Hypothyroid Heart Research Articles

Thyroid-stimulating hormone regulates cardiac function through modulating HCN2 via targeting microRNA-1a.

Previous studies have found microRNA-1 (miR-1) and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) may be involved in the pathogenesis of thyroid hormone (TH) induced cardiac hypertrophy. However, little is known about the role of miR-1 and HCN2 in thyroid stimulation hormone (TSH)-induced cardiac dysfunction. In order to investigate the molecular mechanisms of TSH induced cardiac dysfunction and the role of miR-1/HCN2 in that process, we evaluated the expression of miR-1a/HCN2 in the ventricular myocardium of hypothyroid mice and in TSH-stimulated H9c2 cardiomyocytes. Our data revealed that hypothyroidism mice had smaller hearts, ventricular muscle atrophy, and cardiac contractile dysfunction compared with euthyroid controls. The upregulation of miR-1a and downregulation of HCN2 were found in ventricular myocardium of hypothyroid mice and TSH-stimulated H9c2 cardiomyocytes, indicating that miR-1a and HCN2 may be involved in TSH-induced cardiac dysfunction. We also found that the regulation of miR-1a and HCN2 expression and HCN2 channel activity by TSH requires TSHR, while the regulation of HCN2 expression and HCN2 channel function by TSH requires miR-1a. Thus, our data revealed the potential mechanism of TSH-induced cardiac dysfunction and might shed new light on the pathological role of miR-1a/HCN2 in hypothyroid heart disease.

Особливості ремоделювання міокарда лівого шлуночка при гіпотиреозі й ішемічній хворобі серця на тлі хронічного системного запалення

Актуальність. Дисфункція щитоподібної залози у сучасній медичній науці розглядається як один із факторів ризику серцево-судинних захворювань, на жаль, непередбачливо недооцінюваний. Вiдомо, що навіть незначнi порушення тиреоїдної функцiї можуть супроводжуватися зростанням кардiометаболiчного ризику. Гіпотиреоз вже на ранній (субклінічній) стадії серйозно впливає на формування і розвиток серцево-судинних захворювань. Результати масштабних досліджень демонструють, що субклінічний гіпотиреоз асоціюється з підвищенням ризику розвитку ішемічної хвороби серця (ІХС), інфаркту міокарда і смертності від серцево-судинних захворювань. Мета дослідження — вивчення структурно-функціонального стану міокарда лівого шлуночка при гіпотиреозі та ішемічній хворобі серця на тлі хронічного системного запалення. Матеріали та методи. Проаналізовано 140 історій хвороб та обстежено 55 хворих на гіпотиреоз, ІХС та за умов поєднаної патології. Пацієнти були розподілені на 3 групи: І група — хворі на гіпотиреоз — 81, ІІ група — хворі на ІХС — 67, ІІІ група — хворі на гіпотиреоз в поєднанні з ІХС — 67. Групу контролю становили 20 осіб віком від 20 до 25 років. Результати. Виявлено, що гіпертрофія міокарда розвивається у всіх групах хворих, зниження функції щитоподібної залози характеризується ремоделюванням міокарда лівого шлуночка з розвитком ексцентричної гіпертрофії, з прогресуванням систолічної дисфункції серця в умовах коморбідності. Виявлений прямий кореляційний зв’язок зниження фракції викиду з підвищенням рівня IЛ-8. Висновки. Активація хронічного системного запалення більш виражена в умовах коморбідності з негативним прогностичним впливом на стан серцево-судинної системи. Зниження функції щитоподібної залози призводить до розвитку гіпертрофії міокарда лівого шлуночка з подальшою зміною геометрії серця в бік розвитку ексцентричного ремоделювання. Гіпотиреоз характеризується порушенням центральної гемодинаміки, прояви систолічної дисфункції серця наростають за умов поєднання тиреоїдної патології та ІХС. Активація хронічного системного запалення більш виражена в умовах коморбідності з негативним прогностичним впливом на стан серцево-судинної системи.

