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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.
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PMID:Mitochondrial and energetic cardiac phenotype in hypothyroid rat. Relevance to heart failure. 1763 11

Thyroid hormones have many effects on the heart and vascular system. Although cardiac output is reduced in hypothyroidism, heart failure is relatively rare because there is a lower demand for peripheral oxygen delivery. Hypothyroidism may also result in accelerated atherosclerosis and coronary artery disease. We report the case of a 55-year-old man with severe heart failure associated with severe longstanding untreated hypothyroidism. The patient was admitted for shortness of breath and chest pain. On presentation, signs and symptoms of severe hypothyroidism and heart failure were noticed. The electrocardiogram showed sinus bradycardia and ischemia. Thyroid stimulating hormone was extremely elevated and thyroid hormone levels were undetectable. A cardiac ultrasonography exam revealed abnormalities of the left ventricular dimensions and function consistent with dilated cardiomyopathy. Coronary angiography showed severe multivessel disease. Coronary by-pass was deemed necessary, but surgery was postponed because of severe heart failure. After an increasingly downhill clinical course, the patient died, eight month after his initial presentation, owing to severe heart failure. This patient represents an example of an overlooked diagnosis of severe hypothyroidism, rarely encountered nowadays, leading to dramatic consequences.
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PMID:Heart failure and dilated cardiomyopathy associated with severe longstanding untreated hypothyroidism. 1796 46

An altered thyroid hormone profile has been reported in patients with congestive heart failure. However, information regarding the status of thyroid hormone receptors in human failing cardiomyocytes is lacking. Therefore the expression of thyroid hormone and beta-adrenergic receptors was investigated in human ventricular cardiomyocytes isolated from patients with end-stage heart failure (FM, n=12), or from tentative donors (C, n=4). The expression of thyroid (TRalpha1, and TRbeta1) and beta-adrenergic receptors (ARB1 and ARB2) was measured at both the gene, and at the protein level. In FM the reduced mRNA expression of ARB1 (p<0.05, -37%) and ARB2 (p<0.05, -42%) was associated with a reduction of the messenger for TRalpha1 (p<0.05, -85%) and TRalpha2 (p<0.05, -73%). These findings were confirmed at the protein level for ARB1, ARB2 and TRalpha1. These data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors.
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PMID:Reduced expression of thyroid hormone receptors and beta-adrenergic receptors in human failing cardiomyocytes. 1803 13

Thyroid hormone is a critical determinant of cellular metabolism and differentiation. Precise tissue-specific regulation of the active ligand 3,5,3'-triiodothyronine (T3) is achieved by the sequential removal of iodine groups from the thyroid hormone molecule, with type 3 deiodinase (D3) comprising the major inactivating pathway that terminates the action of T3 and prevents activation of the prohormone thyroxine. Using cells endogenously expressing D3, we found that hypoxia induced expression of the D3 gene DIO3 by a hypoxia-inducible factor-dependent (HIF-dependent) pathway. D3 activity and mRNA were increased both by hypoxia and by hypoxia mimetics that increase HIF-1. Using ChIP, we found that HIF-1alpha interacted specifically with the DIO3 promoter, indicating that DIO3 may be a direct transcriptional target of HIF-1. Endogenous D3 activity decreased T3-dependent oxygen consumption in both neuronal and hepatocyte cell lines, suggesting that hypoxia-induced D3 may reduce metabolic rate in hypoxic tissues. Using a rat model of cardiac failure due to RV hypertrophy, we found that HIF-1alpha and D3 proteins were induced specifically in the hypertrophic myocardium of the RV, creating an anatomically specific reduction in local T3 content and action. These results suggest a mechanism of metabolic regulation during hypoxic-ischemic injury in which HIF-1 reduces local thyroid hormone signaling through induction of D3.
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PMID:Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. 1825 11

Recent research has revealed novel actions of thyroid hormone (TH) on the heart which may be of important physiological and therapeutic relevance. TH, apart from its "classical" actions on cardiac contractility and heart rhythm, appears to regulate various intracellular signaling pathways related to stress responses and cardiac remodelling. Accumulating experimental evidence suggests that changes in TH may constitute an important component in the pathophysiology of heart failure. In fact, TH seems to be a "switch" for the fetal cardiac phenotype. Changes in the TH-thyroid hormone receptor axis are also evident in patients with heart failure and associated with impaired cardiac function and increased mortality. More importantly, experimental and clinical studies demonstrate that TH can limit ischaemic injury, attenuate cardiac remodeling and improve cardiac hemodynamics. TH analogs have already been developed and may allow exploitation of the TH-thyroid hormone receptor in clinical practice. At present, the therapeutic potential and efficacy of TH in the treatment of cardiac diseases await evaluation in large clinical trials.
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PMID:Thyroid hormone and "cardiac metamorphosis": potential therapeutic implications. 1845 2

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T(4)) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T(4)/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (CI) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T(4) did not have an increased QTc interval (3.2 ms (95% CI -1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% CI 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% CI -4.2, 6.3) in the fifth quintile of free T(4) in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T(4) had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% CI 1.20, 4.80)). High levels of free T(4) are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T(4) is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.
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PMID:High free thyroxine levels are associated with QTc prolongation in males. 1846 46

