Heinrich Taegtmeyer

Return to the fetal gene program

A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of “adult” isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the “fetal” gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal‐like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart.

Downregulation of Myocardial Myocyte Enhancer Factor 2C and Myocyte Enhancer Factor 2C–Regulated Gene Expression in Diabetic Patients With Nonischemic Heart Failure

Background—In animal studies, diabetes has been shown to induce changes in gene expression of key regulators in cardiac energy metabolism and calcium homeostasis. In the present study, we tested the hypothesis that metabolic gene expression in nonischemic failing hearts of diabetic patients differs from that in nonischemic failing hearts of nondiabetic patients. Methods and Results—Left ventricular tissue was obtained from nonfailing hearts (n=6) and from nonischemic failing hearts of patients with or without type 2 diabetes. Myocardial transcript levels of key regulators in energy substrate metabolism (glucose transporter 1, glucose transporter 4, pyruvate dehydrogenase kinase 4, peroxisome proliferator–activated receptor &agr;, muscle carnitine palmitoyl transferase-1, medium-chain acyl-CoA dehydrogenase, and uncoupling protein 3), calcium homeostasis (sarcoplasmic reticulum Ca2+-ATPase [SERCA2a], phospholamban, and cardiac ryanodine receptor), and contractile function (myosin heavy chain &agr;) were measured using real-time quantitative reverse transcription–polymerase chain reaction. In addition, we measured myocyte enhancer factor 2C (MEF2C) and SERCA2a protein levels. Only MEF2C regulated transcripts (glucose transporter 4, SERCA2a, and myosin heavy chain &agr;) were lower in the diabetic group compared with the nondiabetic group. MEF2C protein content was also decreased. Conclusion—MEF2C and MEF2C-regulated genes are decreased in the failing hearts of diabetic patients. This transcriptional mechanism may contribute to the contractile dysfunction in heart failure patients with diabetes.

Association of plasma free fatty acids and left ventricular diastolic function in patients with clinically severe obesity

BACKGROUNDnObesity is an important contributor to many cardiovascular risk factors and has been associated with abnormalities in cardiac contractile function. Causes of impaired contractile function are not fully understood and may include an oversupply of substrates.nnnOBJECTIVEnWe tested the hypothesis that metabolic dysregulation may adversely influence cardiac function. Specifically, we examined the effects of plasma free fatty acids and insulin sensitivity on left ventricular function in patients with clinically severe obesity.nnnDESIGNnWe measured metabolic and cardiac variables in 64 obese patients [body mass index (BMI; in kg/m(2)) > 35], including 2-D complete echocardiogram with M-mode and tissue Doppler imaging, anthropometric measurements, and analysis of blood chemistries.nnnRESULTSnThe median (25th and 75th percentile) age and BMI were 46 y (36, 53 y) and 51.5 (42.5, 56.5), respectively. The prevalence of diabetes, hypertension, and insulin resistance were 38%, 53%, and 90%, respectively. Plasma free fatty acid (FFA) concentrations were elevated in the cohort. No association was observed between insulin sensitivity or anthropometric measurements and left ventricular contractile function. However, FFA concentration was independently associated with diastolic function (r = -0.33, P = 0.01), and 40% of the cohort showed age-adjusted diastolic impairment as measured by tissue Doppler imaging.nnnCONCLUSIONnThe negative association between FFA and diastolic function, in the setting of insulin resistance, suggests that excess FFA may exert a lipotoxic effect on the heart.

Progressive regression of left ventricular hypertrophy two years after bariatric surgery.

BACKGROUNDnObesity is a systemic disorder associated with an increase in left ventricular mass and premature death and disability from cardiovascular disease. Although bariatric surgery reverses many of the hormonal and hemodynamic derangements, the long-term collective effects on body composition and left ventricular mass have not been considered before. We hypothesized that the decrease in fat mass and lean mass after weight loss surgery is associated with a decrease in left ventricular mass.nnnMETHODSnFifteen severely obese women (mean body mass index [BMI]: 46.7+/-1.7 kg/m(2)) with medically controlled hypertension underwent bariatric surgery. Left ventricular mass and plasma markers of systemic metabolism, together with body mass index (BMI), waist and hip circumferences, body composition (fat mass and lean mass), and resting energy expenditure were measured at 0, 3, 9, 12, and 24 months.nnnRESULTSnLeft ventricular mass continued to decrease linearly over the entire period of observation, while rates of weight loss, loss of lean mass, loss of fat mass, and resting energy expenditure all plateaued at 9 [corrected] months (P <.001 for all). Parameters of systemic metabolism normalized by 9 months, and showed no further change at 24 months after surgery.nnnCONCLUSIONSnEven though parameters of obesity, including BMI and body composition, plateau, the benefits of bariatric surgery on systemic metabolism and left ventricular mass are sustained. We propose that the progressive decrease of left ventricular mass after weight loss surgery is regulated by neurohumoral factors, and may contribute to improved long-term survival.