Sex impacts cardiac function and the proteome response to thyroid hormone in aged mice

BackgroundSex and age have substantial influence on thyroid function. Sex influences the risk and clinical expression of thyroid disorders (TDs), with age a proposed trigger for the development of TDs. Cardiac function is affected by thyroid hormone levels with gender differences. Accordingly, we investigated the proteomic changes involved in sex based cardiac responses to thyroid dysfunction in elderly mice.MethodsAged (18–20 months) male and female C57BL/6 mice were fed diets to create euthyroid, hypothyroid, or hyperthyroid states. Serial echocardiographs were performed to assess heart function. Proteomic changes in cardiac protein profiles were assessed by 2-D DIGE and LC-MS/MS, and a subset confirmed by immunoblotting.ResultsSerial echocardiographs showed ventricular function remained unchanged regardless of treatment. Heart rate and size increased (hyperthyroid) or decreased (hypothyroid) independent of sex. Pairwise comparison between the six groups identified 55 proteins (≥ 1.5-fold difference and p < 0.1). Compared to same-sex controls 26/55 protein changes were in the female hypothyroid heart, whereas 15/55 protein changes were identified in the male hypothyroid, and male and female hyperthyroid heart. The proteins mapped to oxidative phosphorylation, tissue remodeling and inflammatory response pathways.ConclusionWe identified both predicted and novel proteins with gender specific differential expression in response to thyroid hormone status, providing a catalogue of proteins associated with thyroid dysfunction. Pursuit of these proteins and their involvement in cardiac function will expand our understanding of mechanisms involved in sex-based cardiac response to thyroid dysfunction.

Abstract 15486: Subclinical Hypothyroidism and Left Heart Strain in the General Population

Background: Although subclinical hypothyroidism (SCH) is a common clinical entity and carries independent risk for incident heart failure (HF), its possible association with subclinical cardiac dysfunction has not been extensively evaluated. Left ventricular global longitudinal strain (LVGLS) and left atrial (LA) phasic strain can unmask subclinical left heart dysfunction and are excellent predictors for HF. This study aimed to investigate the association between the presence of SCH and subclinical left heart dysfunction in a sample of the general population without overt cardiac disease. Methods: We examined 1,078 participants who underwent extensive cardiovascular health check-up including laboratory tests and 2-dimensional speckle-tracking echocardiography to assess LVGLS and LA reservoir, conduit and pump strain. SCH was defined as an elevated serum thyroid stimulating hormone level with normal concentration of free thyroxine. Results: Mean age was 62±12 years, and 56% were men. Seventy-eight (7.2%) participants exhibited SCH. Individuals with SCH had significantly reduced LA reservoir and conduit strain (both p&lt;0.05) compared with those with euthyroidism, whereas there was no significant difference in LV ejection fraction, LA volume index, LVGLS and LA pump strain between the 2 groups. In multivariable analyses, the presence of SCH was significantly associated with impaired LA reservoir strain, independent of age, traditional cardiovascular risk factors and pertinent laboratory and echocardiographic parameters including LVGLS. Conclusions: In an unselected community-based cohort, individuals with SCH had significantly impaired LA function. This association may be involved in the higher incidence of HF in subjects with SCH.

What lies beneath: hypothyroid heart and valvular disease.

What lies beneath: hypothyroid heart and valvular disease.

Cardiac ischemia/reperfusion injury is inversely affected by thyroid hormones excess or deficiency in male Wistar rats.

