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Biomedical subjects

Irwin Klein

Publications and source records attributed to Irwin Klein.

15 recordsLinked to original sources
PubMed2005

Effect of serum triiodothyronine on regulation of cardiac gene expression: role of histone acetylation.

Thyroid hormone regulates the transcription of several important cardiac genes. Although the thyroid gland produces predominantly thyroxine (T(4)), it is triiodothyronine (T(3)) that is transported across the sarcolemma and binds to nuclear thyroid hormone receptor proteins; yet various studies suggest that serum T(3) levels do not accurately reflect cellular T(3) action. To address this question, we studied the dose-response relationship of T(3) administered by constant infusion in hypothyroid animals with the simultaneous in vivo transcription rate of the cardiac-specific alpha-myosin heavy chain (MHC) gene, measured by quantitating alpha-MHC heteronuclear (hn)RNA content. Constant infusion of 4 mug T(3) x kg body wt(-1) x day(-1) for 3 days normalized serum T(3) and restored transcription to euthyroid levels; in contrast, daily injections of the same dose increased alpha-MHC transcription by only 55% of that obtained by infusion. Although infusion of T(3) at 1.25 microg T(3) x kg body wt(-1) x day(-1) was not sufficient to restore serum T(3) to normal, it was capable of restoring transcription to normal at 3 days, but when administered for 12 days, transcription of alpha-MHC was found to be 50% of euthyroid levels, demonstrating a decreased sensitivity to T(3) over time. Treatment with trichostatin A (TSA) to inhibit histone deacetylation increased levels of total nuclear acetylated histone H4 by almost 50% but was without effect on the real-time PCR measures of alpha-MHC hnRNA. TSA administered together with T(3) (10 mug T(3)/kg body wt) significantly increased transcription of alpha-MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T(3) regulation of cardiac alpha-MHC transcription.

Acetylation↗
PubMed2005

Effect of triiodothyronine on gene transcription during cardiopulmonary bypass in infants with ventricular septal defect.

We tested the hypothesis that triiodothyronine (T3) supplementation alters gene transcription in the left ventricular myocardium of infants undergoing cardiopulmonary bypass for ventricular septal defect repair. To our knowledge, a novel heteronuclear assay demonstrated for the first time in human heart that rapid change in T3 levels altered the adenine nucleotide translocase-1 transcription rate during cardiopulmonary bypass.

Adenine Nucleotide Translocator 1↗
PubMed2005

Potential uses of T3 in the treatment of human disease.

Treatments for hypothyroidism have been available since the late 19th century, and have been continually improved by advancing our understanding of thyroid hormone pharmacology. Thyroxine (T4) monotherapy is currently the standard of care, but may leave some hypothyroid symptoms unaddressed. Triiodothyronine (T3), formed by the monodeiodination of T4, is the biologically active form of thyroid hormone based upon its ability to regulate gene expression at the nuclear level. A variety of human and animal studies have raised the question of whether T4 monotherapy is sufficient to restore tissue and organ intracellular T3 levels to normal. Furthermore, some evidence, albeit controversial, suggests that the addition of T3 (Cytomel) to T4 replacement therapy may improve patients' quality of life, psychometric performance and mood. Further developmental work is needed to refine T3 therapy in a way to enhance efficacy and lower the potential for unwanted effects.

Animals↗
PubMed2005

Posttranscriptional regulation of myosin heavy chain expression in the heart by triiodothyronine.

Triiodothyronine (T3) regulates cardiac contractility in part by regulating the expression of several important cardiac myocyte genes. In the rat, the T3-mediated induction of alpha-myosin heavy chain (MHC) transcription in hypothyroid hearts is rapid, exhibiting zero-order kinetics, whereas the repression of beta-MHC in these same hearts is much slower. To elucidate the mechanism for T3 transcriptional as well as posttranscriptional regulation of both MHC gene isoforms, we used an RT-PCR-based transcription assay and the RNA polymerase II inhibitor actinomycin D in an in vivo model to simultaneously measure specific alpha- and beta-MHC heterogeneous nuclear RNA (hnRNA), mRNA kinetics, and MHC antisense RNA. In vivo actinomycin D treatment blocked alpha-MHC transcription in euthyroid rats by >80% at 2 h and suggested a half-life of alpha-MHC hnRNA of approximately 1 h, whereas actinomycin D inhibited beta-MHC transcription in hypothyroid rats by >75% at 6 h, suggesting a significantly longer hnRNA half-life of approximately 4 h. The effect of actinomycin D on beta-MHC transcription was independent of T3. T3 treatment in hypothyroid animals caused beta-MHC mRNA to decline more rapidly than beta-MHC hnRNA, demonstrating, for the first time, a posttranscriptional mechanism(s). The measured change in beta-MHC mRNA half-life indicates a T3-mediated destabilization of beta-MHC mRNA. To understand the mechanism by which T3 destabilizes beta-MHC mRNA, we measured beta-MHC antisense RNA. beta-MHC antisense RNA is present in euthyroid myocytes, but levels are not significant in hypothyroid myocytes. This differential expression may explain some of the effects of T3 on MHC posttranscriptional regulation.

