propylthiouracil and Cardiomyopathy--Dilated

Topics: Cardiomyopathy, Dilated; Dexamethasone; Drug Therapy, Combination; Female; Humans; Middle Aged; Potassium Iodide; Propylthiouracil; Remission Induction; Thyrotoxicosis

We hypothesized that the functional effects of R206L-a rat analog of the dilated cardiomyopathy (DCM) mutation R205L in human cardiac troponin T (TnT)-were differently modulated by myosin heavy chain (MHC) isoforms and T204E, a protein kinase C (PKC) phosphomimic of TnT. Our hypothesis was based on two observations: (1) α- and β-MHC differentially influence the functional effects of TnT; and (2) PKC isoforms capable of phosphorylating TnT are upregulated in failing human hearts.. We generated 4 recombinant TnT variants: wild type; R206L; T204E; and R206L+T204E. Functional effects of the TnT variants were tested in cardiac muscle fibers (minimum 14 per group) from normal (α-MHC) and propylthiouracil-treated rats (β-MHC) using steady-state and dynamic contractile measurements. Notably, in α-MHC fibers, Ca(2+)-activated maximal tension was attenuated by R206L (≈32%), T204E (≈63%), and R206L+T204E (≈64%). In β-MHC fibers, maximal tension was unaffected by R206L, but was attenuated by T204E (≈33%) and R206L+T204E (≈40%). Thus, β-MHC differentially counteracted the attenuating effects of the TnT variants on tension. However, in β-MHC fibers, R206L+T204E attenuated tension to a greater extent when compared to T204E alone. In β-MHC fibers, R206L+T204E attenuated the magnitude of the length-mediated recruitment of new cross-bridges (≈28%), suggesting that the Frank-Starling mechanism was impaired.. Our findings are the first (to our knowledge) to demonstrate that the functional effects of a DCM-linked TnT mutation are not only modulated by MHC isoforms, but also by the pathology-associated post-translational modifications of TnT.

Topics: Adenosine Triphosphatases; Animals; Cardiomyopathy, Dilated; Genetic Predisposition to Disease; Heart Ventricles; Male; Mutation; Myocardial Contraction; Phosphorylation; Propylthiouracil; Protein Isoforms; Protein Kinase C; Protein Processing, Post-Translational; Rats, Sprague-Dawley; Time Factors; Troponin T; Ventricular Myosins

The primary causal link between disparate effects of human hypertrophic cardiomyopathy (HCM)-related mutations in troponin T (TnT) and α- and β-myosin heavy chain (MHC) isoforms on cardiac contractile phenotype remains poorly understood. Given the divergent impact of α- and β-MHC on the NH2-terminal extension (44-73 residues) of TnT, we tested if the effects of the HCM-linked mutation (TnTF70L) were differentially altered by α- and β-MHC. We hypothesized that the emergence of divergent thin filament cooperativity would lead to contrasting effects of TnTF70L on contractile function in the presence of α- and β-MHC. The rat TnT analog of the human F70L mutation (TnTF72L) or the wild-type rat TnT (TnTWT) was reconstituted into demembranated muscle fibers from normal (α-MHC) and propylthiouracil-treated (β-MHC) rat hearts to measure steady-state and dynamic contractile function. TnTF72L-mediated effects on tension, myofilament Ca(2+) sensitivity, myofilament cooperativity, rate constants of cross-bridge (XB) recruitment dynamics, and force redevelopment were divergently modulated by α- and β-MHC. TnTF72L increased the rate of XB distortion dynamics by 49% in α-MHC fibers but had no effect in β-MHC fibers; these observations suggest that TnTF72L augmented XB detachment kinetics in α-MHC, but not β-MHC, fibers. TnTF72L increased the negative impact of strained XBs on the force-bearing XBs by 39% in α-MHC fibers but had no effect in β-MHC fibers. Therefore, TnTF72L leads to contractile changes that are linked to dilated cardiomyopathy in the presence of α-MHC. On the other hand, TnTF72L leads to contractile changes that are linked to HCM in the presence of β-MHC.