AimThyroid dysfunctions can increase the risk of myocardial ischemia and infarction. However, the repercussions on cardiac ischemia/reperfusion (IR) injury remain unclear so far. We report here the effects of hypothyroidism and thyrotoxicosis in the susceptibility to IR injury in isolated rat hearts compared to euthyroid condition and the potential role of antioxidant enzymes.MethodsHypothyroidism and thyrotoxicosis were induced by administration of methimazole (MMZ, 300 mg/L) and thyroxine (T4, 12 mg/L), respectively in drinking water for 35 days. Isolated hearts were submitted to IR and evaluated for mechanical dysfunctions and infarct size. Superoxide dismutase types 1 and 2 (SOD1 and SOD2), glutathione peroxidase types 1 and 3 (GPX 1 and GPX3) and catalase mRNA levels were assessed by quantitative RT-PCR to investigate the potential role of antioxidant enzymes.ResultsThyrotoxicosis elicited cardiac hypertrophy and increased baseline mechanical performance, including increased left ventricle (LV) systolic pressure, LV developed pressure and derivatives of pressure (dP/dt), whereas in hypothyroid hearts exhibited decreased dP/dt. Post-ischemic recovery of LV end-diastolic pressure (LVEDP), LVDP and dP/dt was impaired in thyrotoxic rat hearts, whereas hypothyroid hearts exhibited improved LVEDP and decreased infarct size. Catalase expression was decreased by thyrotoxicosis.ConclusionThyrotoxicosis was correlated, at least in part, to cardiac remodeling and increased susceptibility to IR injury possibly due to down-regulation of antioxidant enzymes, whereas hypothyroid hearts were less vulnerable to IR injury.

COMPLEX DISORDERS OF HEART RHYTHM AND CONDUCTIVITY IN A PATIENT WITH HYPOTHYROIDISM (CLINICAL OBSERVATION)

The article describes a clinical case of the occurrence of complex disorders of the heart rhythm and conductivity in a patient of 45 years with decompensated hypothyroidism. The literature data on specific cardiomyopathy appearing in patients with hypothyroidism (“hypothyroid heart”), metabolic, hemodynamic changes against the background of hypothyroidism and possible violations of heart rhythm and conductivity are given. In the described clinical case the patient’s medical history is given, who has been observed in an endocrinologist for hypothyroidism for the last 3 years. 6 months before this hospitalization patient stopped taking levothyroxine on her own initiative. She noticed deterioration in the last 3 months: the clinic of hypothyroidism appeared and began to grow, a frequent extrasystole appeared. At an objective survey — a symptomatology of the expressed hypothyroidism. A comprehensive examination of the patient was performed, which revealed atrioventricular blockade of the 1st degree, frequent ventricular extrasystole, prolongation of the QT interval on the ECG, late ventricular potentials against the background of low concentrations of sodium and potassium in the blood. During the first 24 hours of hospitalization, there was a clinical death. A clear positive dynamics was traced against the background of therapy aimed at the correction of electrolyte disorders, as well as hormone replacement therapy with levothyroxine.

Perinatal hypothyroidism modulates antioxidant defence status in the developing rat liver and heart.

In the present study, we investigated oxidative stress parameters and antioxidant defence status in perinatal hypothyroid rat liver and heart. We found that the proteincarbonyl content did not differ significantly between the three groups both in the pup liver and in the heart. The OH˙ level was significantly decreased in the hypothyroid heart but not in the liver compared with controls. A slight but not significant decrease in SOD activity was observed in both perinatal hypothyroid liver and heart. A significantly increased activity of CAT was observed in the liver but not in the heart of hypothyroid pups. The GPx activity was considerably increased compared with controls in the perinatal hypothyroid heart and was unaltered in the liver of hypothyroid pups. We also found that vitamin E levels in the liver decreased significantly in hypothyroidism and were unaltered in the heart of perinatal hypothyroid rats. The GSH content was elevated significantly in both hypothyroid liver and heart. The total antioxidant capacity was higher in the liver of the hypothyroid group but not in the hypothyroid heart. Thyroxine replacement could not repair the above changes to normal. In conclusion, perinatal hypothyroidism modulates the oxidative stress status of the perinatal liver and heart.

