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Atherosclerosis, myocardial infarction (MI) and heart failure (HF) are the main causes of mortality and morbidity around the globe. New therapies are needed to better manage ischemic heart disease and HF as existing strategies are not curative. Resveratrol is a stilbene polyphenolic compound with favorable biological effects that counter chronic diseases. Current evidence suggests that resveratrol is cardioprotective in animal models of atherosclerosis, ischemic heart disease, and HF. Though clinical studies for resveratrol have been promising, evidence remains inadequate to introduce it to the clinical setting. In this narrative review, we have comprehensively discussed the relevant compelling evidence regarding the efficacy of resveratrol as a new therapeutic agent for the management of atherosclerosis, MI and HF.

The development and progression of heart failure (HF) due to myocardial infarction (MI) is a major concern even with current optimal therapy. Resveratrol is a plant polyphenol with cardioprotective properties. Sacubitril/valsartan is known to be beneficial in chronic HF patients. In this study, we investigated the comparative and combinatorial benefits of resveratrol with sacubitril/valsartan alongside an active comparator valsartan in MI-induced male Sprague Dawley rats. MI-induced and sham-operated animals received vehicle, resveratrol, sacubitril/valsartan, valsartan alone or sacubitril/valsartan + resveratrol for 8 weeks. Echocardiography was performed at the endpoint to assess cardiac structure and function. Cardiac oxidative stress, inflammation, fibrosis, brain natriuretic peptide (BNP), creatinine and neutrophil gelatinase associated lipocalin were measured. Treatment with resveratrol, sacubitril/valsartan, valsartan and sacubitril/valsartan + resveratrol significantly prevented left ventricular (LV) dilatation and improved LV ejection fraction in MI-induced rats. All treatments also significantly reduced myocardial tissue oxidative stress, inflammation and fibrosis, as well as BNP. Treatment with the combination of sacubitril/valsartan and resveratrol did not show additive effects. In conclusion, resveratrol, sacubitril/valsartan, and valsartan significantly prevented cardiac remodeling and dysfunction in MI-induced rats. The reduction in cardiac remodeling and dysfunction in MI-induced rats was mediated by a reduction in cardiac oxidative stress, inflammation and fibrosis.

Saskatoon berry (SKB) may have the potential to counter reno-cardiac syndrome owing to its antioxidant capacity. Here, we investigated the renal and cardiovascular effects of SKB-enriched diet in a rat model of reno-cardiac disease. Two groups of wild-type rats (+/+) and two groups of Hannover Sprague-Dawley (Han:SPRD-Cy/+) rats were given either regular diet or SKB diet (10% w/w total diet) for 8 weeks. Body weight, kidney weight, kidney water content, and left ventricle (LV) weight were measured. Blood pressure (BP) was measured by the tail-cuff method. Echocardiography was performed to assess cardiac structure and function. Serum creatinine and malondialdehyde (MDA) were also measured. Han:SPRD-Cy/+ rats had significantly higher kidney weight, kidney water content, LV weight, BP, and creatinine compared with wild-type rats (+/+). The SKB diet supplementation did not reduce kidney weight, kidney water content, BP, and LV weight in Han:SPRD-Cy/+ rats. The SKB diet also resulted in higher systolic BP in Han:SPRD-Cy/+rats. Han:SPRD-Cy/+rats showed cardiac structural remodeling (higher LV wall thickness) without any cardiac functional abnormalities. Han:SPRD-Cy/+ rats also had significantly higher creatinine whereas the concentration of MDA was not different. The SKB diet supplementation reduced cardiac remodeling and the concentration of MDA without altering the concentration of creatinine in Han:SPRD-Cy/+ rats. In conclusion, Han:SPRD-Cy/+ rats developed significant renal disease, high BP, and cardiac remodeling by 8 weeks without cardiac functional impairment. The SKB diet may be useful in preventing cardiac remodeling and oxidative stress in Han:SPRD-Cy/+rats. PRACTICAL APPLICATIONS: Saskatoon berry (SKB) is widely consumed as fresh fruit or processed fruit items and has significant commercial value. It may offer health benefits due to the presence of bioactives such as anthocyanins. SKB has very good culinary flavors, and it is an economically viable fruit crop in many parts of the world. The disease-modifying benefits of SKB are mainly ascribed to the antioxidant nature of its bioactive content. Polycystic kidney disease is a serious condition that can lead to renal and cardiac abnormalities. Here, we showed that SKB supplementation was able to mitigate cardiac remodeling and lower the level of a marker of oxidative stress in an animal model of reno-cardiac syndrome. Our study suggests that SKB possesses beneficial cardioprotective properties. Further evidence from human studies may help in increasing the consumption of SKB as a functional food.

