Thyroid hormones and the cardiovascular system: Pathophysiology and interventions

Cini, G; Carpi, Angelo; Mechanick, Jeffrey I.; Cini, Lorenzo; Camici, Marcella; Galetta, Fabio; Giardino, Roberto; Russo, Maria Teresa; Iervasi, Giorgio

doi:10.1016/j.biopha.2009.08.003

Cited by 65 publications

(51 citation statements)

References 139 publications

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“…At the onset of these studies, we hypothesized that stimulation of GPBAR1 by compound 12 or 16 in long-term dog studies led to cardiovascular effects via increased expression of type II iodothyronine deiodinase (Bianco and Kim, 2006) that converts T4 to T3 and may lead to cardiovascular sequelae (Fazio et al, 2004;Cini et al, 2009;Danzi and Klein, 2012) similar to that suggested by Futatsugi et al (2012) and Piotrowski et al (2012). Whether long-term administration of GPBAR1 agonists in rats would have led to modulation of the T3/T4 axis, and subsequent cardiovascular responses, remains untested yet is a plausible risk for therapeutics targeted at long-term GPBAR1 stimulation.…”

Section: Direct Vasodilatory Effect Of Gpbar1 Agonists In Dogmentioning

confidence: 99%

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

Fryer

Mazurek

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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Bile acids (BAs) and BA receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), represent novel targets for the treatment of metabolic and inflammatory disorders. However, BAs elicit myriad effects on cardiovascular function, although this has not been specifically ascribed to GPBAR1. This study was designed to test whether stimulation of GPBAR1 elicits effects on cardiovascular function that are mechanism based that can be identified in acute ex vivo and in vivo cardiovascular models, to delineate whether effects were due to pathways known to be modulated by BAs, and to establish whether a therapeutic window between in vivo cardiovascular liabilities and on-target efficacy could be defined. The results demonstrated that the infusion of three structurally diverse and selective GPBAR1 agonists produced marked reductions in vascular tone and blood pressure in dog, but not in rat, as well as reflex tachycardia and a positive inotropic response, effects that manifested in an enhanced cardiac output. Changes in cardiovascular function were unrelated to modulation of the levothyroxine/thyroxine axis and were nitric oxide independent. A direct effect on vascular tone was confirmed in dog isolated vascular rings, whereby concentration-dependent decreases in tension that were tightly correlated with reductions in vascular tone observed in vivo and were blocked by iberiotoxin. Compound concentrations in which cardiovascular effects occurred, both ex vivo and in vivo, could not be separated from those necessary for modulation of GPBAR1-mediated efficacy, resulting in project termination. These results are the first to clearly demonstrate direct and potent peripheral arterial vasodilation due to GPBAR1 stimulation in vivo through activation of large conductance Ca 21 activated potassium channel K Ca 1.1.

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Section: Direct Vasodilatory Effect Of Gpbar1 Agonists In Dogmentioning

confidence: 99%

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

Fryer

Mazurek

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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“…There is a close relationship between thyroid hormones (THs) and the cardiovascular system (1). As the principal bioactive hormone, triiodothyronine (T3) exerts many effects on myocardial contractility, the resistance of arterioles in the peripheral circulation and cardiovascular hemodynamics through the modulation of the transcription of target genes in the cardiovascular system such as myosin heavy chain, phospholamban, sarcoplasmic reticulum Ca 2+ -ATPase, Na + / Ca 2+ exchanger and so on (2).…”

Section: Introductionmentioning

confidence: 99%

A Low fT3 Level as a Prognostic Marker in Patients with Acute Myocardial Infarctions

et al. 2012

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Objective To investigate the association between low free triiodothyronine (fT3) levels and the severity and prognosis of patients with acute myocardial infarction. Methods A total of 501 patients with acute myocardial infarctions were enrolled in our study. The circulating levels of thyroid hormones and clinical parameters were assayed. The patients were categorized into either the low fT3 group or the normal fT3 group according to the fT3 level on admission. All patients underwent a follow-up for 10±2 months for mortality from any cause and the occurrence of any adverse major cardiac events (MACE). Results There were 171 patients in the low fT3 group (fT3<3.5 pmol/L) and 330 patients in the normal fT3 group (! 3.5 pmol/L). During the follow-up period, 33 patients died (6.6%) and the overall survival rates were 86.0% and 97.3% in patients with a low fT3 level and a normal fT3 level, respectively. The rates of MACE were 66.7% and 45.5% in the patients with and those without low fT3 levels, respectively. Using a multivariable Cox proportional hazards model, the fT3 level was found to be the most important predictor of cumulative death and MACE (hazard ratio [HR] for death: 0.142, p<0.001 and HR for major adverse cardiac events: 0.748, p=0.007). A Kaplan-Meier analysis revealed that those patients with low fT3 levels had higher rates of MACE and death. Conclusion A low fT3 level, a common phenomenon in patients with acute myocardial infarctions, is a strong predictor of short-term and long-term poor prognoses in patients with acute myocardial infarctions.