Thyroid stimulating hormone directly modulates cardiac electrical activity

BackgroundThe electrocardiogram of hypothyroid patients shows a series of abnormalities of cardiac repolarization due to a reduction of some repolarizing K+ currents and an increase of the L-type calcium current. Experimental and clinical works call into question the unique role of T3 and T4 in these mechanisms and correlate increased serum TSH levels with the repolarization abnormalities in patients with both subclinical and overt hypothyroidism. In this context, the aim of the present study was to investigate the direct effects of TSH upon cardiac electrical properties. MethodsThe action potential recording and the ion channel subunits mRNA expression were obtained from left ventricle of adult rats. Additionally, the repolarizing K+ currents and the L-type Ca2+ current (ICa-L) were recorded in isolated rat adult ventricular myocytes by the patch-clamp technique. Results24h exposure to TSH lengthened the action potential and slightly depolarized the resting membrane potential. TSH- receptor activation causes a reduction of the amplitude of Ito and IK1 currents caused by a reduction in channels expression. However, TSH had no effect on ICa-L, IK or IKur. ConclusionThese results support the idea that some of the electrical disturbances seen in hypothyroid hearts, such as the Ito and IK1 current reduction, could be caused not by low T3 but by the elevation of circulating TSH.

Protective Effects of the Somatostatin Analogue (Octeriotide) Versus Ischemic Preconditioning on Cardiac Dysfunction Induced by Ischemia Reperfusion Injury in Hypothyroid Rats

Background The phenomenon of ischemic preconditioning (IPC) would protect the heart from hazards of ischemia reperfusion (IR) injury. However, IPC may lose its cardioprotective effect in the diseased states such as hypothyroidism. Octeriotide (OCT) mimics IPC in cardioprotection in normal hearts but no evidenced information in hypothyroid hearts. Hence, the present study investigated the responses of isolated hearts to IR injury after exposure to OCT in hypothyroidism induced by i.p. injection of 6-propyl 2-thouracil using a Langendorff preparation. Methods: Wister male rats were divided into four groups; Group I, normal rats, Isolated hearts were subjected to 20 min of stabilization, 20 min of zero-flow global ischemia and 45 min of reperfusion. Group II, hypothyroid group subjected to the same protocol of IR. Group III, hypothyroid rats subjected to a PC protocol (3 cycles of ischemia for 5 min and reperfusion for 5 min) prior to global ischemia. Group IV, hypothyroid rats were supplemented with OCT, 35 µg/kg S.C. in the living animal, 20 minutes before sacrifice, followed by in_vitro study of cardiac responses to IR. All rats were subjected to measurement of ABP, ECG recording, blood levels of T3, T4 and TSH, plasma total cholesterol, HDL, In_vitro study of isolated hearts to record the intrinsic activity of the heart under baseline condition, responses of the heart to IR.The levels of lactic dehydrogenase (LDH), TNFα in the coronary efflux were measured. Cardiac tissues are then stored at -80C and used for later determination of cardiac weights and cardiac tissue MDA. Results: OCT improved the post-ischemic recovery of cardiac function as evidenced by the improved isometric force developed tension (PT), PT/LV, systolic time (TPT) as well as ½ relaxation time and reduced the extent of injury, as indicated by the low LDH levels in Group IV compared to NORM hearts, which could be ascribed partly to the reducing effect of OCT on oxidative and inflammatory responses to IR as determined by the lowered MDA and TNFα consequently. On the other hand, hearts of Group II and Group III, showed significant improvement of post-ischemic recovery of cardiac inotropic parameters and LDH compared to NORM group, nevertheless, these parameters remained insignificant between both groups, suggesting that IPC didn't confer additional protection to hypothyroidism against IR injury. Conclusion Hypothyroid hearts are tolerant to IR injury. OCT administration to hypothyroid rats made their hearts more tolerant which is, partly, due to the reduced oxidative and inflammatory stresses. On the other hand, IPC failed to confer added protection in the hypothyroid hearts.