Long-chain saturated fatty acids, especially palmitic acid (PA), contribute to cardiomyocyte lipotoxicity. This study tests the effects of PA on adult rat cardiomyocyte contractile function and proteins associated with calcium regulating cardiomyocyte contraction and relaxation. Adult rat cardiomyocytes were pretreated with resveratrol (Resv) and then treated with PA. For the reversal study, cardiomyocytes were incubated with PA prior to treatment with Resv. Cardiomyocyte contractility, ratio of rod- to round-shaped cardiomyocytes, and Hoechst staining were used to measure functional and morphological changes in cardiomyocytes. Protein expression of sarco-endoplasmic reticulum ATPase 2a (SERCA2a), native phospholamban (PLB) and phosphorylated PLB (pPLB ser16 and pPLB thr17), and troponin I (TnI) and phosphorylated TnI (pTnI) were measured. SERCA2a activity was also measured. Our results show that PA (200 μM) decreased the rate of cardiomyocyte relaxation, reduced the number of rod-shaped cardiomyocytes, and increased the number of cells with condensed nuclei; pre-treating cardiomyocytes with Resv significantly prevented these changes. Post-treatment with Resv did not reverse morphological changes induced by PA. Protein expression levels of SERCA2a, PLB, pPLBs, TnI, and pTnI were unchanged by PA or Resv. SERCA2a activity assay showed that Vmaxand Iono ratio were increased with PA and pre-treatment with Resv prevented this increase. In conclusion, our results show that Resv protect cardiomyocytes from contractile dysfunction induced by PA.

This study investigated the blood pressure (BP) lowering and cardioprotective effects of oat avenanthramide C and beta-glucan alone or in combination in spontaneously hypertensive rats (SHR). Five-weeks-old male SHR and Wistar-Kyoto rats received vehicle, avenanthramide C and beta-glucan alone or a combination of avenanthramide C and beta-glucan via gavage for 15 weeks. BP was measured at 0, 10, and 15 weeks of treatment. Echocardiography was performed at 15 weeks of treatment. Oxidative stress and inflammation were also measured. Beta-glucan alone prevented the increase in systolic and diastolic BP in SHR, but avenanthramide C alone or the combination did not prevent the increase in systolic and diastolic BP. SHRs treated with beta-glucan and not avenanthramide C or the combination reduced isovolumetric relaxation time when compared to SHR treated with vehicle. Beta-glucan and avenanthramide C decreased the levels of malondialdehyde, a marker of oxidative stress in SHR. In conclusion, beta-glucan is a potential antihypertensive agent that may alleviate cardiovascular abnormalities. PRACTICAL APPLICATIONS: Oats products are believed to contain many bioactives that possess potential beneficial properties against chronic diseases. Specifically, oats beta-glucan has been well-established for its efficacy in positively modulating the risk factor for dyslipidemia. This preliminary in vivo study shows that beta-glucan is a potential antihypertensive agent that may alleviate cardiac dysfunction as well. In light of the current findings, further human studies may establish the efficacy of oats beta-glucan in hypertensive patients alongside the current antihypertensive medications. This novel attribute established via rigorous studies may provide an impetus for oats products and oats industry. Last but not least, it will also help improve the cardiovascular disease burden in a cost-effective way.

