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Heinrich Taegtmeyer

Publications and source records attributed to Heinrich Taegtmeyer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Acclimatization to chronic hypobaric hypoxia is associated with a differential transcriptional profile between the right and left ventricle.

Acute hypobaric hypoxia induces a transient reactivation of the fetal-metabolic gene program in the rat heart. Although chronic hypobaric hypoxia causes alterations in metabolism and cardiac function, little is known about the transcriptional profile associated with acclimatization to chronic hypoxia. Because in chronic hypoxia only the right ventricle is exposed to pressure overload (pulmonary hypertension), we hypothesized that chronic hypobaric hypoxia induces a differential transcriptional profile in the right and left ventricle. Male Wistar rats were exposed to a hypobaric environment (11% O2) for 4, 10, and 12 weeks. Right and left ventricular tissue was isolated for histology and candidate gene expression. Chronic hypobaric hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle, changes in metabolic gene expression suggested a downregulation of fatty acid metabolism and an increase in glucose metabolism, while left ventricular metabolic gene expression suggested restoration of fatty acid metabolism. While myosin heavy chain isoform transcript levels in the right ventricle indicated a progressive reactivation of the fetal iso-gene pattern, there was normalization of myosin iso-gene expression in the left ventricle. Similarly, sarcoendoplasmic reticulum ATPase 2a (SERCA2a) transcript levels in the right ventricle decreased by 12 weeks of chronic hypoxia exposure, whereas, left ventricular SERCA2a expression was unchanged. In conclusion, acclimatization to chronic hypobaric hypoxia induced a differential transcriptional response between the right and left ventricle. We speculate that reactivation of the fetal-metabolic program in the right ventricle is adaptive to pressure overload.

Acclimatization↗
PubMed2005

Metabolic energetics and genetics in the heart.

From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The "multitasking" of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post-translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.

Animals↗
PubMed2004

PPAR-gamma agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation.

Previously we reported that the beneficial effects of beta-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 +/- 0.11*; 3 mo MR, 2.12 +/- 0.34; baseline, 4.01 +/- 0.29; ANOVA, P = 0.038; *P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-gamma agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.

Animals↗
PubMed2004

Nonacute effects of H-FABP deficiency on skeletal muscle glucose uptake in vitro.

Heart-type fatty acid-binding protein (H-FABP) is required for high rates of skeletal muscle long-chain fatty acid (LCFA) oxidation and esterification. Here we assessed whether H-FABP affects soleus muscle glucose uptake when measured in vitro in the absence of LCFA. Wild-type and H-FABP null mice were fed a standard chow or high-fat diet before muscle isolation. With the chow, the mutation increased insulin-dependent deoxyglucose uptake by 141% (P < 0.01) at 0.02 mU/ml of insulin but did not cause a significant effect at 2 mU/ml of insulin; skeletal muscle triglyceride and long-chain acyl-CoA (LCA-CoA) levels remained normal. With the high-fat diet, the mutation increased insulin-dependent deoxyglucose uptake by 190% (P < 0.01) at 2 mU/ml of insulin, thus partially preventing insulin resistance, and it completely prevented the threefold (P < 0.001) diet-induced increase of muscle triglyceride levels; however, muscle LCA-CoA levels showed little or no reduction. With both diets, the mutation reduced the basal (insulin-independent) soleus muscle deoxyglucose uptake by 28% (P < 0.05). These results establish a close relation between FABP-dependent lipid pools and insulin sensitivity and indicate the existence of a nonacute, antagonistic, and H-FABP-dependent fatty acid regulation of basal and insulin-dependent muscle glucose uptake.

Acyl Coenzyme A↗
PubMed2004

Reversal of glucose-insulin-potassium-induced hyperglycemia by aggressive insulin treatment in postoperative heart failure. An observational study.

Metabolic support with glucose-insulin-potassium (GIK) significantly reduces the morbidity and mortality of patients in cardiogenic shock after hypothermic ischemic arrest for aortocoronary bypass surgery. However, a small subset of these patients develops postoperative insulin resistance regardless of their preoperative diabetic status. Whether GIK directly contributes to higher mortality in these patients is unknown. We reviewed the records of 322 patients whose treatment for postoperative cardiogenic shock included GIK. Ten patients (3%) had postoperative hyperglycemia (serum glucose > or =250 mg/dl or 13.9 mmol/l) due to insulin resistance. These were compared to randomly selected GIK-treated, insulin-responsive patients (n = 10) and non-GIK-treated patients (n = 10) for comparison. The insulin-resistant patients required increasing amounts of regular insulin up to 130 U/h until blood glucose levels fell below 250 mg/dl. However, short-term outcomes (IABP support time, length of stay in ICU, 7-day mortality) for insulin- resistant patients were indistinguishable from those for insulin-responsive patients. These data indicate that postoperative iatrogenic hyperglycemia in patients after cardiopulmonary bypass may not be detrimental per se and is reversible when treated with supplemental insulin.

Aged↗
PubMed2004

Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling.

Mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3) are postulated to contribute to antioxidant defense, nutrient partitioning, and energy efficiency in the heart. To distinguish isotype function in response to metabolic stress we measured cardiac mitochondrial function and cardiac UCP gene expression following chronic hypobaric hypoxia. Isolated mitochondrial O(2) consumption and ATP synthesis rate were reduced but respiratory coupling was unchanged compared to normoxic groups. Concurrently, left ventricular UCP3 mRNA levels were significantly decreased with hypoxia (p<0.05) while UCP2 levels remained unchanged versus controls. Diminished UCP3 expression was associated with coordinate regulation of counter-regulatory metabolic genes. From these data, we propose a role for UCP3 in the regulation of fatty acid oxidation in the heart as opposed to uncoupling of mitochondria. Moreover, the divergent hypoxia-induced regulation of UCP2 and UCP3 supports distinct mitochondrial regulatory functions of these inner mitochondrial membrane proteins in the heart in response to metabolic stress.