Thyroid hormone induces sprouting angiogenesis in adult heart of hypothyroid mice through the PDGF-Akt pathway.

Study of physiological angiogenesis and associated signalling mechanisms in adult heart has been limited by the lack of a robust animal model. We investigated thyroid hormone-induced sprouting angiogenesis and the underlying mechanism. Hypothyroidism was induced in C57BL/6J mice by feeding with propylthiouracil (PTU). One year of PTU treatment induced heart failure. Both 12 weeks- (young) and 1 year-PTU (middle age) treatment caused a remarkable capillary rarefaction observed in capillary density. Three-day Triiodothyronine (T3) treatment significantly induced cardiac capillary growth in hypothyroid mice. In cultured left ventricle (LV) tissues from PTU-treated mice, T3 also induced robust sprouting angiogenesis where pericyte-wrapped endothelial cells formed tubes. The in vitro T3 angiogenic response was similar in mice pre-treated with PTU for periods ranging from 1.5 to 12 months. Besides bFGF and VEGF164, PDGF-BB was the most robust angiogenic growth factor, which stimulated notable sprouting angiogenesis in cultured hypothyroid LV tissues with increasing potency, but had little effect on tissues from euthyroid mice. T3 treatment significantly increased PDGF receptor beta (PDGFR-β) protein levels in hypothyroid heart. PDGFR inhibitors blocked the action of T3 both on sprouting angiogenesis in cultured LV tissue and on capillary growth in vivo. In addition, activation of Akt signalling mediated in T3-induced angiogenesis was blocked by PDGFR inhibitor and neutralizing antibody. Our results suggest that hypothyroidism leads to cardiac microvascular impairment and rarefaction with increased sensitivity to angiogenic growth factors. T3-induced cardiac sprouting angiogenesis in adult hypothyroid mice was associated with PDGF-BB, PDGFR-β and downstream activation of Akt.

A case of hepatotoxicity by Pelargonium sidoides

Background Pelargonium sidoides (PS) is an African herbaceous, perennial plant in the geranium family. The root is the medically part used for respiratory problems [1]. The reported pharmacological activities include moderate direct antibacterial and antiviral potencies and immunomodulatory properties. An alcohol extract of PS has become popular in Germany as a treatment for different respiratory problems, including acute bronchitis, the common cold, sinusitis, pharyngitis and tonsillitis. The chemical composition of the Pelargonium sidoides consists mainly of sesquiterpenes, the most abundant, coumarin and high quantity of tannins. Case Presentation In March 2011, a 46 year-old male patient was admitted to Emergency Department (ED) of Prato for severe asthenia associated to a wide complex tachycardia sensitive to intravenous amiodarone. The patient suffered from epilepsy, oligophrenia, hypothyroidism, hypertension and congenital heart disease. He had been on well tolerated therapy with furosemide, acetylsalicylic acid, phenobarbital sodium, carbamazepine, olanzapine, valproate sodium, lansoprazole, allopurinol, canrenone, for ten years. On admission, vital signs were normal except for heart rate (108 beats per minute) and pulse oximetry (oxygen saturation level of 91%). The blood tests, performed about 15 days before, showed normal values (especially ALT, AST and bilirubin were in normal range). Just before hospital admission, the patient was treated with a remedy for a common cold: PS 30 drops three times a day, stopped after six days. In ED the routine blood tests showed increased liver enzymes: ALT: 2385 IU I-1 (normal range: 1-45) and AST: 4072 IU I-1 (normal range: 1-36). After three days, blood tests showed a decrease of ALT: 1813 IU I-1 and AST: 1251 IU I-1 and INR (International Normalized Ratio): 1.89. The patient died the 4th day, probably due to acute liver failure and respiratory distress related to the above comorbidities. The PS causality assessment was defined as 'possible' according to Naranjo algorithm. Discussion Adverse drug reactions (ADRs) related to PS are quite rare in the published clinical trials and generally, they are of mild severity and comparable to placebo. The most frequent ADRs reported, due to PS, were gastrointestinal disorders, nervous system, ear and labyrinth disorders. It is known that high concentrations of coumarins and tannins can cause liver toxicity. Recently, 15 cases of suspected hepatotoxicity induced by PS has been published, but they were evaluated as 'doubtful' by the authors [2]. It is important to remember that concomitant diseases and drug interactions may have contributed to the above adverse event. Our case underlines the importance of further studies to establish the real association between PS and liver damage.

