**4. Pathogenesis**

#### **4.1 Cardiac effects, molecular and cellular mechanisms**

Cellular and molecular mechanisms by which thyroid exerts its action on almost every cell and organ in the body have been well studied [12]. Thyroid gland

#### *Graves' Disease and Cardiac Complications DOI: http://dx.doi.org/10.5772/intechopen.97128*

maintains T4 and T3 excretion according to TSH levels. The thyroid gland primarily secretes T4 (≈85%), which is converted to T3 by 5′-monodeiodination in the liver, kidney, and skeletal muscle. The heart function is mainly based on T3, because of the absence of myocyte intracellular deiodinase activity and T3 migrates into the myocyte instead T4 [13]. Then, the activity of T3 is administered after binding to thyroid hormone nuclear receptors (THRs). Then, these receptor proteins binds to thyroid hormone response elements (TREs) in the promoter regions of positively regulated genes thus regulates the transcription [12, 14]. T3 acts on THRs in the nucleus, and creating dimers of 9-cis-retinoic acid receptor (RXR) [15]: the formed complexes recognize some specific DNA consensus sequences, TREs, located in the enhanced region of the genes to initiate the transcription [16]. Although, TRs considered as a steroid hormone receptors, unlikely, bind to TREs regardless of whether ligand is present or not. TRs connect to TREs with 1 of 3 isoforms of retinoid X receptor (RXRα, RXRβ, or RXRˠ) as homodimers or heterodimers [17]. While bound to T3, TRs induce transcription, and in the absence of T3 they repress transcription. Thyroid hormone upregulates α, but downregulates β-chain in myocytes [18]. Negatively regulated cardiac genes such as β-myosin heavy chain and phospholamban are induced in the absence of T3 and repressed in the presence of T3 [19, 20].

Thyroid hormone has a direct impact on cardiac activity through myocytes by achieving structural and regulatory gene expressions. The 2 isoforms of a contractile protein pertain to thick filament of cardiac myocyte is codified by myosin heavy chain gene.

The sarcoplasmic reticulum Ca2+-ATPase and its inhibitor, phospholamban, regulate intracellular calcium cycling. Together they are largely responsible for enhanced contractile function and diastolic relaxation in the heart [21]. T3 levels are also intimately associated with the β –adrenergic receptors and sodium potassium ATPase.

Thyroid hormone cause extranuclear genome-free effects on both the cardiac myocyte and systemic vasculature. These effects of T3 can occur rapidly and do not involve

TRE-mediated transcriptional events [22]. These T3-mediated effects include changes in various membrane ion channels for sodium, potassium, and calcium, effects on actin polymerization, adenine nucleotide translocator-1 in the mitochondrial membrane, and a variety of intracellular signaling pathways in the heart and vascular smooth muscle cells (VSM)**A27**. The collaboration of the both genomic and nongenomic features of the T3 activity regulate the cardiovascular system.

Thyroid hormone express its activity in myocytes via various TREs, such as alpha myosin heavy chain fusion (MHC-α), sarcoplasmic reticulum calciumactivated ATPase (SERCA): which maintains calcium uptake during diastole, by calcium activated ATPase and phospholamban -the inhibitory cofactor- [23, 24] the cellular membrane Na-K pump (Na-K ATPase), β1 adrenergic receptor, cardiac troponin I, and atrial natriuretic peptide (ANP), and some genes are also suppressed, such as β-myosin heavy chain fusion (MHC-β), adenylyl cyclase (IV and V) and the Na-Ca antiporter [25–27]. The final effect of thyroid hormones in animal studies-and also similar effects have also been observed in preliminary human studies-is increased rate of V1 isoform of MHC (MHCα/α) synthesis that is characteristically faster in myocardial fiber shortening [28–30]. Thyroid hormones enhance myocardial relaxation by upregulating expression of SERCA, and downregulating expression of phospholamban. Cytoplasmic calcium concentration substantially decrease at the end of the diastole. This cause a higher magnitude of systolic transient of calcium; therefore heightens capacity for actin-myosin subunits activation. As a supportive evidence, a phospholamban deficient mice demonstrated no tachycardia in response to thyroid hormone treatment [31] on the

plasma membranes, T3 has extragenic actions on various ion channels such as Na/K ATPase, Na/Ca++ exchanger, and voltage gated K channels (Kv 1.5, Kv 4.2, Kv 4.3) affecting cardiovascular hemodynamics [32].

