10 years earlier than their normal BMI counterparts [82]. Cardiovascular complications are one of the major contributors to poor health and lower life expectancy among obese populations [83, 84]. Obesity, especially abdominal obesity, is an independent risk factor for CVD [85, 86]. Higher BMI is directly associated with adipocyte dysfunction, increased release of adipokines, insulin resistance, hypertension, increased inflammation and oxidative stress that promotes the development of cardiovascular disease [87]. Although not unanimously accepted, the ‘obese paradox’ theory claims that obese individuals have a better prognosis to CVD when compared to normal weight individuals [82]. A possible explanation for this paradoxical theory is that the BMI measurements are insufficient to accurately assess the state of obesity and adipocyte dysfunction in an individual [88]. Additional measurements such as waist circumference and waist to hip ratio would better classify the subjects based on the levels of fat deposition. A study on the Monza population has shown that with every 1 kg/m2 increase in BMI, the risk of developing left ventricular (LV) hypertrophy increases by 5.1%, and for every 1 cm increase in waist circumference the risk increase by 2.5% [89]. Visceral adiposity and subcutaneous fat deposits contribute to increased waist circumference which has been found to be an independent risk factor for developing heart disease [90]. For increased risk of CVD, the WHO’s cut-off values for waist circumference are 102 cm in men and 88 cm in women [91].

Obesity exerts stress on the heart by increasing the blood volume and cardiac output simultaneously, placing a larger workload on the heart [10]. This results in adverse changes to hemodynamics, cardiovascular structure and function. Obesity increases total body area and volume by additional fat tissue and the changes in cardiovascular system are aimed at maintaining sufficient blood supply to the whole body [10]. Adipose tissue contains a large volume of fluid which is present in the interstitial spaces of the tissue. The interstitial space adds up to approximately 10% of the total adipose tissue weight. Obesity also increases lean body mass which independently elevates cardiac output [92]. A combination of increase in lean and fat mass could account for a large increase in stroke volume and cardiac output. The expansion in volume of blood increases the preload on the heart and shifts the Frank-Starling curve to the left. A significant change in vascular structure and function is also observed in obesity. Obesity causes arterial stiffness [93], increased intima-media thickness [94, 95] and increased calcification [96]. All these vascular changes are also independent predictors of CVD. Further, these vascular changes may also contribute to the development of hypertension in obese individuals [97].

These changes in hemodynamics increases wall tension and induces LV dilation and hypertrophy [82]. Prolonged exposure to these stressful conditions reduces LV wall compliance and then diastolic dysfunction ensues. Initial adaptations by the LV help preserve LV systolic function in the early stages of cardiac remodeling. Overtime, impairment in systolic function will develop and heart failure will be initiated [98]. It was also found that the fatty heart, as a result of increased fat deposits is more prone to cardiomyopathy [99]. Damage to heart muscles by fat accumulation happens in two ways, metaplasia and lipotoxicity [100]. In metaplasia, some cells (epithelial or mesenchymal) are replaced by fat cells, disrupting the cardiac electroconduction. In lipotoxicity, free fatty acid accumulation in cardiomyocytes induces cell death in the myocardium. In either case, damage to cells results in myocardial weakening, resulting in the development of cardiomyopathy [10]. The obesity associated increase in blood volume also induces left atrial enlargement, which increases the risk of developing atrial fibrillation. Based on the findings from Women Health Study, obesity was associated with increased risk for atrial fibrillation [101]. Other types of arrhythmias and sudden cardiac death are also found at higher rates in obese populations [82, 102]. Obesity and metabolic dysfunction increases the risk of coronary artery disease. The incidence of coronary atherosclerosis is very high in adult obesity and is a major risk factor for heart disease [103]. Obesity is also directly linked to increased incidence of stroke. The INTESTROKE study has found that waist to hip ratio was strongly associated with increased risk for stroke [104]. Obstructive sleep apnea is another risk factor for hypertension and CVD [105]. Obesity is one of the major risk factors for obstructive sleep apnea, and in many sleep apnea patients are undiagnosed which increases the risk of heart disease.