Altered in vivo left ventricular torsion and principal strains in hypothyroid rats

The twisting and untwisting motions of the left ventricle (LV) lead to efficient ejection of blood during systole and filling of the ventricle during diastole. Global LV mechanical performance is dependent on the contractile properties of cardiac myocytes; however, it is not known how changes in contractile protein expression affect the pattern and timing of LV rotation. At the myofilament level, contractile performance is largely dependent on the isoforms of myosin heavy chain (MHC) that are expressed. Therefore, in this study, we used MRI to examine the in vivo mechanical consequences of altered MHC isoform expression by comparing the contractile properties of hypothyroid rats, which expressed only the slow β-MHC isoform, and euthyroid rats, which predominantly expressed the fast α-MHC isoform. Unloaded shortening velocity (V(o)) and apparent rate constants of force development (k(tr)) were measured in the skinned ventricular myocardium isolated from euthyroid and hypothyroid hearts. Increased expression of β-MHC reduced LV torsion and fiber strain and delayed the development of peak torsion and strain during systole. Depressed in vivo mechanical performance in hypothyroid rats was related to slowed cross-bridge performance, as indicated by significantly slower V(o) and k(tr), compared with euthyroid rats. Dobutamine infusion in hypothyroid hearts produced smaller increases in torsion and strain and aberrant transmural torsion patterns, suggesting that the myocardial response to β-adrenergic stress is compromised. Thus, increased expression of β-MHC alters the pattern and decreases the magnitude of LV rotation, contributing to reduced mechanical performance during systole, especially in conditions of increased workload.

Thyroid Replacement Therapy and Heart Failure

Heart failure (HF) is a major public health and economic problem in Western countries and is one of the most common causes of hospitalization and death. Coronary artery disease is the underlying cause in more than two thirds of chronic HF patients. By 2020, the World Health Organization projects that ischemic heart disease alone will be the most important global cause of morbidity and mortality. The estimated increases in HF-related morbidity and mortality suggest that our understanding of the pathophysiological mechanisms of this syndrome is inadequate. Interest in the role of thyroid hormones (THs) in HF has increased in recent years. The driving considerations can be summarized as follows: (1) the known effects of THs on contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis that TH signaling is critical in preserving cardiac structure and performance under normal conditions and after cardiac injury; and (3) evidence that mildly altered TH function is strongly associated with a worsening prognosis in cardiac patients in general and in HF patients in particular. Diastolic function and systolic function are clearly influenced by THs.1 Ventricular contractile function is also influenced by changes in hemodynamic conditions secondary to TH effects on peripheral vascular tone.1 TH homeostasis preserves positive ventricular-arterial coupling, leading to a favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4 (thyroxine).3–6 This review highlights a growing body of evidence from animal studies and small-scale clinical trials suggesting that low cellular thyroid activity at the cardiac tissue level may adversely affect HF …

Thyroid Hormone-Induced Cardiac Mechano Growth Factor Expression Depends on Beating Activity

