[Show abstract][Hide abstract] ABSTRACT: (-)-Epicatechin ((-)-EPI), a naturally occurring flavanol, has emerged as a likely candidate for cocoa-based product reported reductions in cardiometabolic risk. The present study aimed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of purified (-)-EPI administered to healthy volunteers. In this phase I, open-label, two-part single- and multiple-dose study, subjects received either a single dose (n = 9) of 50, 100 or 200 mg or multiple doses (n = 8) of 50 mg daily (q.d.) or twice daily (b.i.d) for 5 days. Blood was collected at 0, 0.5, 1, 2, 4 and 6 h after (-)-EPI administration in the single and multiple dose groups (blood collection repeated in day 5). Samples were analyzed by HPLC-HR-ESI-MS for EPI and metabolite quantification. In the q.d. and b.i.d. groups, blood samples were analyzed for NO surrogates and follistatin levels as well as, platelet mitochondrial complexes I, V and citrate synthase activity levels. (-)-EPI was well tolerated and readily absorbed with further phase 2 metabolism. On day 5, in the q.d. and b.i.d. groups, there were significant increases in plasma nitrite of 30% and 17%, respectively. In the q.d. group on day 5 vs. day 1, platelet mitochondrial complexes I, IV and citrate synthase activities demonstrated a significant increase of ∼92, 62 and 8%, respectively. Average day 5 follistatin AUC levels were ∼2.5 fold higher vs. day 1 AUC levels in the b.i.d. group. (-)-EPI was safe to use, with no observed adverse effects, and our findings suggest that increases in NO metabolites, mitochondrial enzyme function and plasma follistatin levels may underlie some of the beneficial effects of cocoa products or (-)-EPI as reported in other studies
Food & Function 01/2015; 6(3). DOI:10.1039/c4fo00596a · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims:
Acute kidney injury (AKI) occurs in up to 40% of patients undergoing cardiac surgery. Proenkephalin A 119-159 (pro-ENK) is a novel, stable surrogate biomarker for enkephalins, endogenous opioids involved in various physiological processes, including neurohormonal stress.
Material and methods:
92 patients undergoing cardiac surgery at the Veterans Affairs San Diego Healthcare System had a post-hoc analysis performed to determine the ability of pro-ENK to predict AKI as well as to compare it against other risk factors for development of AKI.
Of 92 patients, 20 patients developed AKI post-operatively. Pro-ENK levels were significantly elevated in patients who develop AKI. Log pro-ENK value pre-operatively has an odds ratio of 23.8 (p = 0.011, 95% CI = 2 - 270) in its association with AKI. Pro-ENK performs similarly to baseline creatinine in its ability to predict post-operative AKI. Importantly, pro-ENK has a strong positive correlation with creatinine (r = 0.806). Additionally, changes in pro-ENK level, from pre-operatively to 12 hours post-operatively have greatest area under curve by ROC analysis for AKI after post-operative day 1.
Pro-ENK is associated with prediction of AKI in patients undergoing cardiac surgery. Pro-ENK likely has decreased clearance in the setting of AKI. However, future studies analyzing this novel biomarker should be considered to further elucidate its clinical utility and to better understand mechanisms of renal injury.
[Show abstract][Hide abstract] ABSTRACT: (-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10mg/kg) combined with DOX (5mg/kg). The first dose was given 15min prior to reperfusion and the second 12h post-MI. The effects of EPI +/- DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ∼46% at 48h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury.
European Journal of Pharmacology 10/2014; 744. DOI:10.1016/j.ejphar.2014.09.042 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Heart failure is a common cause of hospitalization that can be divided into preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). In this subanalysis of the Heart failure Assessment with Bnp In The home (HABIT) trial, we examine the differences between home B-type natriuretic peptide (BNP) testing and weight monitoring in patients with HFpEF and HFrEF prior to decompensation.