Thyroid hormone has many effects on the heart and cardiovascular system. Thyrotoxicosis is associated with increased cardiovascular morbidity and mortality, primarily due to heart failure and thromboembolism. However, the relationship between thyroid hormone excess and the cardiac complications of angina pectoris and myocardial infarction remains largely speculative. Moreover, few studies have been reported on the effect of thyroid hormone levels within normal range on coronary artery disease (CAD). Therefore we examined the association of thyroid function with coronary artery diseases in euthyroid angina patients. Total 192 subjects (mean age; 60.8 yrs) were enrolled in which coronary angiograms were performed due to chest pain. We measured free thyroxine (FT(4)), thyroid stimulating hormone (TSH), serum lipid levels and high-sensitivity C-reactive protein (hsCRP) levels and analyzed their association with the presence of CAD. Serum FT(4) levels were higher in patients with CAD compared with the patients without CAD (1.31 +/- 0.30 vs 1.20 +/- 0.23, p = 0.006), and high FT(4) level was associated with the presence of multi-vessel disease. Multivariate analysis showed that age (odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.07, p = 0.007), hypertension (OR 2.04; 95% CI 1.06-3.90, p = 0.036) and FT(4) (OR 4.23; 95% CI 1.12-15.99, p = 0.033), were the determinants for CAD. The relative risk (RR) for CAD in highest tertile of FT(4) showed increased risk compared with the lowest tertile (RR 1.98; 95% CI 0.98-3.99, p<0.001). Our study showed that FT(4) levels were associated with the presence and the severity of CAD. Also, this study suggests that elevated serum FT(4) levels even within normal range could be a risk factor for CAD. Further studies will be necessary to confirm the relationship of thyroid function and CAD.
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PMID:Higher serum free thyroxine levels are associated with coronary artery disease. 1849 53

Reduced expression of sarcoplasmic reticulum calcium ATPase (SERCA)2 and other genes in the adult cardiac gene program has raised consideration of an impaired responsiveness to thyroid hormone (T3) that develops in the advanced failing heart. Here, we show that human and murine cardiomyopathy hearts have increased expression of friend of GATA (FOG)-2, a cardiac nuclear hormone receptor corepressor protein. Cardiac-specific overexpression of FOG-2 in transgenic mice led to depressed cardiac function, activation of the fetal gene program, congestive heart failure, and early death. SERCA2 transcript and protein levels were reduced in FOG-2 transgenic hearts, and FOG-2 overexpression impaired T3-mediated SERCA2 expression in cultured cardiomyocytes. FOG-2 physically interacts with thyroid hormone receptor-alpha1 and abrogated even high levels of T3-mediated SERCA2 promoter activity. These results demonstrate that SERCA2 is an important target of FOG-2 and that increased FOG-2 expression may contribute to a decline in cardiac function in end-stage heart failure by impaired T3 signaling.
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PMID:Increased FOG-2 in failing myocardium disrupts thyroid hormone-dependent SERCA2 gene transcription. 1865 59

Serum BNP (brain naturiuretic peptide) and ANP (atrial natriuretic peptide) levels are reportedly elevated in patients with thyrotoxicosis. The increases may not be due to thyrotoxicosis itself but to secondary cardiovascular changes such as chronic heart failure (HF) or atrial fibrillation (AF) which frequently accompany thyrotoxicosis. We measured serum ANP and BNP levels in 130 patients with thyrotoxicosis and correlated them with HF severity and thyroid function. Thirty-seven normal subjects served as controls. Serum BNP levels in thyrotoxic patients were significantly higher than those in control subjects and significantly correlated with serum free T4, free T3 and ANP levels. In untreated Graves' disease serum BNP level was significantly elevated in patients with HF or AF. Multiple regression analysis revealed that HF, free T4, female gender and AF are independent contributing factors to the elevated BNP level, and that these four factors contributed about 40%. On the other hand, HF and AF were contributing variables for ANP level but the overall contribution of these factors was only 10%. After normalization of thyroid function, serum BNP levels were normalized in 70.5% of Graves' patients. BNP level in euthyroid state was dependent on the presence of HF and the BNP value before therapy, but not on thyroid hormone levels or AF. These data suggest that the cardiovascular condition is the major factor responsible for the elevated serum BNP and ANP levels in thyrotoxic patients, while thyrotoxicosis itself is an independent but minor contributing factor. Thus, the determination of serum BNP levels in thyrotoxic patients is useful for monitoring cardiovascular conditions of HF.
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PMID:Serum concentrations of BNP and ANP in patients with thyrotoxicosis. 1882 6

MicroRNAs act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Because individual microRNAs often regulate the expression of multiple target genes with related functions, modulating the expression of a single microRNA can, in principle, influence an entire gene network and thereby modify complex disease phenotypes. Recent studies have identified signature expression patterns of microRNAs associated with pathological cardiac hypertrophy, heart failure, and myocardial infarction in humans and mouse models of heart disease. Gain- and loss-of-function studies in mice have revealed profound and unexpected functions for these microRNAs in numerous facets of cardiac biology, including the control of myocyte growth, contractility, fibrosis, and angiogenesis, providing glimpses of new regulatory mechanisms and potential therapeutic targets for heart disease. Especially intriguing is the discovery of a network of muscle-specific microRNAs embedded within myosin heavy chain genes, which control myosin expression and the response of the heart to stress and thyroid hormone signaling. Disease-inducing cardiac microRNAs can be persistently silenced in vivo through systemic delivery of antimiRs, allowing for the direct therapeutic modulation of disease mechanisms. Here, we summarize current knowledge of the roles of miRNAs in heart disease and consider the advantages and potential challenges of microRNA-based approaches compared to conventional drug-based therapies.
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PMID:Toward microRNA-based therapeutics for heart disease: the sense in antisense. 1894 30


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