Foods and food bioactives have shown to be effective in preventing some human disease conditions. In this study, we examined the effects of carrot powder, rich in carotenoids, as a dietary supplement for the prevention of cardiac anomalies in streptozotocin (STZ) induced type 1 diabetic rats. Male Wistar rats were fed either control or carrot powder containing diet for 3 weeks. Type 1 diabetes was induced with STZ injection (65 mg/kg body weight) in half of the rats in each group. All rats were continued on their respective diet for a further 9 weeks. Cardiac structural and functional parameters were measured using echocardiography at 8 weeks post STZ administration. In comparison to non-diabetic rats, diabetic rats showed significant increase in isovolumetric relaxation time and a significant decrease in systolic function parameter, cardiac output. Left ventricular internal dimension and left ventricular posterior wall thickness were significantly higher in diabetic animals. Blood glucose levels were significantly lower in carrot supplemented diabetic rats when compared with non-treated diabetic rats. Diabetic rats treated and untreated had elevated level of lipid peroxidation. Catalase levels were significantly elevated in the carrot powder supplemented diabetic rats when compared to the control rats. Carrot supplementation lowered blood glucose levels significantly but did not normalize it to control levels. It had no effect on cardiac abnormalities and anti-oxidant status in rats with type 1 diabetes.

Dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been associated with a lower incidence of cardiovascular events and sudden cardiac death. Flaxseed is a rich plant source of n-3 PUFAs and can retard the progression and accelerate the regression of atherosclerotic plaques. The aim of the study was to examine the preventive and therapeutic effects of dietary flaxseed on arrhythmias and heart dysfunction that develops after a myocardial infarction (MI). The left anterior descending coronary artery was ligated in rats to induce the MI. Rats were randomized into five groups: sham MI with normal chow, MI with normal chow, MI with 10% milled flaxseed supplementation (flax), MI with 4.4% supplemented flax oil enriched in alpha-linolenic acid (ALA) and MI with flax lignan secoisolariciresinol diglucoside (SDG) supplementation (0.44%). Animals were fed with their respective diets for 2 weeks before and for 8 weeks after the surgery. Echocardiography and continuous electrocardiographic recordings were obtained after ligation to confirm the induction of the MI, to check for arrhythmias and to assess cardiac function. Histological examination was also performed to evaluate cardiac fibrosis. Dietary supplementation with flaxseed, ALA or SDG before and after the induction of the MI significantly reduced the incidence of arrhythmias and resulted in significantly smaller infarct size, less left ventricle dilation, and decreased myocardial fibrosis and tumor necrosis factor-α levels compared to the control MI group. Together, this study supports a beneficial effect of dietary flaxseed in patients for the prevention and treatment of arrhythmias and ventricular remodeling post-MI.

Plasma and urine metabolomics profiles of spontaneously hypertensive rats (SHRs) fed with chicken skin protein hydrolysates (CSPHs) were investigated to establish possible biomarkers of blood pressure regulation. SHR and wistar Kyoto (WKY) rats were randomised into groups that received casein-only (control), CSPHs (0.5 or 1%) or chicken skin meal (CSM 1%) diets for six weeks. Results showed that the diets significantly (P