Animals↗
PubMed2004

Cardiomyocyte-specific desmin rescue of desmin null cardiomyopathy excludes vascular involvement.

Mice deficient in desmin, the muscle-specific member of the intermediate filament gene family, display defects in all muscle types and particularly in the myocardium. Desmin null hearts develop cardiomyocyte hypertrophy and dilated cardiomyopathy (DCM) characterized by extensive myocyte cell death, calcific fibrosis and multiple ultrastructural defects. Several lines of evidence suggest impaired vascular function in desmin null animals. To determine whether altered capillary function or an intrinsic cardiomyocyte defect is responsible for desmin null DCM, transgenic mice were generated to rescue desmin expression specifically to cardiomyocytes. Desmin rescue mice display a wild-type cardiac phenotype with no fibrosis or calcification in the myocardium and normalization of coronary flow. Cardiomyocyte ultrastructure is also restored to normal. Markers of hypertrophy upregulated in desmin null hearts return to wild-type levels in desmin rescue mice. Working hearts were perfused to assess coronary flow and cardiac power. Restoration of a wild-type cardiac phenotype in a desmin null background by expression of desmin specifically within cardiomyocyte indicates that defects in the desmin null heart are due to an intrinsic cardiomyocytes defect rather than compromised coronary circulation.

Animals↗
PubMed2004

Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support.

BACKGROUND: There have been increasing reports of cardiac improvement in heart failure patients supported by left ventricular assist devices (LVADs i.e.), including a number of patients who have tolerated removal of the device without the benefit of cardiac transplant. In the current study, we retrospectively investigated echocardiographic and histologic changes in patients supported by LVADs (n = 18). The goal of our study was to determine if the degree of cardiac fibrosis and myocyte size in pre-implant biopsies could predict myocardial improvement as assessed by improvements in ejection fraction (EF) during LVAD support. METHODS: We determined total collagen content in myocardial biopsy specimens by a semi-quantitative analysis of positive Picro-Sirius Red-stained areas and myocyte size measurements by computerized edge detection software. RESULTS: During LVAD support, 9 of the 18 patients (Group A) were distinguished by significant improvement in ejection fraction (pre <20% vs unloaded 34 +/- 5%). In addition, Group A patients had significantly less fibrosis and smaller myocytes than their Group B counterparts, whose EF did not improve. There was an inverse correlation between pre-implant biopsy collagen levels and myocyte size with increases in EF during LVAD unloading. CONCLUSIONS: We found that the patients who demonstrated the greatest improvements in EF during support had less fibrosis and smaller myocytes at the time of device implantation. We propose that tissue profiling a patient's pre-implant biopsy for fibrosis and myocyte size may allow stratification in Stage IV heart failure and may predict myocardial improvement during LVAD support.

Adolescent↗
PubMed2004

Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.

Adult↗
PubMed2004

Linking gene expression to function: metabolic flexibility in the normal and diseased heart.

Metabolism transfers energy from substrates to ATP. As a "metabolic omnivore," the normal heart adapts to changes in the environment by switching from one substrate to another. We propose that this flexibility is lost in the maladapted, diseased heart. Both adaptation and maladaptation are the results of metabolic signals that regulate transcription of key cardiac regulatory genes. We propose that metabolic remodeling precedes, initiates, and sustains functional and structural remodeling. The process of metabolic remodeling then becomes a target for pharmacological intervention restoring metabolic flexibility and normal contractile function of the heart.

Diabetes Mellitus↗
PubMed2003

Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy.

Hypobaric hypoxia induces right ventricular hypertrophy. The relative contribution of pulmonary hypertension, decreased arterial oxygen, and neuroendocrine stimulation to the transcriptional profile of hypoxia-induced right ventricular hypertrophy is unknown. Whereas both ventricles are exposed to hypoxia and neuroendocrine stimulation, only the right ventricle is exposed to increased load. We postulated that right ventricular hypertrophy would reactivate the fetal gene transcriptional profile in response to increased load. We measured the expression of candidate genes in the right ventricle of rats exposed to hypobaric hypoxia (11% O(2)) and compared the results with the left ventricle. Hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle only, atrial natriuretic factor transcript levels progressively increased starting at day 7. Metabolic genes were differentially regulated, suggesting a substrate switch from fatty acids to glucose during early hypoxia and a switch back to fatty acids by day 14. There was also a switch in myosin isogene expression and a downregulation of sarcoplasmic/endoplasmic ATPase 2a during early hypoxia, whereas later, both myosin isoforms and SERCA2a were upregulated. When the right and left ventricle were compared, the transcript levels of all genes, except for myosin isoforms and pyruvate dehydrogenase kinase-4, differed dramatically suggesting that all these genes are regulated by load. Our findings demonstrate that hypoxia-induced right ventricular hypertrophy transiently reactivates the fetal gene program. Furthermore, myosin iso-gene and pyruvate dehydrogenase kinase-4 expression is not affected by load, suggesting that either hypoxia itself or neuroendocrine stimulation is the primary regulator of these genes.

Adaptation, Physiological↗