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“…21) But persistently low fT3 represented a maladaptive mechanism in favor of structural and functional cardiac remodeling, which had a key role in the pathogenesis of HF. 22) Secondly, low fT3 was correlated to deteriorative hemodynamic status and had been proved in catheterization-based studies. 18,19) Worse hemodynamic status and low ejection fraction were clearly associated with low fT3 level.…”

Section: Discussionmentioning

confidence: 90%

A Low-Normal Free Triiodothyronine Level Is Associated with Adverse Prognosis in Euthyroid Patients with Heart Failure Receiving Cardiac Resynchronization Therapy

Chen

Shu

et al. 2017

Int. Heart J.

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SummaryThyroid dysfunction is prevalent in patients with heart failure (HF) and hypothyroidism is related to the adverse prognosis of HF subjects receiving cardiac resynchronization therapy (CRT). We aim to investigate whether low-normal free triiodothyronine (fT3) level is related to CRT response and the prognosis of euthyroid patients with HF after CRT implantation.One hundred and thirteen euthyroid patients who received CRT therapy without previous thyroid disease and any treatment affecting thyroid hormones were enrolled. All of patients were evaluated for cardiac function and thyroid hormones (serum levels of fT3, free thyroxine [fT4] and thyroid-stimulating hormone [TSH]). The end points were overall mortality and hospitalization for HF worsening. During a follow-up period of 39 ± 3 weeks, 36 patients (31.9%) died and 45 patients (39.8%) had hospitalization for HF exacerbation. A higher rate of NYHA III/IV class and a lower fT3 level were both observed in death group and HF event group. Multivariate Cox regression analyses disclosed that a lower-normal fT3 level (HR = 0.648, P = 0.009) and CRT response (HR = 0.441, P = 0.001) were both independent predictors of overall mortality. In addition, they were also both related to HF re-hospitalization event (P < 0.01 for both). Patients with fT3 < 3.00 pmol/L had a significantly higher overall mortality than those with fT3 !3.00 pmol/L (P = 0.027). Meanwhile, a higher HF hospitalization event rate was also found in patients with fT3 < 3.00 pmol/L (P < 0.001).A lower-normal fT3 level is correlated with a worse cardiac function an adverse prognosis in euthyroid patients with HF after CRT implantation.(Int Heart J 2017; 58: 908-914) Key words: Thyroid hormones, Cardiac dysfunction, Left ventricular dyssynchrony, CRT response, Mortality, Hospitalization C ardiac resynchronization therapy (CRT) is a considerable treatment for patients with drugrefractory heart failure (HF) and electromechanical dyssynchronoy.1,2) Though CRT improves heart failure symptoms and quality of life, and reduces both HF-related morbidity and mortality, non-response to CRT has been reported in nearly one third of patients.3) The reason of non-response to CRT is complicated and remains a question of different opinions.Thyroid hormones (THs) have cardiac and vascular effects, and they also regulate biochemical reactions in most tissues.4) TH consists of thyroxine (T4) and triiodothyronine (T3), and the cardiac myocyte does not convert T4 to T3. In other word, T3 is the bioactive form of thyroid hormone for cardiomyocytes and plays an important role in cardiovascular regulation. Many studies have confirmed that T3 is a prognostic predictor or risk stratification of HF.5-7) Recently, fT3 level was shown to be associated with cardiac function and heart structure in euthyroid subjects without HF.8) In addition, another research reported hypothyroidism was associated with a worse prognosis after CRT implantation, but it did not supply values for complete thyroid panel (fT3 and fT4). 9) Is the prognos...

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Thyroid hormones and the cardiovascular system: Pathophysiology and interventions

Cited by 65 publications

References 139 publications

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

A Low fT3 Level as a Prognostic Marker in Patients with Acute Myocardial Infarctions

A Low-Normal Free Triiodothyronine Level Is Associated with Adverse Prognosis in Euthyroid Patients with Heart Failure Receiving Cardiac Resynchronization Therapy

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