Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.

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O besity appears to be a major cause of hypertension and associated cardiovascular pathophysiology, including cardiac dysfunction. However, obesity may lead to abnormal cardiac function through mechanisms that are independent of, or that act in concert with, hypertension. One hypothesis of obesity-induced cardiac dysfunction is that an oversupply of substrates leads first to adaptive changes and eventually to contractile dysfunction of the heart. We reason that increased supply of nonesterified fatty acids, together with metabolic dysregulation in obesity, including an inadequate activation of fat oxidation, results in the accumulation of toxic lipid byproducts and subsequent contractile dysfunction. Although the phenomenon may have already been known to Virchow 1 when he described "fatty metamorphosis" of the heart, the concept of cardiac "lipotoxicity" re-emerged only recently with its description in the heart of the obese Zucker diabetic fatty rat. 2 The concept is, however, still a hypothesis rather than an established physiological principle. In spite of the many investigations performed in rodent models, the mechanism(s) responsible for impaired contractile function of the heart is still obscure, and it is uncertain whether lipid metabolites contribute to "obesity cardiomyopathy" in humans. Our brief review is an attempt to understand the chronic regulatory effects of changes in systemic metabolism on cardiac function. In other words, we discuss current concepts of cardiac adaptation and maladaptation to a deranged metabolic environment. Heart Muscle Disease in Human ObesityChanges in cardiovascular function in the setting of clinically severe obesity were first reported in obese volunteers undergoing cardiac catheterization. The patients demonstrated reduced left ventricular (LV) compliance and a decrease in stroke work index in the presence of increased LV end diastolic pressure that correlated with the severity of obesity. 3 There is a significant correlation between obesity and LV mass, even after controlling for age and blood pressure, 4 and there is also a significant correlation between weight and impaired diastolic filling of the left ventricle. 5 Both systolic and diastolic function are decreased in otherwise healthy obese young women. 6 In the same population there is a decrease of cardiac efficiency. 7 In severely obese patients with a body mass index Ͼ50, the serum concentrations of nonesterified fatty acid show a negative association with load-independent diastolic function. 8 In addition to hemodynamic changes, obesity is also associated with increased risk of atrial fibrillation 9 and ventricular ectopic activity. 10 The mechanisms of cardiac remodeling with obesity are complex. 11,12 A major obstacle in any attempt to characterize "obesity cardiomyopathy" is the prevalence of comorbid disorders and confounding variables, such as the metabolic syndrome, 13 insulin resistance, hypertension, type 2 diabetes, and physical inactivity. It is of note that both increased blood pressure and increase...

Previous studies suggest that disease recurrence peaks at around 2 years in patients with early stage breast cancer (EBC), but provide no data regarding recurrence type. This retrospective analysis aimed to identify early recurrence types and risk factors in estrogen receptor-positive (ER?) EBC patients treated with adjuvant tamoxifen following breast cancer surgery. Postmenopausal women diagnosed with ER? EBC from 1995 to 2004 were evaluated. Annual hazard ratios (HR) for recurrence at different sites were calculated. Time-dependent Cox regression analysis was used to identify predictors of recurrence within 2.5 years of diagnosis, including factors that were more strongly predictive of early than later recurrence. Of 3,614 patients evaluated, 476 developed recurrence during the 5-year median follow-up. Cumulative recurrence rates at 2.5 years (95% confidence interval) were: overall 6.3% (5.5-7.1), locoregional 1.1% (0.7-1.5), contralateral 0.5% (0.3-0.7), and distant 4.8% (4.0-5.6). The annual HR of overall recurrence peaked at 2 years (4.3% per annum).The majority of this peak represented distant recurrence (3.4% per annum). In Cox regression analysis, tumor size and grade, lymph node involvement, lymphovascular invasion, and symptomatic presentation were significant independent predictors of early recurrence. Age at diagnosis was independently predictive of recurrence within 2.5 years of diagnosis but not later recurrence. This study identified an early recurrence peak at 2 years, most of which were distant recurrences. Implementing an aromatase inhibitor after an initial 2-3 years of tamoxifen fails to address this early peak of distant recurrence and the potential breast cancer-associated mortality.

Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). Specific PPARalpha stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARgamma agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARalpha expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.