Romain Harmancey

Adaptation and Maladaptation of the Heart in Obesity

Obesity 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 Virchow1 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.nnChanges 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 …

Obesogenic high fat western diet induces oxidative stress and apoptosis in rat heart

Feeding Wistar rats a high calorie “Western” diet (45% fat) for up to 48xa0weeks induces obesity and cardiac dysfunction, while a high fat diet (60% fat) induces obesity only. Here we investigated the molecular “footprints” of the two forms of diet-induced obesity in the heart. In rats fed Western diet for a long term, cardiac mRNA transcript levels of malic enzyme were decreased (−72%, Pxa0<xa00.05), suggesting impaired anaplerotic flux of the Krebs cycle (KC) and mitochondrial dysfunction. In addition, there was a marked decrease in the expression of the transcription factor MEF2C (myocyte enhancer factor 2C) and its target gene SERCA2a (sarco-endo-plasmic reticulum Ca2+-ATPase). Oxidative stress was reflected in reduced transcript levels of manganese superoxide dismutase, glutathione peroxidase 1, and increased protein levels of mitochondrial transcription factor A, suggesting compensatory mitochondrial biogenesis in the face of increased mitochondrial damage. Oxidant injury was accompanied by increased protein glycosylation, increased transcript levels of glutamine fructose 6-phosphate amidotransferase 2, and decreased protein levels of acetyl Co-A carboxylase. Lastly, apoptosis was evident by TUNEL positivity and elevated mRNA transcript levels and activity of caspase 3. Consistent with these results, protein levels of Bcl2 were markedly reduced. We conclude that inadequate supplementation of KC intermediates due to reduced levels of malic enzyme, downregulation of MEF2C and its target gene SERCA2a, oxidative stress, and programmed cell death are all potential contributors to contractile dysfunction of the heart.

Insulin resistance improves metabolic and contractile efficiency in stressed rat heart

Insulin resistance is a prominent feature in heart failure, while hyperglycemia impairs cardiac contraction. We propose that decreased insulin‐mediated glucose uptake by the heart preserves cardiac function in response to metabolic and hemodynamic stress. To test this hypothesis, we fed rats a high‐sucrose diet (HSD). Energy substrate metabolism and cardiac work were determined ex vivo in a sequential protocol simulating metabolic and hemodynamic stress. Compared to chow‐fed, control rats, HSD impaired myocardial insulin responsiveness and induced profound metabolic changes in the heart, characterized by reduced rates of glucose uptake (7.91 ±0.30 vs. 10.73±0.67 μmol/min/g dry weight; P<0.001) but increased rates of glucose oxidation (2.38±0.17 vs. 1.50±0.15 μmol/min/g dry weight; P<0.001) and oleate oxidation (2.29±0.11 vs. 1.96±0.12 μmol/ min/g dry weight; P<0.05). Tight coupling of glucose uptake and oxidation and improved cardiac efficiency were associated with a reduction in glucose 6‐phosphate and oleoyl‐CoA levels, as well as a reduction in the content of uncoupling protein 3. Our results suggest that insulin resistance lessens fuel toxicity in the stressed heart. This calls for a new exploration of the mechanisms regulating substrate uptake and oxidation in the insulin‐resistant heart.—Harmancey, R., Lam, T. N., Lubrano, G. M., Guthrie, P. H., Vela, D., Taegtmeyer, H. Insulin resistance improves metabolic and contractile efficiency in stressed rat heart. FASEB J. 26, 3118–3126 (2012). www.fasebj.org

Virchow's metamorphosis revealed triglycerides in the heart.

The essence of cardiac metabolism is easy to understand: in the normal human heart, supply and demand of energy-providing substrates is finely balanced to meet the energy needs for contraction by oxidative metabolism of fatty acids and carbohydrates. When it comes to energy, the heart is always on

Virchow's Metamorphosis Revealed

The essence of cardiac metabolism is easy to understand: in the normal human heart, supply and demand of energy-providing substrates is finely balanced to meet the energy needs for contraction by oxidative metabolism of fatty acids and carbohydrates. When it comes to energy, the heart is always on

Clinical ResearchMyocardial Metabolism: Editorial CommentVirchow's Metamorphosis Revealed: Triglycerides in the Heart⁎

The essence of cardiac metabolism is easy to understand: in the normal human heart, supply and demand of energy-providing substrates is finely balanced to meet the energy needs for contraction by oxidative metabolism of fatty acids and carbohydrates. When it comes to energy, the heart is always on