Adipose tissue is also an endocrine organ releasing a number of molecules into the blood stream. TNF-α, IL-6, leptin, angiotensinogen, resistin and plasminogen activator inhibitor-1 are released from adipose tissues and have direct or indirect effect on promoting development or progression of heart disease [106]. A significant proportion of the circulating concentrations of these molecules have originated from adipose tissue. Most of these are mediators of the inflammatory response and may be involved in progression of coronary artery diseases [107].

Indirect effect of obesity on cardiovascular pathology involves impairments of kidney structure and function. Glomerular hyperfiltration, increased albumin loss, glomerulosclerosis and progressive loss of kidney function are associated with obesity-induced kidney damages [108]. Population studies, PREVEND [109] and Framingham Heart Study [110] have found direct correlation between kidney damage and obesity.

Lipids and Heart

Fatty acids are the primary energy source of the heart. In normal physiological conditions, approximately 70% of energy is derived from the oxidation of fatty acids [111]. The remaining energy is derived from glucose, lactate and ketones. Generation of ATP from fatty acid oxidation is a comparatively more oxygen demanding process than generating ATP from glucose. The heart has the ability to switch to glucose as the major energy source during oxygen deficient conditions such as ischemia, hypertension and other pathological conditions [112, 113]. This allows the heart to adapt to difficult conditions, preserve available oxygen and minimize the damage to the tissue. Fetal hearts also depend more on glucose and lactate for energy, while adult hearts shift to fatty acid oxidation to meet their energy needs [112]. Diet, hepatic fatty acid synthesis and lipolysis in adipose tissue are the major sources of lipid for the heart. Heart tissues can use both non-esterified (free fatty acids) and esterified (bound to lipoproteins) fatty acids. Circulating triglycerides undergo lipolysis mediated by endothelium-bound lipoprotein lipase and are then internalized via membrane receptors, transporters or simply by diffusion [114]. Internalized free fatty acids are then converted to fatty acyl-CoAs and then either stored as acyl glycerides (mono, di or tri) or transported to mitochondria for ATP generation [115]. Triglycerides stored intracellularly are processed to free fatty acids by hormone sensitive lipase and adipose triglyceride lipase [116].

Lipotoxicity

The balancing act of energy homeostasis is much more complex than the earlier mentioned equation (Fig. 15.1). For example, there is a significant difference between white adipose tissue (WAT) and brown adipose tissue (BAT). While both are fat deposits, their physiological roles are different. WAT is associated with the genesis of metabolic syndrome while, BAT contributes to thermogenesis [117]. Diet is the major source of fatty acids (FA); it is also synthesized from other sources through de novo lipogenesis [118]. Depending on physiologic demands FAs are released into circulation from adipose tissue by lipolysis and will be used by other organs. FAs can also be transported into the cells by different protein transport mechanisms [115, 119]. These FAs are then used for a variety of cellular mechanisms involving synthesis of membrane, signaling molecules, post-translational protein modification, transcriptional regulation and more importantly for energy production through beta oxidation [120]. Normally, a balance is maintained between lipid uptake and oxidation thereby preventing lipid accumulation. Metabolic disturbances often results in increased lipid levels in the circulation. Higher circulating FAs in obesity and type 2 diabetes causes excess deposition of FAs in non-adipose tissues such as kidney, liver, skeletal muscles and heart [121]. The excess lipid accumulating inside the cell may cause cellular dysfunction through ER stress, mitochondrial dysfunction, oxidative stress and ultimately results in cell death [122]. This process of lipid induced cellular damage and death is known as lipotoxicity [123,124,125].

Lipotoxicity in the Heart

The heart is one of the major organs affected by lipid accumulation [21]. Lipid accumulation is also observed in cardiac pathologies wherein the myocardium reverts to glucose as the primary source of energy [112]. Lipotoxic effects leads to cardiomyocyte dysfunction, contractile abnormalities, cell death and pathogenesis of heart failure [111, 126]. Cardiomyopathies observed in in the setting of type 2 diabetes and obesity are often a result of lipotoxic damage to the myocardium [116]. Long chain fatty acids like palmitate have been found to induce lipotoxicity in the heart muscle cells when compared to short chain fatty acids [127, 128]. Some pathological cellular changes associated with lipid accumulation are ER stress, mitochondrial dysfunction and oxidative stress. Increased ceramide accumulation has been observed as a contributor towards cell death in the heart [129]. Insulin is involved in regulation of glucose metabolism, activation of survival pathways in ischemia and also in intracellular Ca2+ handling. Lipotoxicity induces insulin resistance and thereby causes cardiomyocyte dysfunction. Activation of protein kinase C (PKC), mitogen activated protein kinases and reduced peroxisome proliferator-activated receptors are also considered to be involved in the process of lipid accumulation and cellular responses in the cell [21]. Lipid accumulation also induces contractile abnormalities through the degeneration of myofibrils [130].