Background Angiotensin-converting enzyme (ACE) inhibitors improve prognosis in patients with post-myocardial infarction (MI) related cardiac dysfunction. Resveratrol is a polyphenol that has been reported to be beneficial in hypertension, ischemic heart disease, and cardiotoxicity in preclinical studies. Accordingly, we investigated the comparative and combinatorial efficacy of resveratrol and perindopril (ACE inhibitor) treatment on MI-related cardiac remodeling and contractile dysfunction. Methods Left anterior descending artery-ligated and sham-operated male Sprague–Dawley rats were gavaged with vehicle, resveratrol, perindopril, and combination of resveratrol+perindopril (2.5 mg/kg bodyweight/day) for 8 weeks (starting immediately after acute MI). Echocardiography was performed to assess cardiac structure and function at baseline and 8 weeks. Results At 8 weeks, vehicle-MI rats had a significantly lower left ventricular ejection fraction (LVEF) and increased LV dilatation compared to vehicle-sham rats. MI rats treated with resveratrol, perindopril and a combination of both had significantly improved LVEF and reduced LV dilatation. Vehicle-treated MI rats also had increased level of lipid peroxidation product- malondialdehyde (MDA), proinflammatory protein- tumor necrosis factor-alpha (TNF-α) and cardiac fibrosis marker- collagen and decreased enzymatic activity of superoxide dismutase and catalase compared to vehicle-sham rats. Resveratrol, perindopril and combination of both significantly prevented the /ed to determine systolic functional parameter increase in MDA, TNF-α and collagen and improved the activity of superoxide dismutase and catalase in MI rats compared to vehicle-MI rats. Conclusion Treatment with resveratrol or perindopril was equivalent in significantly improving remodeling and attenuation of contractile dysfunction in MI rats. Combination treatment also attenuated the cardiac abnormalities. The improvement in cardiac abnormalities may partly be through reducing oxidative stress by preventing the decrease in the activity of superoxide dismutase and catalase, and decreasing cardiac inflammation and fibrosis.

Resveratrol has been reported to be beneficial against diabetes complications. The objective of this study was to evaluate the efficacy of resveratrol in decreasing hyperglycemia in patients with type 1 diabetes (T1D) by a preliminary investigation designed as an exploratory clinical trial. Thirteen patients with T1D from both the sexes participated in this trial. All patients received resveratrol in 500 mg capsules, twice daily for 60 days. Bodyweight, fasting blood sugar (FBS), hemoglobin A1c (HbA1c), insulin, homeostasis model of assessment for insulin resistance (HOMA-IR), homeostasis model of assessment for &beta, cell function (HOMA-&beta, ), and markers of liver and kidney damage, inflammation, and oxidative stress were measured before the intervention, at 30 days and at 60 days. Resveratrol supplementation for 60 days significantly decreased FBS and HbA1c in comparison with the baseline values. Resveratrol treatment also resulted in a decrease in the level of a marker for oxidative stress, malondialdehyde, and an increase in total antioxidant capacity in T1D patients. Insulin, HOMA-IR, HOMA-&beta, and markers of liver and kidney function and inflammation were not significantly affected by resveratrol treatment. Overall, the results showed that 60 days of resveratrol supplementation exerted strong antidiabetic and antioxidant effects in patients with T1D.

Cardiovascular disease (CVD) is the number one cause of death in both men and women. Younger women have a lower risk for CVD, but their risk increases considerably after menopause when estrogen levels decrease. The cardiovascular protective properties of estrogen are mediated through decreasing vascular inflammation and progression of atherosclerosis, decreasing endothelial cell damage by preventing apoptosis and anti-hypertrophic mechanisms. Estrogen also regulates glucose and lipid levels, which are 2 important risk factors for CVD. Resveratrol (RES), a cardioprotective polyphenolic compound, is classified as a phytoestrogen due its capacity to bind to and modulate estrogen receptor signalling. Due to its estrogen-like property, we speculate that the cardioprotective effects of RES treatment could be sex-dependent. Based on earlier reports and more recent data from our lab presented here, we found that RES treatment may have more favourable cardiovascular outcomes in females than in males. This review will discuss estrogen- and phytoestrogen-mediated cardioprotection, with a specific focus on sex-dependent effects reported in preclinical and clinical studies.

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague&ndash, Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-&alpha, were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-&alpha, in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-&alpha, levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease.