Tracing Cardiac Metabolism In Vivo: One Substrate at a Time

In the myocardial cell, a series of enzyme-catalyzed reactions results in the efficient transfer of chemical energy into mechanical energy. The goals of this article are to emphasize the ability of noninvasive imaging techniques using isotopic tracers to detect the metabolic footprints of heart disease and to propose that cardiac metabolic imaging is more than a useful adjunct to current myocardial perfusion imaging studies. A strength of metabolic imaging is in the assessment of regional myocardial differences in metabolic activity, probing for 1 substrate at a time. We hope that new and developing methods of cardiac imaging will lead to the earlier detection of heart disease and improve the management and quality of life for patients afflicted with ischemic and nonischemic heart muscle disorders.

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.

Too much or not enough of a good thing? Cardiac glucolipotoxicity versus lipoprotection

Article history: Received 14 July 2010 Received in revised form 15 September 2010 Accepted 16 September 2010 Available online 24 September 2010 obesity and/or type 2 diabetes and heart failure [5]. Severa Roger Unger and his group called the deleterious conseq lipid overload in the heart “cardiac lipotoxicity” [6]. Th knowledge concerning cardiac lipotoxicity has recen reviewed [7]. At about the same time that lipotoxicity en thinking evidence grew for protein glycosylation via the he biosynthetic pathway [8,9], and for reactive oxygen speci

Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart

Mechanical unloading of the rat heart increases both protein synthesis and protein degradation. The transcriptional mechanism underlying increased protein synthesis during atrophic remodeling is not known. The aim of this study was to identify transcriptional regulators and the gene expression profile regulating protein synthesis in the unloaded rat heart and in the unloaded failing human heart. We measured DNA binding activity, transcript levels, and protein expression of transcriptional regulators of protein synthesis in a model of atrophic remodeling induced by heterotopic transplantation of the rat heart (duration 1 and 7 days). Using microarray analysis and quantitative RT‐polymerase chain reaction, we found an increase in c‐myc‐regulated gene expression including an induction of ribosomal subunit messenger RNAs (RPS 10, RPL 21) and rRNA (18S). Consistent with the gene expression profile, DNA binding activity of c‐myc and the nuclear protein concentration of its coactivator, upstream binding factor (UBF), increased in the atrophied heart whereas protein levels of the c‐myc inhibitor MAD1 decreased. We found the same increase of ribosomal subunit messenger RNA and rRNA in 21 paired samples of failing human hearts obtained before and after left ventricular assist device treatment (mean duration: 157±31 days). In summary, mechanical unloading increases c‐myc activity and c‐myc‐regulated gene expression in the rat heart. Changes in transcript levels of genes regulating ribosomal biogenesis in the unloaded rat heart resemble those found in the unloaded failing human heart. We concluded c‐myc and c‐myc‐regulated gene expression are transcriptional regulators of protein synthesis during atrophic remodeling of the heart.—Razeghi, P., Buksinska‐Lisik, M., Palanichamy, N., Stepkowski, S., Frazier, O. H., Taegt‐meyer, H. Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart. FASEB J. 20, 1090–1096 (2006)

Insulin sensitizers and heart failure: An engine flooded with fuel

Since the FDA approved rosiglitazone in May 1999, there have been concerns about adverse lipid effects, edema and increased cardiovascular risk.[1] Nissen and Wolski’s 2007 meta-analysis of 42 clinical trials drew special attention to increased death and disability from cardiovascular complications in patients treated with rosiglitazone; thus many questions have been raised regarding the safety of this drug.[2] In 2007, the FDA revealed similar results in a separate meta-analysis showing a statistically significant increase in cardiovascular risk with the use of rosiglitazone.[3] The manufacturers of rosiglitazone therefore felt compelled to release an interim analysis of the RECORD Trial in 2007, with final results published in 2009. The RECORD Trial supports that the addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes does indeed increase the risk of heart failure. However, the data were inconclusive about any possible effect on myocardial infarction, and it suggested no increased risk of overall cardiovascular morbidity or mortality in those treated with rosiglitazone compared with standard glucose-lowering drugs.[4] The RECORD Trial was criticized as being underpowered and flawed by the publication of unblinded, preliminary data.[5] In June 2009, the FDA therefore mandated an adequately powered cardiovascular outcomes study for rosiglitazone known as the TIDE Trial. n nIn July 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee joint meeting with the Drug Safety and Risk Management Advisory Committee convened. At this meeting, Dr. Nissen (Cardiovascular Medicine Chairman of the Cleveland Clinic) presented an updated meta-analysis which again demonstrated an increased risk of AMI associated with rosiglitazone.[6] In addition, Dr. Graham (Associate Director of the FDA’s Office of Drug Safety) presented the results of the retrospective cohort study discussed here, also suggesting adverse cardiovascular events associated with the use of rosiglitazone. A representative from the manufacturers of rosiglitazone was also present at the joint meeting to defend its product utilizing results from the RECORD Trial. One week following the advisory committee meeting, the FDA announced that the TIDE Trial has been placed on partial clinical hold, with no new patients eligible for enrollment until further notice. In addition, the FDA has instructed the manufacturers of rosiglitazone to update their investigators, institutional review boards and ethics committees involved in the TIDE Trial regarding any new safety information, along with information concerning the deliberations and votes of the FDA joint advisory committee meeting. The FDA is currently still evaluating all available information on rosiglitazone’s safety, in conjunction with discussions of the recent advisory committee meeting, and will update the public on the outcome of its review and its implications for both the TIDE Trial and rosiglitazone.