Methods and results:
This is a retrospective review of patients with HFpEF and HFrEF from the HABIT trial. The HFpEF patients compared to HFrEF patients were older, more obese and had lower baseline BNP values. Intra-individual BNP dispersion (spread of distribution over time) is greater in HFpEF than in HFrEF due to rapid fluctuations (within 3 days). Slowly varying changes in BNP (estimated by a moving average) are equally predictive of ADHF risk in both HFpEF and HFrEF. However, in HFpEF, a rapid rise in BNP >200 pg/mL within 3 days is associated with an increased risk of ADHF (hazard ratio of 4.0), whereas a similar association is not observed in HFrEF. Weight gain ≥5 lbs. in 3 days has a high specificity but low sensitivity for ADHF in both HFpEF and HFrEF, while a lower threshold of at least 2 lbs. of weight gain over 3 days in patients with HFpEF (but not HFrEF) is a moderately sensitive cutoff associated with decompensation (60% sensitivity).
Patients with HFpEF and HFrEF have variations in their BNP and weight prior to decompensation. The rapid time-scale behaves differently between the groups. In those with HFpEF, a 3 day period characterized by ≥2 lbs. of weight gain and/or >200 pg/mL of BNP rise is significantly associated with decompensation. Future prospective studies investigating different weight and BNP cutoffs for home monitoring of HFpEF and HFrEF patients should be performed to fully learn the value of BNP changes prior to clinical deompensation.
Journal of the American College of Cardiology 04/2014; 63(12):A772. DOI:10.1016/S0735-1097(14)60772-5 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and objectiveIn low and middle-income countries where HIV infection is prevalent, identifying patients at high risk of dying from lower respiratory tract infections is challenging and validated prognostic models are lacking. Serum procalcitonin may be a useful prognostic tool in these settings. We sought to determine if elevated serum procalcitonin is associated with increased in-hospital mortality and to combine serum procalcitonin with available clinical characteristics to create a clinically useful prognostic model. Methods
We conducted a prospective, nested case-control study of 241 HIV-infected adults admitted to Mulago Hospital in Kampala, Uganda with cough ≥2 weeks in duration. We collected demographic and clinical information, baseline serum for procalcitonin analysis, and followed patients to determine in-hospital mortality. ResultsSerum procalcitonin was a strong and independent predictor of inpatient mortality (aOR = 7.69, p = 0.01, sensitivity = 93%, negative predictive value = 97%). Best subset multivariate analysis identified 3 variables that were combined into a prognostic model to risk stratify patients; these variables included respiratory rate ≥30 breaths/minute (aOR = 2.07, p = 0.11), oxygen saturation 0.5 ng/ml (aOR = 7.69, p = 0.01). The predicted probability of inpatient mortality ranged from 1% when no variables were present, to 42% when all variables were present. Conclusions
Elevated serum procalcitonin >0.5 ng/ml is an independent predictor of in-hospital mortality. Elevated serum procalcitonin, tachypnea, and hypoxemia may be combined into a prognostic model to identify patients at high risk of dying in the hospital. This model may be used to estimate the probability of death and to guide triage and treatment decisions.
[Show abstract][Hide abstract] ABSTRACT: Sarcopenia is a notable and debilitating age-associated condition. Flavonoids are known for their healthy effects and limited toxicity. The flavanol (-)-epicatechin (Epi) enhances exercise capacity in mice, and Epi-rich cocoa improves skeletal muscle structure in heart failure patients. (-)-Epicatechin may thus hold promise as treatment for sarcopenia. We examined changes in protein levels of molecular modulators of growth and differentiation in young vs. old, human and mouse skeletal muscle. We report the effects of Epi in mice and the results of an initial proof-of-concept trial in humans, where muscle strength and levels of modulators of muscle growth were measured. In mice, myostatin and senescence-associated β-galactosidase levels increase with aging, while those of follistatin and Myf5 decrease. (-)-Epicatechin decreases myostatin and β-galactosidase and increases levels of markers of muscle growth. In humans, myostatin and β-galactosidase increase with aging while follistatin, MyoD and myogenin decrease. Treatment for 7 days with (-)-epicatechin increases hand grip strength and the ratio of plasma follistatin/myostatin. In conclusion, aging has deleterious effects on modulators of muscle growth/differentiation, and the consumption of modest amounts of the flavanol (-)-epicatechin can partially reverse these changes. This flavanol warrants its comprehensive evaluation for the treatment of sarcopenia.