The present study investigated the effects of cyanidin 3-O-glucoside (C3G) in cardiomyocytes (CM) and fibroblasts exposed to endothelin 1 (ET1), as well as in the spontaneously hypertensive rat (SHR) model, alone or in combination with hydrochlorothiazide (HCT). Adult rat CM and cardiac fibroblasts (CF) were pretreated with C3G and co-incubated with ET1 (10−7 M) for 24 hours. Five-week-old male SHR and their normotensive controls, Wistar-Kyoto rats (WKY), received one of 4 treatments via oral gavage daily for 15 weeks: (1) water (control); (2) C3G (10 mg per kg per day); (3) HCT (10 mg per kg per day); (4) C3G + HCT (10 mg per kg per day each). Blood pressure (BP) was measured at 1, 8 and 15 weeks. Echocardiography measurements were performed at 15 weeks. C3G prevented ET1-induced CM death and hypertrophy. Stimulating CF with ET1 did not induce their phenoconversion; nevertheless, C3G inhibited un-stimulated CF differentiation. HCT slowed the rise of systolic BP (SBP) in the SHR over time (week 1: SHRs control = 161 ± 6.3 mmHg, SHRs HCT = 129 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs HCT = 168 ± 7.3 mmHg), but C3G had no effect on SBP (week 1: SHRs control = 161 ± 6.3 mmHg, SHRs C3G = 126 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs C3G = 186 ± 7.3 mmHg). SHRs treated with C3G, HCT, and C3G + HCT had lower left ventricular mass and shorter isovolumetric relaxation time compared to control SHRs. C3G ameliorated cardiac hypertrophy and diastolic dysfunction in SHRs.

Ischemic heart disease is a leading cause of cardiac dysfunction and subsequent morbidity and mortality around the world. New therapies are required to complement or enhance the existing treatment regimen for the management of ischemic heart disease-related clinical complications. In this regard, compounds derived from natural sources have recently gained attention for their cardioprotective properties. In particular, the potential of food-derived compounds that exhibit medicinal properties (termed nutraceuticals) appears promising, an example being the plant polyphenol resveratrol. In the past two decades, many preclinical and a few pilot clinical studies have shown that resveratrol is beneficial in protecting against cardiovascular disease. In this short review, we will discuss current evidence on the efficacy of resveratrol in preventing or reversing deleterious effects on the heart in the setting of ischemic heart disease.

Cyanidin 3-0-glucoside (CG) is a polyphenol with potential health benefits. In this study, we investigated, for the first time, the cardioprotective effects of CG in an animal model of myocardial infarction (MI), a major cause of death worldwide. Sham and MI rats were administered CG (10 mg kg-1 day-1) daily for one week prior to surgery, and 8 weeks post-surgery. Echocardiography was performed to assess cardiac structure and function at 4 and 8 weeks. At 4 weeks, MI rats had significantly lower body mass when compared to control rats, and CG administration significantly prevented this decrease. Four-week MI rats also showed significantly increased left ventricle dilation, end systolic and end diastolic volumes in comparison to controls, and CG significantly prevented these adverse changes. Ejection fraction was significantly lower in 4-week MI rats in comparison to controls, and CG had no effect on this parameter. At 8 weeks, body mass was significantly lower in MI rats when compared to control rats, and CG significantly prevented this decrease. At 8 weeks, MI rats showed a significant increase in left ventricle dilation and isovolumic relaxation time, while ejection fraction was significantly lower when compared to controls; these parameters were not altered by CG treatment. Eight-week MI rats had significantly higher level of oxidative stress in heart tissue in comparison to controls, and CG administration did not prevent this increase. In conclusion, administration of CG was able to significantly preserve body mass in both 4 and 8 weeks MI rats, as well as significantly prevent cardiac dilation in 4 weeks MI rats. However, CG was unable to sustain this cardioprotection, as cardiac structure and function were not significantly improved in 8 weeks MI rats.