Animals↗
PubMed2004

Altered myocardial Ca2+ cycling after left ventricular assist device support in the failing human heart.

OBJECTIVES: The objective of the present study was to determine whether improved contractility after left ventricular assist device (LVAD) support reflects altered myocyte calcium cycling and changes in calcium-handling proteins. BACKGROUND: Previous reports demonstrate that LVAD support induces sustained unloading of the heart with regression of pathologic hypertrophy and improvements in contractile performance. METHODS: In the human myocardium of subjects with heart failure (HF), with non-failing hearts (NF), and with LVAD-supported failing hearts (HF-LVAD), intracellular calcium ([Ca(2+)](i)) transients were measured in isolated myocytes at 0.5 Hz, and frequency-dependent force generation was measured in multicellular preparations (trabeculae). Abundance of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA), Na(+)/Ca(2+) exchanger (NCX), and phospholamban was assessed by Western analysis. RESULTS: Compared with NF myocytes, HF myocytes exhibited a slowed terminal decay of the Ca(2+) transient (DT(terminal), 376 +/- 18 ms vs. 270 +/- 21 ms, HF vs. NF, p < 0.0008), and HF-LVAD myocytes exhibited a DT(terminal) that was much shorter than that observed in HF myocytes (278 +/- 10 ms, HF vs. HF-LVAD, p < 0.0001). Trabeculae from HF showed a negative force-frequency relationship, compared with a positive relationship in NF, whereas a neutral relationship was observed in HF-LVAD. Although decreased SERCA abundance in HF was not altered by LVAD support, improvements in [Ca(2+)](i) transients and frequency-dependent contractile function were associated with a significant decrease in NCX abundance and activity from HF to HF-LVAD. CONCLUSIONS: Improvement in rate-dependent contractility in LVAD-supported failing human hearts is associated with a faster decay of the myocyte calcium transient. These improvements reflect decreases in NCX abundance and transport capacity without significant changes in SERCA after LVAD support. Our results suggest that reverse remodeling may involve selective, rather than global, normalization of the pathologic patterns associated with the failing heart.

Blotting, Western↗
PubMed2004

Hypothyroidism as a risk factor for cardiovascular disease.

The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The "traditional" risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH >10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of L-thyroxine outweigh the risk.

Cardiovascular Diseases↗
PubMed2003

Triiodothyronine-mediated myosin heavy chain gene transcription in the heart.

We developed an RT-PCR assay to study both the time course and the mechanism for the triiodothyronine (T(3))-induced transcription of the alpha- and beta-myosin heavy chain (MHC) genes in vivo on the basis of the quantity of specific heterogeneous nuclear RNA (hnRNA). The temporal relationship of changes in transcriptional activity to the amount of alpha-MHC mRNA and the coordinated regulation of transcription of more than one gene in response to T(3) are demonstrated here for the first time. Quantitation of alpha-MHC hnRNA demonstrated that T(3) induced alpha-MHC transcription in hypothyroid rats within 30 min of a single injection of T(3) (0.5 microg/100 g body wt). Maximal transcription rates (135% +/- 15.8 of euthyroid values) occurred 6 h after injection and subsequently declined in parallel with serum T(3) levels. The transcription of beta-MHC was reduced to 86% of peak hypothyroid levels 6 h after a single T(3) injection and reached a nadir of 59% of hypothyroid levels at 36 h. Analysis of the time course of T(3)-mediated induction of alpha-MHC hnRNA and repression of beta-MHC hnRNA indicates that separate molecular mechanisms are involved in the coordinated regulation of these genes.

Animals↗
PubMed2003

Thyroid hormone and blood pressure regulation.