The Journal of nutritional biochemistry 01/2014; 25(1):91-4. DOI:10.1016/j.jnutbio.2013.09.007 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to evaluate the long-term prognostic utility of mid-region prohormone adrenomedullin (MR-proADM) in stable outpatients with heart failure (HF).
Echocardiogram and serum for MR-proADM and BNP levels were obtained in 724 stable outpatients. These patients were followed for up to 6 years for the primary endpoint of all-cause mortality. There were 198 stage A patients, 328 stage B patients, and 200 stage C/D patients, with an average age of 68 ± 12 years. There were 195 deaths during the 6-year follow-up period. MR-proADM was predictive of mortality in the overall patient population. The predictive value of MR-proADM for long-term mortality was independent of BNP, echocardiographic indices of structural heart disease, clinical predictors of mortality, and the Framingham risk score. Patients with elevated MR-proADM had significantly increased risk for mortality in stage A and stage C/D HF, with hazard ratio (HR) 3.780, P < 0.001 and HR 2.744, P < 0.001, respectively. There was a trend toward increased mortality in patients with elevated MR-proADM and stage B HF (HR 1.579, P = 0.05005). MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score.
MR-proADM was a potent independent predictor of long-term all-cause mortality in stable outpatients with stage A-D HF, especially in patients in stage A and stage C/D HF. MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score.
European Journal of Heart Failure 07/2013; 15(12). DOI:10.1093/eurjhf/hft116 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes (T2D) and heart failure (HF) are associated with high levels of skeletal muscle (SkM) oxidative stress (OS). Health benefits attributed to flavonoids have been ascribed to antioxidation. However, for flavonoids with similar antioxidant potential, end-biological effects vary widely suggesting other mechanistic venues for reducing OS. Decreases in OS may follow the modulation of key regulatory pathways including antioxidant levels (e.g. glutathione) and enzymes such as mitochondrial superoxide dismutase (SOD2) and catalase.
We examined OS-related alterations in SkM in T2D/HF patients (as compared vs. healthy controls) and evaluated the effects of three-month treatment with (-)-epicatechin (Epi) rich cocoa (ERC). To evidence Epi as the mediator of the improved OS profile we examined the effects of pure Epi (vs. water) on SkM OS regulatory systems in a mouse model of insulin resistance and contrasted results vs. normal mice.
There were severe alterations in OS regulatory systems in T2D/HF SkM as compared with healthy controls. Treatment with ERC induced recovery in glutathione levels and decreases in the nitrotyrosilation and carbonylation of proteins. With treatment, key transcriptional factors translocate into the nucleus leading to increases in SOD2 and catalase protein expression and activity levels. In insulin resistant mice, there were alterations in muscle OS and pure Epi replicated the beneficial effects of ERC found in humans.
Major perturbations in SkM OS can be reversed with ERC in T2D/HF patients. Epi likely mediates such effects and may provide an effective means to treat conditions associated with tissue OS.
International journal of cardiology 07/2013; 168(4). DOI:10.1016/j.ijcard.2013.06.089 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heart failure and type 2 diabetes mellitus associate with detrimental alterations in skeletal muscle structure/function. We have demonstrated that (-)-epicatechin rich cocoa (ERC) improves skeletal muscle mitochondrial structure (Taub et al, 2012. Clin Trans Sci. 5, 43). We hypothesized that improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with heart failure and type 2 diabetes consumed ERC for three months; treadmill testing (VO2 max) and skeletal muscle biopsies were performed. Westerns, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the dystrophin-associated protein complex (DAPC) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC protein levels, sarcomeric microstructure and in a coordinated fashion alterations in markers of skeletal muscle growth/differentiation consistent with myofiber regeneration. VO2 max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function.