The mechano growth factor (MGF), a splice variant of the IGF-I gene, was first discovered in mechanically overloaded skeletal muscle and was shown to play an important role in proliferation of muscle stem cells. Since then, the presence and effects of MGF have been demonstrated in other tissues. MGF has been shown to act neuroprotectively during brain ischemia, and pretreatment with MGF before myocardial infarction improves cardiac function. Because MGF plays a permissive role in exercise-induced skeletal muscle hypertrophy, we hypothesize that MGF is commonly involved in cardiac hypertrophy. To investigate the regulation of MGF expression in heart, mice were treated with thyroid hormone (T(3)) for 12 d to induce physiological cardiac hypertrophy. MGF mRNA expression was specifically increased in midregions of the septum and left ventricular wall. Interestingly, MGF expression strongly correlated with the increased or decreased beating frequency of hyperthyroid and hypothyroid hearts. To further investigate the mechanically dependent induction of MGF, neonatal rat cardiomyocytes were isolated and exposed to T(3). Upon T(3) treatment, cardiomyocytes increased both contractile activity measured as beats per minute and MGF as well as IGF-IEa mRNA expression. Importantly, when cardiomyocytes were contractile arrested by KCl, simultaneous exposure to T(3) prevented the up-regulation of MGF, whereas IGF-IEa was still induced. These studies demonstrated that MGF but not IGF-IEa expression is dependent on beating activity. These findings suggest that MGF is specifically stimulated by mechanical loading of the heart to mediate the hypertrophic response to thyroid hormone.

Increased resistance to hydrogen peroxide‐induced cardiac contracture is associated with decreased myocardial oxidative stress in hypothyroid rats

The purpose of this study was to determine whether decreased oxidative stress would increase the resistance to cardiac contracture induced by H(2)O(2) in hypothyroid rats. Male Wistar rats were divided into two groups: control and hypothyroid. Hypothyroidism was induced via thyroidectomy. Four weeks post surgery, blood samples were collected to perform thyroid hormone assessments, and excised hearts were perfused at a constant flow with or without H(2)O(2) (1 mmol/L), being divided into two sub-groups: control, hypothyroid, control + H(2)O(2), hypothyroid + H(2)O(2). Lipid peroxidation (LPO) was evaluated by chemiluminescence (CL) and thiobarbituric acid reactive substances (TBARS) methods, and protein oxidation by carbonyls assay in heart homogenates. Cardiac tissue was also screened for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and for total radical-trapping antioxidant potential (TRAP). Analyses of SOD and glutathione-S-transferase (GST) protein expression were also performed in heart homogenates. Hypothyroid hearts were found to be more resistant to H(2)O(2)-induced contracture (60% elevation in LVEDP) as compared to control. CL, TBARS, carbonyl, as well as SOD, CAT, GPx activities and TRAP levels were reduced (35, 30, 40, 30, 16, 25, and 33%, respectively) in the cardiac homogenates of the hypothyroid group as compared to controls. A decrease in SOD and GST protein levels by 20 and 16%, respectively, was also observed in the hypothyroid group. These results suggest that a hypometabolic state caused by thyroid hormone deficiency can lead to an improved response to H(2)O(2) challenge and is associated with decreased oxidative myocardial damage.

The changes in β-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac β3-adrenoceptors

Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidism was induced in rats by 3-week administration of 6n-propyl-2-thiouracil in water (0.05 %). Normal and hypothyroid hearts (HYPO) were perfused in Langendorff mode and subjected to 20 min of zero-flow global ischemia and 45 min of reperfusion. A preconditioning protocol (PC) was also applied prior to ischemia. HYPO hearts had significantly improved post-ischemic recovery of left ventricular developed pressure, end-diastolic pressure and reduced lactate dehydrogenase release. Furthermore, phospho-JNK and p38 MAPK levels after ischemia and reperfusion were 4.0 and 3.0 fold lower in HYPO as compared to normal hearts (P<0.05). A different response to PC was observed in normal than in HYPO hearts. PC improved the post-ischemic recovery of function and reduced the extent of injury in normal hearts but had no additional effect on the hypothyroid hearts. This response, in the preconditioned normal hearts, resulted in 2.5 and 1.8 fold smaller expression of the phospho-JNK and phospho-p38 MAPK levels at the end of reperfusion, as compared to non-PC hearts (P<0.05), while in HYPO hearts, no additional reduction in the phosphorylation of these kinases was observed after PC. Hypothyroid hearts appear to be tolerant to ischemia-reperfusion injury. This response may be, at least in part, due to the down-regulation of ischemia-reperfusion induced activation of JNKs and p38 MAPK kinases. PC is not associated with further reduction in the activation of these kinases in the hypothyroid hearts and fails to confer added protection in those hearts.