For instance, Na channel activation period augments in myocardium; this cause prolonged intracellular Na uptake and increased secondary Na-Ca antiporter functions. Thus underlying mechanism under the inotropic effect may be comparatively revealed [33]. T3 effects on L-type calcium channels directly by abbreviating the action potential period [34, 35]. The augmentation of β-adrenergic receptors the may be the main reason for the intense inotropic response to the thyroid hormones [36]. Although, G protein and β-receptors increased; circulating cathecolamine measurements remained similar [37]. The sensitivity of the cardiovascular system to adrenergic stimulation is not changed by thyroid hormones. The changes in the heart rate result from both an increase in sympathetic tone and decrease in parasympathetic tone [38, 39]. Rapid response for the Cardiac and vascular structures of the thyroid hormone response was not sufficiently clarified by genomic effects [40–42].

Hyperthyroidism elicits rapid hemodynamic response as well as non-genomic changes in plasma membranes. Authors, indicate that thyroid hormone stimulates acute phosphorylation of phospholamban. This pathway may be slightly responsible the collaboration between thyroid hormone and the adrenergic effects on the heart [43].

The use of β-adrenergic receptor antagonists in hyperthyroidism reduced heart rate, but systolic or diastolic contractile performance remained similar, supporting the direct cardiac muscle effect of thyroid hormone [44]. Meanwhile, thyroid hormone impacted on the sinoatrial node and caused oxidative stress in experimental studies. The heart rate is parallel to the sinoatrial activity, lower threshold for atrial activity, and shortened atrial repolarization [45]. Hemodynamic changes such as volume preload increase following the renin-angiotensin system activation or augmented contractility due to improved metabolic demand or the reduction in the direct effect of the thyroid hormone on heart muscle, decreased systemic vascular resistance caused by triiodothyronine-induced peripheral vasodilatation, lead to a dramatic impairment in cardiac output [7, 46, 47].

Preload is increased in a state of hyperthyroidism, and the reduced peripheral vascular resistance and elevated heart rate lead to increased cardiac output. The reduction in systemic vascular resistance lead to impaired renal perfusion pressure thus activates renin-angiotensin-aldosterone system (RAAS), hence sodium reabsorption and blood volume increase. In turn, this leads to increased preload, decreased afterload, and **ultimately** a significant increase in stroke volume [48]. Furthermore, it is suggested that T3 enhances renin substrate synthesis in liver and stimulates the cardiac expression of renin mRNA, leading to elevated cardiac renin levels and angiotensin II independent from the circulating renin and angiotensin. The expression of angiotensin II receptors in the myocardium increases in the hyperthyroid state [49]. These hemodynamic responses trigger atrial stretch trigger and stimulate atrial natriuretic peptide (ANP) secretion, resulting in more vasodilation. Such changes figure out a critical role of the myocardial RAAS in thyroxine-induced cardiac hypertrophy as well as potential therapeutic implications of agents that block this system.

Adrenomedullin, a polypeptide of 52 amino acids, is a potent vasodilator and thyroid gland is responsible for regulation transcription of adrenomedullin. Serum levels therefore proportionally increase in thyrotoxicosis [50]. Interestingly, however, Diekman and colleagues demonstrated that although systemic vascular resistance (SVR) is decreased and adrenomedullin is increased in thyrotoxicosis, restoration of euthyroidism normalized SVR but was not correlated with plasma adrenomedullin levels [51]. In the present study, only T3 was an independent determinant of SVR.