[Show abstract][Hide abstract] ABSTRACT: Objectives
This study was a multicenter, single-arm, double-blinded observational prospective clinical trial designed to monitor daily concentrations of B-type natriuretic peptide (BNP) and to determine how these concentrations correlate with acute clinical heart failure decompensation (ADHF) and related adverse clinical outcomes in at-risk HF patients.
Although BNP at discharge is predictive of 30-day outcomes, outpatient serial testing may improve the risk of detecting early decompensation.
A total of 163 patients with HF signs and symptoms of ADHF discharged from the hospital or in an outpatient setting measured their weight and BNP levels daily for 60 days with a finger-stick test. Patients and physicians were blinded to BNP levels. The composite outcome was ADHF events: cardiovascular death, admission for decompensated HF, or clinical HF decompensation requiring either parenteral HF therapy or changes in oral HF medications.
A total of 6,934 daily BNP values were recorded, with a median of 46 measures per patient over a monitoring period of 65 days. Forty patients had 56 events. Correlations between BNP measures weakened over time, and the dispersion between BNP measures grew. During 10,035 patient-days, there were 494 (4.9%) days of weight gain (≥5 lbs). The hazard ratio per unit increase of ln BNP was 1.84, and the hazard ratio on a day of weight gain was 3.63. These effects retained significance when controlling for symptoms. When the monitoring period for each subject was broken into intervals based on ADHF events, there were 39 (18.4%) intervals of upward trending BNP corresponding to a risk increase of 59.8% and 64 (30.2%) downward trending intervals corresponding to a risk decrease of 39.0%. There were 94 (44.3%) intervals with 1 or more days of weight gain corresponding to a risk increase of 26.1%.
This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231)
Journal of the American College of Cardiology 04/2013; 61(16):1726–1735. DOI:10.1016/j.jacc.2013.01.052 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidemiological data demonstrates that improved regulation of blood glucose correlates with better cardiovascular (CV) outcomes. Conversely, some interventional studies have demonstrated that tight glycemic control has no benefit or can even result in worse CV outcomes. These conclusions parallel the paradox that glycemic control has proven beneficial for microvascular outcomes, while few studies have demonstrated significant macrovascular benefits. This imprecise understanding conveys the need to better comprehend the mechanisms of glycemic control and its impact on CV disease. Such variations in data also require a more comprehensive approach to diabetes and CV disease in which multiple biomarkers such as low density lipoprotein (LDL), low adiponectin, elevated C-reactive protein (CRP) and well established clinical parameters such as high blood pressure, weight, and functional status are incorporated into clinical decision making. Reliance on one parameter in isolation such as glycemic control and one biomarker such as HbA1C does not provide an accurate assessment of CV outcomes.