Topics: Animals; Calcium Signaling; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Genetic Predisposition to Disease; Kinetics; Male; Muscle Strength; Mutation; Myocardial Contraction; Myofibrils; Myosin Heavy Chains; Papillary Muscles; Phenotype; Phosphorylation; Propylthiouracil; Protein Binding; Rats, Sprague-Dawley; Troponin T; Ventricular Function, Left

Thyroid hormone (TH) has prominent effects on the heart, and hyperthyroidism is occasionally found to be a cause of dilated cardiomyopathy (DCM). We aim to explore the potential role of TH in the pathogenesis of DCM.. The pathophysiological role of TH in the heart was investigated using a knock-in mouse model of inherited DCM with a deletion mutation DeltaK210 in the cardiac troponin T gene. Serum tri-iodothyronine (T(3)) levels showed no significant difference between wild-type (WT) and DCM mice, whereas cardiac T(3) levels in DCM mice were significantly higher than those in WT mice. Type 2 iodothyronine deiodinase (Dio2), which produces T(3) from thyroxin, was up-regulated in the DCM mice hearts. The cAMP levels were increased in DCM mice hearts, suggesting that transcriptional up-regulation of Dio2 gene is mediated through the evolutionarily conserved cAMP-response element site in its promoter. Propylthiouracil (PTU), an anti-thyroid drug, prevented the hypertrophic remodelling of the heart in DCM mice and improved their cardiac function and life expectancy. Akt and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation increased in the DCM mice hearts and PTU treatment significantly reduced the phosphorylation levels, strongly suggesting that Dio2 up-regulation is involved in cardiac remodelling in DCM through activating the TH-signalling pathways involving Akt and p38 MAPK. Dio2 gene expression was also markedly up-regulated in the mice hearts developing similar eccentric hypertrophy after myocardial infarction.. Local hyperthyroidism via transcriptional up-regulation of the Dio2 gene may be an important underlying mechanism for the hypertrophic cardiac remodelling in DCM.

Topics: Animals; Antithyroid Agents; Cardiomyopathy, Dilated; Cells, Cultured; Cyclic AMP; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Iodide Peroxidase; Iodothyronine Deiodinase Type II; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myocardium; Oligonucleotide Array Sequence Analysis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Propylthiouracil; Proto-Oncogene Proteins c-akt; Transcription, Genetic; Triiodothyronine; Troponin T; Up-Regulation; Ventricular Remodeling

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.

Topics: Animals; Antimetabolites; Cardiomyopathy, Dilated; Carrier Proteins; Disease Models, Animal; Gene Expression; Hemodynamics; Mice; Mice, Transgenic; Microfilament Proteins; Myocardial Contraction; Myofibrils; Propylthiouracil; Tropomodulin

Thyrotoxicosis rarely precipitates heart failure. Older patients and those with underlying cardiac disease are at greater risk of experiencing this complication of thyrotoxicosis. A 43 year old male who presented with subclinical thyrotoxicosis, atrial fibrillation, and a dilated cardiomyopathy is discussed. There was no evidence of clinically significant underlying cardiac disease. At admission, the patient had an ejection fraction of 25%. Thyrotoxicosis was treated with propylthiouracil. At 14 weeks after hospitalization, the patient had an ejection fraction of 50% with significant reduction in cardiac chamber sizes and left ventricular mass index. He was biochemically euthyroid at that time. After ten months of propylthiouracil therapy, he had progressive improvement in cardiac function and decrease in left ventricular mass index. Thyrotoxicosis-associated cardiomyopathy may reverse significantly with treatment of thyrotoxicosis alone; this complication of thyrotoxicosis should be considered in any young individual with a dilated cardiomyopathy of unknown etiology.

Topics: Adult; Antithyroid Agents; Body Weight; Cardiomyopathy, Dilated; Disease Progression; Echocardiography; Heart Ventricles; Humans; Male; Propylthiouracil; Thyrotoxicosis; Thyroxine