Thyroid hormone has well-recognized effects on the cardiovascular system and blood pressure regulation. Blood pressure is altered across the entire spectrum of thyroid disease. The effects of hyperthyroidism include increased cardiac output, contractility, tachycardia, widened pulse pressure, decreased systemic vascular resistance, and increased basal metabolic rate. The manifestations of hypothyroidism are in marked contrast to those of hyperthyroidism and include decreased cardiac output, narrow pulse pressure, increased systemic vascular resistance, and decreased metabolic rate. Although thyroid hormone affects almost all tissues of the body and mediates changes in homeostasis, adaptations of the cardiovascular system can result in changes in blood pressure to accommodate the new demands on the system. In this paper, we review the direct and indirect thyroid hormone-mediated effects on blood pressure.

Blood Pressure↗
PubMed2003

Interleukin-6 and thyroid hormone metabolism in pediatric cardiac surgery patients.

Pediatric patients undergoing cardiac surgery have been reported to have low serum triiodothyronine (T(3)) levels in the postoperative period. The cause of this dysfunction is not known, although proinflammatory cytokines such as interleukin-6 (IL-6) have been implicated in the inhibition of hepatic conversion of thyroxine (T(4)) to T(3). This study measured serum levels of IL-6 and T(3) during the first 4 postoperative days in 16 children (mean age, 28 +/- 7 days) undergoing cardiopulmonary bypass surgery. The mean preoperative serum total T(3) level was 164 +/- 30 ng/dL (2.5 +/- 0.5 nmol/L) that decreased significantly to a nadir of 43 +/- 8 ng/dL (0.6 +/- 0.01 nmol/L) within 48 hours after surgery. Serum IL-6 levels increased significantly from 16 +/- 7 pg/mL preoperatively to a peak value of 374 +/- 134 pg/mL measured 2-3 hours after surgery. A positive correlation (r(2) = 0.507) was found between the peak serum level of IL-6 and the lowest serum T(3) level in each patient attained during the 4 postoperative days. Potential treatments directed toward diminishing the rise in proinflammatory cytokines in the immediate postoperative period may prove effective in preventing the low serum T(3) in children undergoing cardiac surgery, and thus diminish the associated postoperative morbidity.

Aortic Valve↗
PubMed2003

Evaluation of the therapeutic efficacy of different levothyroxine preparations in the treatment of human thyroid disease.

At the present time, optimal therapy for hypothyroidism requires replacement of the deficiency in thyroid hormone with synthetic levothyroxine. Precise titration of this narrow therapeutic index drug is necessary to return the patient to a chemically and clinically euthyroid state. Seven levothyroxine formulations are Food and Drug Administration (FDA)-approved and four are available to the physician. Proper dosage is established based on thyrotropin (TSH) testing and clinical evaluation. Each levothyroxine preparation must comply with FDA standards for bioavailability but may vary with respect to its dissolution and absorption properties and are not interchangeable. This equivalence testing is done on normal volunteers and requires a suprapharmacologic dose of levothyroxine in order to make the determination of bioavailability. In this review we discuss the various methods to evaluate therapeutic efficacy and bioequivalence of levothyroxine preparations in the treatment of thyroid disease. These are relevant to the physician and patient because small differences in the efficacy can produce unwanted effects of either underreplacement or overreplacement.

Absorption↗
PubMed2002

Thyroid hormone-regulated cardiac gene expression and cardiovascular disease.

The effects of hypothyroidism on the cardiovascular system have been the subject of much research over the last several decades. The hypothyroid cardiac phenotype includes impaired contractile function, decreased cardiac output, and alterations in myocyte gene expression. In the setting of cardiac disease, as in other acute illnesses, alterations in thyroid hormone metabolism occur that result in decreased serum triiodothyronine (T(3)) levels. This is referred to as low T(3) syndrome. Similarities between the heart failure phenotype and the hypothyroid cardiac phenotype are numerous including changes in the expression of thyroid hormone regulated myocyte specific genes. The heart responds in a very sensitive manner to reduced circulating levels of T(3) with decreased expression of positively regulated genes and increased expression of negatively regulated genes. In the present paper we review data on thyroid hormone mediated cardiac specific gene transcriptional regulation. T(3) replacement therapy for hypothyroidism restores normal expression of these T(3) regulated genes and recent experiments suggest that the diseased human heart in congestive failure would benefit from similar T(3) replacement therapy.

Amiodarone↗