Current Cardiology Reports 02/2013; 15(2):332. DOI:10.1007/s11886-012-0332-4 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A specific and sensitive LC-MS/MS method for analysis of F(2)-isoprostanes (F(2)-IsoPs) and prostaglandins (PGs) in urine was developed and validated to examine the levels of F(2)-IsoPs and prostaglandin F(2α) (PGF(2α)), in human urine in patients undergoing cardiac surgery. The rapid extraction for F(2)-IsoPs and PGs from urine was achieved using a polymeric weak anion solid phase extraction cartridge. The base-line separation of 8-iso-PGF(2α), 8-iso-15(R)-PGF(2α), PGF(2α), and 15(R)-PGF(2α) was carried out on a Hydro-RP column (250mm×2.0mm i.d., Phenomenex, CA) using a linear gradient of methanol:acetonitrile (1:1, v/v) in 0.1% formic acid at a flow rate of 0.2mL/min. The method was proved to be accurate and precise for simultaneous quantification of each analyte over a linear dynamic range of 0.05-50ng/mL with correlation coefficients greater than 0.99. The intra-day and inter-day assay precision at the lowest quality control (0.07ng/mL) level were less than 17%. The mean extraction recoveries of F(2)-IsoPs and PGs were in a range of 79-100%. In applications of this method to patients undergoing cardiac surgery, post-surgery urinary concentrations of 8-iso-PGF(2α) increased significantly in patients (n=14) who did not develop acute kidney (AKI) (pre-surgery 0.344±0.039 vs. post-surgery 0.682±0.094ng/mg creatinine, p<0.01), whereas there was no significant change in this isoprostane in the patients (n=4) who developed AKI (pre-surgery 0.298±0.062 vs. post-surgery 0.383±0.117ng/mg creatinine, NS). Therefore, the method is suitable for the analysis of individual F(2)-IsoPs and PGF(2α)'s in both clinical and research studies.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 12/2012; 913-914C:161-168. DOI:10.1016/j.jchromb.2012.12.009 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An increasing body of evidence reported in the literature indicates a possible role for post-traumatic stress disorder (PTSD) as a cause for cardiovascular disease (CVD). However, mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. In this review, we examine the potential paths by which CVD could occur in those with PTSD. Dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous dysfunction are commonly observed in PTSD, which in turn lead to a variety of physiological changes potentially damaging to the heart. Increased inflammation, dysfunction of the vascular endothelium, hypercoagulability, and cardiac hyperreactivity all have been noted in patients with PTSD. Altered neurochemistry, most notably increased arginine vasopressin, as well as an increased prevalence of the metabolic syndrome, may also contribute to adverse cardiac outcomes. While the association between PTSD and physical disease is often complicated by health risk behaviors or comorbid psychiatric conditions, the evidence for a link between PTSD and CVD is substantial. In our examination, we attempt to identify potential cardiac biomarkers that may be useful in detecting increased cardiac risk in PTSD patients. As research in this area is exceedingly limited, we hope to inspire further research, as there is great potential value in identifying prognostically useful cardiac biomarkers so as to predict and prevent the onset of CVD in PTSD patients.
Cardiology in review 06/2012; 21(1). DOI:10.1097/CRD.0b013e318265343b · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac and renal disease frequently coexist but have long been difficult to diagnose in a timely manner and treat effectively. Noninvasive and cost-effective biomarkers are needed to help identify cardiac patients who are at risk of acute kidney injury early in the course of disease. Biomarkers can provide insights into underlying mechanisms and lead to a better understanding of complex disease states such as the cardiorenal syndrome, which can lead to better therapies and, ultimately, to improved patient outcomes. The natriuretic peptides are established biomarkers in heart failure and have set the standard for how a well-validated biomarker can be useful for diagnosis/prognosis, monitoring response to therapy and chronic disease management. For patients with acute kidney injury in the setting of cardiac disease, new biomarkers such as neutrophil gelatinase-associated lipocalin, cystatin C, kidney injury molecule-1 and IL-18 are emerging as early signals of renal dysfunction prior to any elevations in serum creatinine. Other promising candidate biomarkers for the early diagnosis of acute kidney injury include osteopontin, N-acetyl-b-d-glucosaminidase, stromal cell-derived factor-1 and exosomes. More research with all of these novel biomarkers is needed; however, the early results are very promising.