Upregulation of the α1-adrenoceptor-induced phosphoinositide and inotropic response in hypothyroid rat heart

In this study, we examined changes in the biochemical and inotropic events of the alpha(1)-adrenoceptor signaling pathway in hypothyroid rat hearts. Hypothyroidism was induced by treating experimental animals with 0.05% 6-n-propyl-2-thiouracil (PTU) in drinking water for 7 weeks. A significant decrease of beta- and an increase in alpha(1)-adrenoceptor density as well as an increase in the basal activity of the phosphoinositide (4,5) bisphosphate hydrolyzing phospholipase C was observed in sarcolemmal membranes purified from hypothyroid hearts as compared to age-matched euthyroid controls. Following stimulation with 10 microM phenylephrine (in the presence of 10 microM atenolol), the increase of contractile parameters over baseline values was significantly higher in hypo- than euthyroid hearts, while the opposite occurred under beta-stimulation with 0.1 microM isoproterenol. Interestingly, the increase in phenylephrine-mediated positive inotropy was accompanied by a significant increase in the sarcolemmal phospholipase C activity and in the inositol 1,4,5-trisphosphate content in hypothyroid as compared to euthyroid controls. Our results suggest that cardiac alpha(1)-adrenoceptor and its associated phosphoinositide signaling pathway may act as a reserve for catecholamine inotropic response in hypothyroidism, where the beta-adrenoceptors are compromised.

Thyroid hormone controls myocardial substrate metabolism through nuclear receptor-mediated and rapid posttranscriptional mechanisms

Thyroid hormone regulates metabolism through transcriptional and posttranscriptional mechanisms. The integration of these mechanisms in heart is poorly understood. Therefore, we investigated control of substrate flux into the citric acid cycle (CAC) by thyroid hormone using retrogradely perfused isolated hearts (n = 20) from control (C) and age-matched thyroidectomized rats (T). We determined substrate flux and fractional contributions (Fc) to the CAC by 13C-NMR spectroscopy and isotopomer analyses in hearts perfused with [1,3-(13)C]acetoacetic acid (0.17 mM), L-[3-(13)C]lactic acid (LAC, 1.2 mM), [U-13C]long-chain mixed free fatty acids (FFA, 0.35 mM), and unlabeled glucose. Some T hearts were supplied triiodothyronine (T3, 10 nM; TT) for 60 min. Prolonged hypothyroid state reduced myocardial oxygen consumption, although T3 produced no significant change. Hypothyroidism reduced overall CAC(flux) but selectively altered only FFA(flux) among the individual substrates, though LAC(flux) trended upward. T3 rapidly decreased lactate Fc and flux. 13C labeling of glutamine through glutamate was increased in T with further enhancement in TT. The glutamate-to-glutamine ratio was significantly lower in T and TT. Immunoblots detected a decrease in hypothyroid hearts for muscle carnitine palmitoyltransferase I (CPT I) and a marked increase in pyruvate dehydrogenase kinase (PDK)-2 with no changes in liver CPT I, PDK-4, or hexokinase 2. TT, but not T, displayed elevated glutamine synthetase (GS) expression. These studies showed that T3 regulates cardiac metabolism through integration of several mechanisms, including changes in oxidative enzyme content and rapid modulation of individual substrates fluxes. T3 also moderates forward glutamine flux, possibly by increasing the overall activity of GS.