Resveratrol

RES is a phytoalexin compound produced by plants mainly in response to fungal infections, UV radiation and other environmental stresses such as cold temperatures [131]. RES is present in significant amounts in grapes, peanuts, soy beans, pomegranates, mulberry and bilberry [132] and to a lesser extend in pine, eucalyptus and spruce trees, and in a few flowering plants, such as Veratrum grandiflorum and Veratrum formosanum [133, 134].

RES was discovered in the roots of white hellebore plants [135]. Later it was also found in roots of Polyganum cuspidatum, a Japaneese knotweed which was also called Ko-jo-kon and is the richest known source of RES. It was used in the preparation of Japanese and Chinese herbal medicines against skin infections like warts, dermatitis and athletes foot [136]. This was followed by reports on presence of RES in eucalyptus and pine [137, 138]. In 1976 Langcake and Price reported the presence of RES in grape vines for the first time [139]. During this period RES was mainly investigated for its anti-fungal properties and used as a screening marker for disease resistant grape cultivars [140, 141]. The first report linking RES to potential cardiovascular benefits was from a Japanese group which showed that RES administration reduced triglyceride synthesis in mice [142]. Later in 1992, moderate red wine consumption was linked to the reduced incidence of cardiovascular disease among the French population; this theory is known as the ‘French Paradox’ [143]. At the same time, Siemann and Creasy reported that RES might be one of the bioactive ingredients in wine [144]. Further, Frankel et al. showed that the phenolic component of red wine inhibited LDL oxidation which is a risk factor for atherogenesis and thereby ischemic heart disease [145]. The association of RES to the French Paradox generated a greater interest in RES research wherein either purified RES or food containing significant amount of RES were tested on a wide range of research models of human disease [131]. The highlights of RES research outcomes are its beneficial effects against different types of cancers, cardiovascular diseases and also against metabolic diseases such as diabetes and obesity [146,147,148].

Resveratrol Chemistry

RES is a stilbene derivative, produced in plants by stilbene synthase. Stilbene synthase catalyze the synthesis of RES from one molecule of p-coumaroyl CoA and three molecules of malonyl CoA. RES exists in two structural isomeric forms, cis- and trans-RES (Fig. 15.3) (molecular weight: 228.24); both isomers are lipophilic in nature [149]. RES has a melting point around 260 °C. It is insoluble in water but soluble in ethanol and DMSO. The trans-RES isomer is relatively more stable as compared to the cis-RES isomer; however, the trans form can get converted to the cis for when exposed to heat or UV radiation [150]. The trans-RES in the powder form is stable in normal atmosphere at room temperature and undergoes negligible oxidation in these conditions. RES is susceptible to photolysis if exposed to direct sunlight. Due to its structural similarity to the synthetic estrogen diethylstilbestrol, RES is also considered to be a phytoestrogen [133].

Fig. 15.3
figure 3

Cis-resveratrol (a) and trans-resveratrol (b). From: https://en.wikipedia.org/wiki/File:Cis_and_trans_resveratrol_notext.svg