Expert Review of Cardiovascular Therapy 05/2012; 10(5):657-67. DOI:10.1586/erc.12.26
[Show abstract][Hide abstract] ABSTRACT: Post-traumatic stress disorder (PTSD) is gaining increasing recognition as a risk factor for morbidity and mortality. The aim of this study was to examine the impact of PTSD and abnormal cardiovascular biomarkers on mortality in military veterans. Eight hundred ninety-one patients presenting for routine echocardiography were enrolled. Baseline clinical data and serum samples for biomarker measurement were obtained and echocardiography was performed at the time of enrollment. Patients were followed for up to 7.5 years for the end point of all-cause mortality. Ninety-one patients had PTSD at the time of enrollment. There were 33 deaths in patients with PTSD and 221 deaths in those without PTSD. Patients with PTSD had a trend toward worse survival on Kaplan-Meier analysis (p = 0.057). Among patients with elevated B-type natriuretic peptide (>60 pg/ml), those with PTSD had significantly increased mortality (p = 0.024). Among patients with PTSD, midregional proadrenomedullin (MR-proADM), creatinine, and C-terminal proendothelin-1 were significant univariate predictors of mortality (p = 0.006, p = 0.024, and p = 0.003, respectively). In a multivariate model, PTSD, B-type natriuretic peptide, and MR-proADM were independent predictors of mortality. In patients with PTSD, MR-proADM was a significant independent predictor of mortality after adjusting for B-type natriuretic peptide, cardiovascular risk factors, cancer, and sleep apnea. Adding MR-proADM to clinical predictors of mortality increased the C-statistic from 0.572 to 0.697 (p = 0.007). In conclusion, this study demonstrates an association among PTSD, abnormal cardiac biomarker levels, and increased mortality.
The American journal of cardiology 02/2012; 109(8):1215-8. DOI:10.1016/j.amjcard.2011.11.063 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: (-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function.
[Show abstract][Hide abstract] ABSTRACT: Non-technical summary During exercise, skeletal muscle performance depends in great part on the use of aerobic metabolism to supply the energetic demand of contractions. Endurance training increases the muscle aerobic capacity, which is not only associated with enhanced exercise performance, but also with a decreased risk of cardiovascular and metabolic diseases. Recently, it has been shown that regular use of small doses of dark chocolate may result in similar health benefits to exercise training. We show here that mice fed for 15 days with (–)-epicatechin (present in dark chocolate) had improved exercise performance accompanied by: (1) an increased number of capillaries in the hindlimb muscle; and (2) an increased amount of muscle mitochondria as well as signalling for mitochondrial biogenesis. These results suggest that (–)-epicatechin increases the capacity for muscle aerobic metabolism, thereby delaying the onset of fatigue. These findings may have potential application for clinical populations experiencing muscle fatigue.
Abstract The flavanol (–)-epicatechin, a component of cacao (cocoa), has been shown to have multiple health benefits in humans. Using 1-year-old male mice, we examined the effects of 15 days of (–)-epicatechin treatment and regular exercise on: (1) exercise performance, (2) muscle fatigue, (3) capillarity, and (4) mitochondrial biogenesis in mouse hindlimb and heart muscles. Twenty-five male mice (C57BL/6N) were randomized into four groups: (1) water, (2) water–exercise (W-Ex), (3) (–)-epicatechin ((–)-Epi), and (4) (–)-epicatechin–exercise ((–)-Epi-Ex). Animals received 1 mg kg−1 of (–)-epicatechin or water (vehicle) via oral gavage (twice daily). Exercise groups underwent 15 days of treadmill exercise. Significant increases in treadmill performance (∼50%) and enhanced in situ muscle fatigue resistance (∼30%) were observed with (–)-epicatechin. Components of oxidative phosphorylation complexes, mitofilin, porin, nNOS, p-nNOS, and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (–)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone. In addition, there were significant increases in skeletal muscle capillarity. The combination of (–)-epicatechin and exercise resulted in further increases in oxidative phosphorylation-complex proteins, mitofilin, porin and capillarity than (–)-epicatechin alone. These findings indicate that (–)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles resulting in greater endurance capacity. These results, therefore, warrant the further evaluation of the underlying mechanism of action of (–)-epicatechin and its potential clinical application as an exercise mimetic.
The Journal of Physiology 09/2011; 589(18):4615 - 4631. DOI:10.1113/jphysiol.2011.209924 · 5.04 Impact Factor