This report shows the antioxidant effects of a hemp seed meal protein hydrolysate (HMH) in spontaneously hypertensive rats (SHR). Defatted hemp seed meal was hydrolyzed consecutively with pepsin and pancreatin to yield HMH, which was incorporated into rat feed as a source of antioxidant peptides. Young (8-week old) SHRs were divided into three groups (8 rats/group) and fed diets that contained 0.0%, 0.5% or 1.0% (w/w) HMH for eight weeks, half of the rats were sacrificed for blood collection. After a 4-week washout period, the remaining 20-week old SHRs were fed for an additional four weeks and sacrificed for blood collection. Plasma total antioxidant capacity (TAC) and superoxide dismutase (SOD), catalase (CAT) and total peroxides (TPx) levels were determined. Results showed that plasma TAC, CAT and SOD levels decreased in the older 20-week old SHRs when compared to the young SHRs. The presence of HMH in the diets led to significant (p &lt, 0.05) increases in plasma SOD and CAT levels in both young and adult SHR groups, these increases were accompanied by decreases in TPx levels. The results suggest that HMH contained antioxidant peptides that reduced the rate of lipid peroxidation in SHRs with enhanced antioxidant enzyme levels and total antioxidant capacity.

The concept of food has expanded beyond its traditional role of survival and hunger satisfaction, to include a role in the prevention and treatment of disease. Polyphenols are classes of compounds that are synthesized by plants to serve a wide variety of functions including growth pollination and defense. These compounds have recently received increased attention in medical research. In this group, one of the most studied has been resveratrol (3,5,4,-trihydroxystilbene), a polyphenol, which is found predominantly in grapes and berries. Over the past two decades, researchers have studied the ability of resveratrol to prevent or reverse the development of abnormalities in heart structure and function in animal models of heart disease and heart failure. The results from animal studies have been promising, and very recently, this knowledge has been translated into examining the efficacy of resveratrol in humans with heart disease/failure. In this review we will discuss the current status of resveratrol research on cardioprotection.

Cardiovascular disease (CVD) is the main cause of death globally and responsible for the second highest number of deaths in Canada. Medical advancements in the treatment of CVD have led to patients living longer with CVD but often progressing to another condition called heart failure (HF). As a result, HF has emerged in the last decade as a major medical concern. Fortunately, various “traditional„ pharmacotherapies for HF exist and have shown success in reducing HF-associated mortality. However, to augment the treatment of patients with CVD and/or HF, alternative pharmacotherapies using nutraceuticals have also shown promise in the prevention and treatment of these two conditions. One of these natural compounds considered to potentially help treat HF and CVD and prevent their development is resveratrol. Herein, we review the clinical findings of resveratrol’s ability to be used as an effective treatment to potentially help treat HF and CVD. This will allow us to gain a more fulsome appreciation for the effects of resveratrol in the health outcomes of specific patient populations who have various disorders that constitute CVD.

Obesity is a leading cause of cardiovascular disease. It directly affects heart structure and function and contributes to heart failure. Diet is a major factor involved in the development of obesity along with genetic factors. We examined the effects of monounsaturated and polyunsaturated fatty acid-rich oils on cardiac structure and function in the diet-induced rodent model of obesity (DIO). Obese prone (OP) rats were fed a high-fat diet (HF; 55% of kcal) for 12 weeks; Sprague–Dawley rats fed commercial chow served as control. Echocardiography was performed to assess the cardiac structure and function in all rats at 12 weeks. OP rats fed the HF diet showed significant impairment in diastolic function compared to control rats. The HF diet containing high oleic canola oil significantly improved diastolic function of OP rats compared to the HF diet with lard. In conclusion, canola oil rich in oleic acid, when incorporated into an HF diet, prevents the development of diastolic dysfunction in DIO rats.