Full size image

Cardioprotection with Resveratrol

RES is present at high amounts in grape skins and subsequently in red wines (Fig. 15.4). This led to the ‘French Paradox’ theory in which lower incidence of cardiovascular disease in the French population was associated with a higher consumption of red wine [150]. Subsequent research confirmed the cardioprotective properties of RES [151]. RES was reported to exhibit cardioprotective properties by reducing cardiac abnormalities in hypertension, ischemic heart disease, obesity, diabetes and cardiomyopathies; RES has been shown to improve heart and blood vessel structure and function in animal models of cardiovascular disease [30, 152, 153]. Major cellular mechanisms that mediate effects of RES range from improving cardiovascular risk factors such as hyperlipidemia and insulin resistance to reducing oxidative stress and inflammation. Among the many molecules identified as RES targets in the heart, AMPK, SIRT1 and nitric oxide (NO) are most frequently reported [152]. RES is found to enhance AMPK activity and thereby its downstream signaling pathway which indirectly results in increased NO production [154, 155]. AMPK activation could also be involved in RES-mediated decrease in fibrosis [156]. An increase in SIRT1 expression is associated with RES administration. SIRT1 could improve cardiac function by increasing SERCA2A expression and thereby improving Ca2+ handling. SIRT1 could also induce AMPK activation and improve mitochondrial function [157]. Anti-inflammatory and antioxidant activities were the first properties to be identified and associated to health benefits of RES. RES inhibits NFkB activation and translocation into the nucleus, preventing the transcription of a variety of genes detrimental to the cell [158]. RES also helps preserve major antioxidant enzyme activities such as superoxide dismutase, catalase, and glutathione peroxidase, while reducing NADPH oxidase activity. Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in maintaining an antioxidant environment inside the cells and RES is found to promote Nrf2 activation [159]. Modulation of L-type calcium channel is also a potential mechanism by which RES could improve Ca2+ irregularities in cardiac cells [160].

Fig. 15.4
figure 4

Major sources of resveratrol: grapes and red wine. From: https://www.publicdomainfiles.com/show_file.php?id=13534675212806 (wine glass). https://www.publicdomainpictures.net/en/view-image.php?image=299825&picture=grapesvintage-illustration (grapes)

Full size image

Resveratrol in Obesity-Induced Heart Disease

There is sufficient evidence showing that RES improves metabolic abnormalities in animals [161]. However, there are only a few studies that have explored the cardioprotective property of RES in obesity. The first study showed that RES administration in rats for 2 weeks reduced both infarct size and cardiac apoptosis in ex-vivo ischemic-reperfused hearts [162]. In another study RES prevented an increase in blood pressure and preserved vascular function in an animal model of diet-induced obesity, the high fat fed rats [163]. Louis et al. reported that RES reversed diastolic heart dysfunction in high fat fed rats [164] and Qin et al. showed a significant decrease in cardiac hypertrophy and improvement in diastolic heart function in obese mice exhibiting characteristics of early stage type II diabetes [165]. Cardiomyopathy is the major form of heart disease affecting the obese and overweight population. Yingjie et al. showed that RES attenuated high fat diet-induced cardiomyopathy in a mouse model [166]. This effect was associated with upregulation of estrogen receptor alpha which has been proposed to mediate RES actions in vivo. As discussed earlier, obesity pathologically affects vascular function. NO is an endogenous vasodilator and an established target of RES [167]. Huang et al. reported that RES treatment mitigated vascular dysfunction in high fat fed mice through upregulating eNOS/NO mechanism [168].

To date, no study has examined the impact of resveratrol in preventing obesity induced deterioration of heart function in humans. However, there are a few clinical studies which have examined the potential of resveratrol in reducing obesity. A recent clinical trial reported significant reductions in weight loss in obese patients who were on a combination of resveratrol and orlistat (a standard anti-obesity medication) [169]. Similarly a combination of resveratrol and hesperetin (a bioactive compound) was reported to reduce glucose levels and improved vascular function in overweight and obese patients [170]. A combination of epigallocatechin-3-gallate (a bioactive compound) and resveratrol was also shown to increase mitochondrial capacity and stimulate fat oxidation in overweight and obese patients [171]. Earlier studies reported that resveratrol supplementation reduced glucose, triglycerides and markers of inflammation in obese men [172], improved cerebral blood flow in obese subjects [173], and reduced intestinal and hepatic lipoprotein production in obese individuals with mild hypertriglyceridemia [174].

Overall, there is some evidence that RES improves heart structure and function in animal models of obesity. However, there is no information on impact of RES on heart structure and function in humans with obesity, therefore future studies should examine this aspect. Given that diet and genetic predisposition are major contributors towards the development of obesity, future research is necessary to examine if RES can protect the human heart in the settings of diet induced obesity. It is also important to know if RES can improve diastolic heart dysfunction in obese animals and thereby prevent the progression to heart failure. Finally, more research exploring cellular mechanisms involved in the cardioprotective action of RES is needed. Given the success of RES in combination with standard medication or other bioactive compounds in improving metabolic parameters in overweight and obese subjects, it would be interesting to examine the potential of combination therapy in preventing heart dysfunction in these subjects.