Objectives: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood. Methods: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-α levels. Results: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- α levels were significantly different between the intervention groups (all P

Diabetes mellitus is associated with increased risk and incidence of cardiovascular morbidity and mortality, independently of other risk factors typically associated with diabetes such as coronary artery disease and hypertension. This promotes the development of a distinct condition of the heart muscle known as diabetic cardiomyopathy. We have previously shown that conjugated linoleic acid (CLA) prevents endothelin-1-induced cardiomyocyte hypertrophy. However, the effects of CLA in preventing alterations in cardiomyocyte structure and function due to high glucose are unknown. We therefore hypothesized that CLA will have protective effects in an in vitro model of diabetic cardiomyopathy using adult rat cardiomyocytes exposed to high glucose. Our results demonstrate that subjecting adult rat cardiomyocytes to high glucose (25 mmol/L) for 24 hours significantly impaired the contractile function as evidenced by decreases in maximal velocity of shortening, peak shortening, and maximal velocity of relengthening. High glucose-induced contractile dysfunction was inhibited by pretreatment with CLA (30 μmol/L; 1 hour). In addition to contractile aberrations, exposing adult rat cardiomyocytes to high glucose for 48 hours induced cardiomyocyte hypertrophy. High glucose-induced cardiomyocyte hypertrophy was likewise prevented by CLA. The antihypertrophic effects of CLA were abolished when cardiomyocytes were pretreated with the pharmacologic inhibitor of peroxisome proliferator-activated receptor γ, GW9662 (1 μmol/L). In conclusion, our findings show that exposing cardiomyocytes to high glucose results in cardiomyocyte functional and structural abnormalities, and these abnormalities are prevented by pretreatment with CLA and mediated, in part, by peroxisome proliferator-activated receptor γ activation.

Stilbenoids are bioactive polyphenols, and resveratrol (trans-3,5,4′-trihydroxystilbene) is a representative stilbenoid that reportedly exerts cardioprotective actions. As resveratrol exhibits low oral bioavailability, we turned our attention to other stilbenoid compounds with a history of medicinal use and/or improved bioavailability. We determined the effects of gnetol (trans-3,5,2′,6′-tetrahydroxystilbene) and pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) on cardiac hypertrophy. In vitro, gnetol and pterostilbene prevented endothelin-1-induced indicators of cardiomyocyte hypertrophy including cell enlargement and protein synthesis. Gnetol and pterostilbene stimulated AMP-activated protein kinase (AMPK), and inhibition of AMPK, using compound C or shRNA knockdown, abolished these anti-hypertrophic effects. In contrast, resveratrol, gnetol, nor pterostilbene reduced blood pressure or hypertrophy in the spontaneously hypertensive heart failure (SHHF) rat. In fact, AMPK levels were similar between Sprague-Dawley and SHHF rats whether treated by stilbenoids or not. These data suggest that the anti-hypertrophic actions of resveratrol (and other stilbenoids?) do not extend to the SHHF rat, which models heart failure superimposed on hypertension. Notably, SHHF rat hearts exhibited prolonged isovolumic relaxation time (an indicator of diastolic dysfunction), and this was improved by stilbenoid treatment. In conclusion, stilbenoid-based treatment as a viable strategy to prevent pathological cardiac hypertrophy, a major risk factor for heart failure, may be context-dependent and requires further study.

The purpose of this study was to examine the efficacy of an aqueous wild blueberry extract and five wild blueberry polyphenol fractions on an in vitro model of heart disease. Adult rat cardiomyocytes were pretreated with extract and fractions, and then exposed to norepinephrine (NE). Cardiomyocyte hypertrophy, cell death, oxidative stress, apoptosis and cardiomyocyte contractile function as well as the activities of calpain, superoxide dismutase (SOD) and catalase (CAT) were measured in cardiomyocytes treated with and without NE and blueberry fraction (BF). Four of five blueberry fractions prevented cell death and cardiomyocyte hypertrophy induced by NE. Total phenolic fraction was used for all further analysis. The NE-induced increase in oxidative stress, nuclear condensation, calpain activity and lowering of SOD and CAT activities were prevented upon pretreatment with BF. Reduced contractile function was also significantly improved with BF pretreatment. Blueberry polyphenols prevent NE-induced adult cardiomyocyte hypertrophy and cell death. The protective effects of BF may be in part attributed to a reduction in calpain activity and oxidative stress.